90 results on '"Ian M. Carroll"'
Search Results
2. The microbiota-gut-brain axis and perceived stress in the perinatal period
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Emily S. Long, Beatriz Penalver Bernabe, Kai Xia, M. Andrea Azcarate-Peril, Ian M. Carroll, Hannah S. Rackers, Karen M. Grewen, Samantha Meltzer-Brody, and Mary C. Kimmel
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Psychiatry and Mental health ,Obstetrics and Gynecology - Abstract
Perinatal perceived stress can contribute to worse health outcomes for the parent–child dyad. Given the emerging relationship between the microbiota-gut-brain axis and stress, this study sought to elucidate connections between bowel symptoms and the gut microbiome in relation to perceived stress at three time points in the perinatal period: two during pregnancy and one postpartum. Ninety-five pregnant individuals participated in a prospective cohort study from April 2017 to November 2019. Researchers assessed Perceived Stress Scale-10 (PSS); bowel symptoms (according to the IBS Questionnaire); psychiatrist assessment of new onset or exacerbated depression and anxiety; and fecal samples analyzed for alpha diversity (measures of gut microbiome diversity utilizing Shannon, Observed OTUs, and Faith’s PD) at each timepoint. Covariates included weeks of gestation and weeks postpartum. PSS scores were divided into “Perceived Self-Efficacy” and “Perceived Helplessness.” Increased gut microbial diversity was associated with decreased bowel symptoms, decreased overall perceived stress, increased ability to cope with adversity, and decreased distress in the postpartum period. This study found a significant association between a less diverse microbial community, lower self-efficacy early in pregnancy, and greater bowel symptoms and perceived helplessness later in the perinatal period, relationships that may ultimately point to novel diagnostic methods and interventions for perceived stress based on the microbiota-gut-brain axis. Graphical Abstract
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- 2023
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3. Associations of disordered eating with the intestinal microbiota and short-chain fatty acids among young adults with type 1 diabetes
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Daria Igudesman, Jamie Crandell, Karen D. Corbin, Dessi P. Zaharieva, Ananta Addala, Joan M. Thomas, Cynthia M. Bulik, Brian W. Pence, Richard E. Pratley, Michael R. Kosorok, David M. Maahs, Ian M. Carroll, and Elizabeth J. Mayer-Davis
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Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Cardiology and Cardiovascular Medicine - Abstract
Disordered eating (DE) in type 1 diabetes (T1D) includes insulin restriction for weight loss with serious complications. Gut microbiota-derived short chain fatty acids (SCFA) may benefit host metabolism but are reduced in T1D. We evaluated the hypothesis that DE and insulin restriction were associated with reduced SCFA-producing gut microbes, SCFA, and intestinal microbial diversity in adults with T1D.We collected stool samples at four timepoints in a hypothesis-generating gut microbiome pilot study ancillary to a weight management pilot in young adults with T1D. 16S ribosomal RNA gene sequencing measured the normalized abundance of SCFA-producing intestinal microbes. Gas-chromatography mass-spectrometry measured SCFA (total, acetate, butyrate, and propionate). The Diabetes Eating Problem Survey-Revised (DEPS-R) assessed DE and insulin restriction. Covariate-adjusted and Bonferroni-corrected generalized estimating equations modeled the associations. COVID-19 interrupted data collection, so models were repeated restricted to pre-COVID-19 data. Data were available for 45 participants at 109 visits, which included 42 participants at 65 visits pre-COVID-19. Participants reported restricting insulin "At least sometimes" at 53.3% of visits. Pre-COVID-19, each 5-point DEPS-R increase was associated with a -0.34 (95% CI -0.56, -0.13, p = 0.07) lower normalized abundance of genus Anaerostipes; and the normalized abundance of Lachnospira genus was -0.94 (95% CI -1.5, -0.42), p = 0.02 lower when insulin restriction was reported "At least sometimes" compared to "Rarely or Never".DE and insulin restriction were associated with a reduced abundance of SCFA-producing gut microbes pre-COVID-19. Additional studies are needed to confirm these associations to inform microbiota-based therapies in T1D.
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- 2023
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4. Calorie Restriction Outperforms Bariatric Surgery in a Murine Model of Obesity and Triple-Negative Breast Cancer
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Michael F Coleman, Kristina K Camp, Tori L McFarlane, Steven S Doerstling, Subreen A Khatib, Erika T Rezeli, Alfor G Lewis, Alex J Pfeil, Laura A Smith, Laura W Bowers, Farnaz Fouladi, Weida Gong, Elaine M Glenny, Joel S Parker, Ginger L Milne, Ian M Carroll, Anthony A Fodor, Randy J Seeley, and Stephen D Hursting
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Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity- driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesity’s procancer effects.
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- 2023
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5. Giardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy
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Natasa Giallourou, Jason Arnold, Elizabeth T. Rogawski McQuade, Muyiwa Awoniyi, Rose Viguna Thomas Becket, Kenneth Walsh, Jeremy Herzog, Ajay S. Gulati, Ian M. Carroll, Stephanie Montgomery, Pedro Henrique Quintela, Angela M. Faust, Steven M. Singer, Anthony A. Fodor, Tahmeed Ahmad, Mustafa Mahfuz, Esto Mduma, Thomas Walongo, Richard L. Guerrant, R. Balfour Sartor, Jonathan R. Swann, Margaret N. Kosek, and Luther A. Bartelt
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia-associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected children demonstrate broad amino acid deficiencies, and overproduction of specific phenolic acids, byproducts of intestinal bacterial amino acid metabolism. Gnotobiotic mice require specific nutritional and environmental conditions to recapitulate these findings, and immunodeficient mice confirm a pathway independent of chronic T/B cell inflammation. Taken together, we propose a new paradigm that Giardia-mediated growth faltering is contingent upon a convergence of this intestinal protozoa with nutritional and intestinal bacterial factors.
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- 2023
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6. A consortia of clinical E. coli strains with distinct in-vitro adherent/invasive properties establish their own co-colonization niche and shape the intestinal microbiota in inflammation-susceptible mice
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Rachel M. Bleich, Chuang Li, Shan Sun, Cassandra J. Barlogio, Christopher A. Broberg, Adrienne R. Franks, Emily Bulik-Sullivan, Belgin Dogan, Kenneth W. Simpson, Ian M. Carroll, Anthony A. Fodor, and Janelle C. Arthur
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Background Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in-vitro definition fully predicts mucosal colonization in-vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis.Results Germ-free inflammation-susceptible interleukin-10-deficient (Il10−/−) and inflammation-resistant WT mice were colonized with a consortia of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10−/− mice. These E. coli expand in Il10−/− mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization.Conclusions Our findings establish the in-vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in-vivo colonization dynamics of patient-derived bacteria in murine models.
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- 2023
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7. Association of Increased Serum Lipopolysaccharide, But Not Microbial Dysbiosis, With <scp>Obesity‐Related</scp> Osteoarthritis
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Anthony A. Fodor, Susan Sumner, Delisha A. Stewart, Kathryn L. Kelley, Jordan B. Renner, Amanda E. Nelson, Shan Sun, Richard F. Loeser, M. Andrea Azcarate-Peril, Ian M. Carroll, Yang Cui, Lara Longobardi, Liubov Arbeeva, Veronica Ulici, R. Balfour Sartor, and Joanne M. Jordan
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Lipopolysaccharides ,Male ,medicine.medical_specialty ,WOMAC ,Immunology ,Alpha (ethology) ,Osteoarthritis ,Gut flora ,Article ,Feces ,Mice ,Rheumatology ,Internal medicine ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Obesity ,Intestinal permeability ,biology ,business.industry ,Osteoarthritis, Knee ,medicine.disease ,biology.organism_classification ,Mice, Inbred C57BL ,Endocrinology ,Dysbiosis ,business - Abstract
OBJECTIVE. To test the hypothesis that an altered gut microbiota (dysbiosis) plays a role in obesity-associated osteoarthritis (OA). METHODS. Stool and blood samples were collected from 92 participants with BMI ≥ 30 kg/m(2) recruited from the Johnston County Osteoarthritis Project. OA cases (n=50) had hand plus knee OA (Kellgren-Lawrence [KL] grade ≥2 or arthroplasty). Controls (N=42) had no hand OA and KL grade 0–1 knees. Compositional analysis of stool samples was carried out by 16S rRNA amplicon sequencing. Alpha and beta diversity and differences in taxa relative abundances were determined. Blood samples were used for multiplex cytokine analysis and measures of lipopolysaccharide (LPS) and LPS binding protein. Germ-free mice were gavaged with case or control pooled fecal samples and placed on a 40% fat, high sucrose diet for 40 weeks. Knee OA was evaluated histologically. RESULTS. OA cases were slightly older with more females and higher BMI, WOMAC pain and KL grades than controls. There were no significant differences in alpha or beta diversity or genus level composition between cases and controls. Cases had higher plasma levels of osteopontin (p=0.01) and serum LPS (p
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- 2022
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8. Interactions between perceived stress and microbial-host immune components: two demographically and geographically distinct pregnancy cohorts
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Beatriz Peñalver Bernabé, Pauline M. Maki, Janet L. Cunningham, Tory Eisenlohr-Moul, Lisa Tussing-Humphreys, Ian M. Carroll, Samantha Meltzer-Brody, Jack A. Gilbert, and Mary Kimmel
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Psychiatry ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Psykiatri ,Biological Psychiatry - Abstract
Higher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota, reflecting environment and social interactions, alongside host immune responses have the potential to better understand perceived stress and identify when stress is excessive in pregnancy. Two U.S. cohorts of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 model (Emotional Distress/ED and Self-Efficacy/SE). Gut microbiota composition was measured by 16 S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines. ED levels were higher in the suburban compared to the urban cohort, but levels of SE were similar. ED and SE levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of SE levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect ofBacteroides uniformisbetween the immune system (through CXCL11) and SE. The study identified links between distinct taxonomical and immunological signatures with perceived stress. The data are congruent with a model where gut microbiome and immune factors, both impacting and reflecting factors such as close social relationships and dietary fiber, may modulate neural plasticity resulting in increased SE during pregnancy. The predictive value of these peripheral markers merit further study.
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- 2023
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9. The intestinal microbiota and anorexia nervosa: Cause or consequence of nutrient deprivation
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Cynthia M. Bulik, Afrouz Abbaspour, Ian M. Carroll, and Kylie K. Reed
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0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Gut flora ,digestive system ,Article ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,medicine ,Depression (differential diagnoses) ,Gastrointestinal tract ,biology ,business.industry ,digestive, oral, and skin physiology ,Inflammatory Bowel Diseases ,medicine.disease ,biology.organism_classification ,Obesity ,stomatognathic diseases ,030104 developmental biology ,Anorexia nervosa (differential diagnoses) ,Immunology ,Anxiety ,medicine.symptom ,business ,Psychopathology - Abstract
The intestinal microbiota is a diverse microbial community that colonizes the gastrointestinal tract of animals. Abnormal changes in intestinal microbiota has been associated with multiple diseases including inflammatory bowel diseases and obesity; however, emerging evidence suggests a role for the gut microbiota in anxiety and depression via the gut-brain axis. As this microbial community is associated with weight dysregulation and host behavior it is not surprising that the intestinal microbiota may have a role to play in anorexia nervosa (AN). In this review we examine recent studies linking the gut microbiota with nutrition, psychopathology, and ultimately AN. We also review potential gut microbiota-based therapies for AN.
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- 2021
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10. Test Anxiety and Poor Sleep: A Vicious Cycle
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Nancy A. Hamilton, Ronald Freche, Gabriella Zeller, Ian M. Carroll, and Yichi Zhang
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Biopsychosocial model ,education ,Context (language use) ,Anxiety ,03 medical and health sciences ,0302 clinical medicine ,Sleep Initiation and Maintenance Disorders ,medicine ,Humans ,030212 general & internal medicine ,Students ,Applied Psychology ,Test anxiety ,030505 public health ,medicine.disease ,Test (assessment) ,Health psychology ,Mood ,Test Anxiety ,Observational study ,medicine.symptom ,Sleep ,0305 other medical science ,Psychology ,Clinical psychology - Abstract
Test anxiety may be better thought of as a biopsychosocial process affecting academic performance during the days leading up to an exam, rather than a static appraisal of attitudes related to test taking. This was a passive observational study following students 2 days before a midterm exam and was designed to test the Sleep Anxiety Performance Process (SAPP) model in the context of a psychology statistics exam. Undergraduates (N = 167) enrolled in a statistics class, January–November 2015. Participants completed an electronic battery of measures and Sleep Mood Study Diaries (SMS) during the mornings, 2 days before a statistics exam. Instructors confirmed exam scores. A path model showed a reciprocal bi-directional relationship between Sleep Quality and restfulness (Q&R) and test anxiety 2 days before a scheduled exam, with test anxiety measured in the morning, before the exam predicting exam performance. Prior exam performance, being a non-native English speaker (ESL), and class performance motivation also predicted exam performance. These data support the SAPP model’s premise that that sleep and anxiety feed one another, as a reciprocal process, that collectively impairs academic performance, with direct effects on academic performance, but with implications for overall student health.
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- 2021
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11. Interactions between perceived stress and microbial-host immune components: two demographically and geographically distinct pregnancy cohorts
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Beatriz, Peñalver Bernabé, Pauline M, Maki, Janet L, Cunningham, Tory, Eisenlohr-Moul, Lisa, Tussing-Humphreys, Ian M, Carroll, Samantha, Meltzer-Brody, Jack A, Gilbert, and Mary, Kimmel
- Abstract
Higher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota, reflecting environment and social interactions, alongside host immune responses have the potential to better understand perceived stress and identify when stress is excessive in pregnancy. Two U.S. cohorts of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 model (Emotional Distress/ED and Self-Efficacy/SE). Gut microbiota composition was measured by 16 S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines. ED levels were higher in the suburban compared to the urban cohort, but levels of SE were similar. ED and SE levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of SE levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect of Bacteroides uniformis between the immune system (through CXCL11) and SE. The study identified links between distinct taxonomical and immunological signatures with perceived stress. The data are congruent with a model where gut microbiome and immune factors, both impacting and reflecting factors such as close social relationships and dietary fiber, may modulate neural plasticity resulting in increased SE during pregnancy. The predictive value of these peripheral markers merit further study.
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- 2022
12. Identifying mechanisms that predict weight trajectory after bariatric surgery: rationale and design of the biobehavioral trial
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Anthony A. Fodor, John Gunstad, Kristine J. Steffen, Ian M. Carroll, James E. Mitchell, Leslie J. Heinberg, Dale S. Bond, Farnaz Fouladi, Christine M. Peat, and Ross D. Crosby
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2019-20 coronavirus outbreak ,Sleeve gastrectomy ,medicine.medical_specialty ,Longitudinal study ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.medical_treatment ,MEDLINE ,Gastric Bypass ,Psychological intervention ,Bariatric Surgery ,030209 endocrinology & metabolism ,Gut flora ,Article ,03 medical and health sciences ,0302 clinical medicine ,Gastrectomy ,Weight loss ,Humans ,Medicine ,Longitudinal Studies ,Prospective Studies ,Microbiome ,biology ,business.industry ,Weight change ,biology.organism_classification ,Obesity, Morbid ,Surgery ,Mood ,Trajectory ,Body-Weight Trajectory ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Abstract
Bariatric surgery is currently the most efficacious and durable intervention for severe obesity. The most commonly performed procedures in the United States are the Roux-en-Y gastric bypass and the sleeve gastrectomy, which involve significant anatomic and physiologic alterations that lead to changes in behavior and biology. Unfortunately, many patients experience suboptimal weight loss and/or substantial weight regain. Eating and physical activity/sedentary behaviors, mood, cognition, and the gut microbiome all change postoperatively and have an association with weight change. The longitudinal relationship between changes in the gut microbiome and postoperative weight trajectory has not been explored thoroughly, and the interactive associations among the gut microbiome and the other variables that impact weight have been similarly understudied. The following is a methods and design description for a prospective, 24-month longitudinal study of 144 bariatric surgery patients, at 2 sites, that aimed to identify predictors of weight loss trajectories over 24 months after Roux-en-Y gastric bypass and the sleeve gastrectomy. Specifically, the study will examine the relationships between empirically supported behavioral and biological variables and their combined impact on postoperative weight trajectories. Novel data collection will include intensive measurement of problematic eating behaviors and diet and physical activity postoperatively, which may be altered in parallel with, or in response to, changes observed in the gut microbiota. Identifying postoperative predictors of weight loss and co-morbidity resolution should inform development of novel interventions that are tailored to individual patients’ risk profiles to optimize and sustain more favorable weight trajectories.
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- 2020
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13. Sequence variant analysis reveals poor correlations in microbial taxonomic abundance between humans and mice after gnotobiotic transfer
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Matthew C. B. Tsilimigras, Anthony A. Fodor, Zorka Djukic, Emily C. Bulik-Sullivan, Elaine M. Glenny, Cynthia M. Bulik, Ian M. Carroll, Quyen Tang, Yunfei Wang, Stephanie A. Thomas, Michael Sioda, Farnaz Fouladi, and Lisa M. Tarantino
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Firmicutes ,In silico ,Microbiology ,Article ,Feces ,Mice ,03 medical and health sciences ,Microbial ecology ,RNA, Ribosomal, 16S ,Animals ,Germ-Free Life ,Humans ,Microbiome ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Genetics ,0303 health sciences ,biology ,030306 microbiology ,Microbiota ,RNA ,Fecal Microbiota Transplantation ,Ribosomal RNA ,biology.organism_classification ,16S ribosomal RNA ,Gastrointestinal Microbiome - Abstract
Transplanting human gut microbiotas into germ-free (GF) mice is a popular approach to disentangle cause-and-effect relationships between enteric microbes and disease. Algorithm development has enabled sequence variant (SV) identification from 16S rRNA gene sequence data. SV analyses can identify which donor taxa colonize recipient GF mice, and how SV abundance in humans is replicated in these mice. Fecal microbiotas from 8 human subjects were used to generate 77 slurries, which were transplanted into 153 GF mice. Strong correlations between fecal and slurry microbial communities were observed; however, only 42.15 ± 9.95% of SVs successfully transferred from the donor to the corresponding recipient mouse. Firmicutes had a particularly low transfer rate and SV abundance was poorly correlated between donor and recipient pairs. Our study confirms human fecal microbiotas colonize formerly GF mice, but the engrafted community only partially resembles the input human communities. Our findings emphasize the importance of reporting a standardized transfer rate and merit the exploration of other animal models or in silico tools to understand the relationships between human gut microbiotas and disease.
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- 2020
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14. The Intestinal Microbiota and Short-Chain Fatty Acids in Association with Advanced Metrics of Glycemia and Adiposity Among Young Adults with Type 1 Diabetes and Overweight or Obesity
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Daria Igudesman, Jamie Crandell, Karen D Corbin, Franklin Muntis, Dessi P Zaharieva, Anna Casu, Joan M Thomas, Cynthia M Bulik, Ian M Carroll, Brian W Pence, Richard E Pratley, Michael R Kosorok, David M Maahs, and Elizabeth J Mayer-Davis
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Nutrition and Dietetics ,Medicine (miscellaneous) ,Food Science - Abstract
BACKGROUND: Comanagement of glycemia and adiposity is the cornerstone of cardiometabolic risk reduction in type 1 diabetes (T1D), but targets are often not met. The intestinal microbiota and microbiota-derived short-chain fatty acids (SCFAs) influence glycemia and adiposity but have not been sufficiently investigated in longstanding T1D. OBJECTIVES: We evaluated the hypothesis that an increased abundance of SCFA-producing gut microbes, fecal SCFAs, and intestinal microbial diversity were associated with improved glycemia but increased adiposity in young adults with longstanding T1D. METHODS: Participants provided stool samples at ≤4 time points (NCT03651622: https://clinicaltrials.gov/ct2/show/NCT03651622). Sequencing of the 16S ribosomal RNA gene measured abundances of SCFA-producing intestinal microbes. GC-MS measured total and specific SCFAs (acetate, butyrate, propionate). DXA (body fat percentage and percentage lean mass) and anthropometrics (BMI) measured adiposity. Continuous glucose monitoring [percentage of time in range (70-180 mg/dL), above range (>180 mg/dL), and below range (54-69 mg/dL)] and glycated hemoglobin (i.e., HbA1c) assessed glycemia. Adjusted and Bonferroni-corrected generalized estimating equations modeled the associations of SCFA-producing gut microbes, fecal SCFAs, and intestinal microbial diversity with glycemia and adiposity. COVID-19 interrupted data collection, so models were repeated restricted to pre-COVID-19 visits. RESULTS: Data were available for ≤45 participants at 101 visits (including 40 participants at 54 visits pre-COVID-19). Abundance of Eubacterium hallii was associated inversely with BMI (all data). Pre-COVID-19, increased fecal propionate was associated with increased percentage of time above range and reduced percentage of time in target and below range; and abundances of 3 SCFA-producing taxa (Ruminococcus gnavus, Eubacterium ventriosum, and Lachnospira) were associated inversely with body fat percentage, of which two microbes were positively associated with percentage lean mass. Abundance of Anaerostipes was associated with reduced percentage of time in range (all data) and with increased body fat percentage and reduced percentage lean mass (pre-COVID-19). CONCLUSIONS: Unexpectedly, fecal propionate was associated with detriment to glycemia, whereas most SCFA-producing intestinal microbes were associated with benefit to adiposity. Future studies should confirm these associations and determine their potential causal linkages in T1D.This study is registered at clinical.trials.gov (NCT03651622; https://clinicaltrials.gov/ct2/show/NCT03651622).
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- 2022
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15. Characterization of Au catalytic activity in low-temperature graphene etching
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Isabel Alvarez, Tanya Klowden, Henk W. Ch. Postma, and Ian M. Carroll
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Materials science ,Fabrication ,Annealing (metallurgy) ,Graphene ,Nanoparticle ,02 engineering and technology ,Surfaces and Interfaces ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,Catalyst poisoning ,0104 chemical sciences ,Surfaces, Coatings and Films ,law.invention ,Catalysis ,Chemical engineering ,law ,Materials Chemistry ,Graphite ,0210 nano-technology ,Nanoscopic scale - Abstract
Recent research into Au nanoparticles has revealed some surprising catalytically favorable properties. We apply these properties to the signficant challenge of patterning graphene at low temperatures in a scalable manner. By utilizing these Au nanoparticles, we demonstrate a simple method for low-temperature gold-catalyzed etching of graphite with predictable characteristics using ambient air at 350–375 °C and an ability to etch only the top graphene layer of a graphite piece with suitable choice of processing steps. The naturally occurring water vapor in ambient air is necessary for this reaction to occur. In addition, we characterize the etch characteristics as a function of process parameters. Ar annealing is required to obtain crystallographically straight etches, and 375 °C may be required to obtain single-layer deep etching. The catalytic activity is around ∼ 1 μ mol C / g Au s and terminates due to catalyst poisoning around ∼ 0.7 mmol C / g Au . We hypothesize that enhanced nanoparticle size control will have the greatest effect on catalytic activity. We anticipate that this work can be adapted by future research to precisely control the shape of the etched areas, allowing for the simple low-temperature creation of nanoscale graphite features, and ultimately can be applied to single-layer graphene sheets for integrated device fabrication.
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- 2019
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16. Gut-Brain Interactions
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Cynthia M. Bulik, Ian M. Carroll, Elizabeth J. Mayer-Davis, Megan Sweeney, and Daria Igudesman
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0301 basic medicine ,Type 1 diabetes ,biology ,business.industry ,digestive, oral, and skin physiology ,Gastroenterology ,Disease ,Gut flora ,Bioinformatics ,biology.organism_classification ,medicine.disease ,digestive system ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Anorexia nervosa (differential diagnoses) ,Diabetes mellitus ,mental disorders ,medicine ,Type i diabetes ,030211 gastroenterology & hepatology ,Microbiome ,Disordered eating ,business - Abstract
Anorexia nervosa has poor prognosis and treatment outcomes and is influenced by genetic, metabolic, and psychological factors. Gut microbes interact with gut physiology to influence metabolism and neurobiology, although potential therapeutic benefits remain unknown. Type 1 diabetes is linked to anorexia nervosa through energy dysregulation, which in both disease states is related to the gut microbiota, disordered eating, and genetics.
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- 2019
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17. Reconceptualizing anorexia nervosa
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Cynthia M. Bulik, Rachael E. Flatt, Ian M. Carroll, and Afrouz Abbaspour
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Anorexia Nervosa ,Genomics ,Genome-wide association study ,Biology ,Gut flora ,Bioinformatics ,Satiety Response ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Obesity ,Microbiome ,Conceptualization ,General Neuroscience ,General Medicine ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,030227 psychiatry ,Psychiatry and Mental health ,Neurology ,Anorexia nervosa (differential diagnoses) ,Dysbiosis ,Gene-Environment Interaction ,Identification (biology) ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Anorexia nervosa (AN) has one of the highest mortality rates of any psychiatric disorder. Treatments are often ineffective and relapse is common. Most research attempting to understand the underlying causes and maintenance factors of AN has focused on environmental contributions, yet there is much to be explored in terms of biological risk and maintenance factors. In this paper, we focus primarily on AN research related to genetics and the complex microbial community in the gut (intestinal microbiota), and how these impact our conceptualization of this disorder. Emerging research identifying significant negative genetic correlations between AN and obesity suggests that the conditions may represent 'metabolic bookends'. The identification of underlying biological mechanisms may provide both insight into extreme weight dysregulation on both ends of the spectrum and new possible points of entry for AN treatment. Additionally, the reported microbial imbalance (dysbiosis) in the gut microbiota in AN patients, potentially due to a nutrient- and energy-deprived gut environment, implies alterations in functional and metabolic capacity of the gut microbiome. The extent to which AN and obesity can also be considered to be 'microbiome bookends' requires further investigation. Finally, we discuss ongoing and future AN projects exploring the interplay between host genomics, the environment, and cumulative microbial genomes (microbiome) as well as interventions at the microbial and gut level.
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- 2019
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18. The Role of the Gut Microbiota in Sustained Weight Loss Following Roux-en-Y Gastric Bypass Surgery
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Michael Sioda, Anthony A. Fodor, Amanda E. Brooks, Ian M. Carroll, Matthew C. B. Tsilimigras, Emily C. Bulik-Sullivan, Farnaz Fouladi, and Kristine J. Steffen
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Nutrition and Dietetics ,biology ,business.industry ,Lactobacillales ,Gastric bypass surgery ,Endocrinology, Diabetes and Metabolism ,Physiology ,030209 endocrinology & metabolism ,Gut flora ,biology.organism_classification ,medicine.disease_cause ,digestive system ,Roux-en-Y anastomosis ,03 medical and health sciences ,0302 clinical medicine ,Weight regain ,Weight loss ,medicine ,030211 gastroenterology & hepatology ,Surgery ,medicine.symptom ,business ,Weight gain ,Feces - Abstract
The aim of the study was to investigate the role of the gut microbiota in weight regain or suboptimal weight loss following Roux-en-Y gastric bypass (RYGB). The gut microbiota composition in post-RYGB patients who experienced successful weight loss (SWL, n = 6), post-RYGB patients who experienced poor weight loss (PWL, n = 6), and non-surgical controls (NSC, n = 6) who were age- and BMI-matched to the SWL group (NSC, n = 6) were characterized through 16S rRNA gene sequencing. To further investigate the impact of the gut microbiota on weight profile, human fecal samples were transplanted into antibiotic-treated mice. Orders of Micrococcales and Lactobacillales were enriched in SWL and PWL groups compared to the NSC group. No significant difference was observed in the gut microbiota composition between PWL and SWL patients. However, transfer of the gut microbiota from human patients into antibiotic-treated mice resulted in significantly greater weight gain in PWL recipient mice compared to SWL recipient mice. A few genera that were effectively transferred from humans to mice were associated with weight gain in mice. Among them, Barnesiella was significantly higher in PWL recipient mice compared to SWL and NSC recipient mice. These results indicate that the gut microbiota are at least functionally, if not compositionally, different between PWL and SWL patients. Some taxa may contribute to weight gain after surgery. Future studies will need to determine the molecular mechanisms behind the effects of the gut bacteria on weight regain after RYGB.
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- 2019
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19. Reframing anorexia nervosa as a metabo-psychiatric disorder
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Phil Mehler, Cynthia M. Bulik, and Ian M. Carroll
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medicine.medical_specialty ,Anorexia Nervosa ,Gut morphology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Microbiota ,Treatment outcome ,Psychological intervention ,Cognitive reframing ,Genomics ,medicine.disease ,Opinion piece ,Article ,Gastrointestinal Tract ,Eating disorders ,Endocrinology ,Effective interventions ,Anorexia nervosa (differential diagnoses) ,medicine ,Humans ,Psychiatry ,business ,Genome-Wide Association Study - Abstract
Anorexia nervosa (AN) is a serious and often fatal illness. Despite decades of research, investigators have failed to adequately advance our understanding of the biological aspects of AN that could inform the development of effective interventions. Genome-wide association studies are revealing the important role of metabolic factors in AN, and studies of the gastrointestinal tract are shedding light on disruptions in enteric microbial communities and anomalies in gut morphology. In this opinion piece, we review the state of the science through the lens of the clinical presentation of illness. We project how the integration of rigorous science in genomics and microbiology, in collaboration with experienced clinicians, has the potential to markedly enhance treatment outcome via precision interventions.
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- 2021
20. Host Immunity, the Microbiome, and Perinatal Anxiety
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Hannah Rackers, Beatriz Penalver Bernabe, Shannon Dowty, Ian M. Carroll, Mary Kimmel, Samantha Meltzer-Brody, Rebecca C. Knickmeyer, Lisa Tussing-Humphreys, Jack A. Gilbert, Pauline M. Maki, and Lacey Pezley
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Host immunity ,Perinatal anxiety ,business.industry ,Immunology ,Medicine ,Microbiome ,business ,Biological Psychiatry ,Uncategorized - Abstract
No description supplied
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- 2021
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21. A Proof of Concept for a Systems Approach to Biologically Characterize the Maternal Gut Microbiome, Immune Patterns and Mental Distress During Pregnancy
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Jack A. Gilbert, Samantha Meltzer-Brody, Pauline M. Maki, Ian M. Carroll, Beatriz Penalver Bernabe, Janet L. Cunningham, Mary Kimmel, and Lisa Tussing-Humphreys
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Pregnancy ,biology ,business.industry ,Gut flora ,biology.organism_classification ,medicine.disease ,Mental health ,Mental distress ,Mood disorders ,Cohort ,medicine ,Anxiety ,Microbiome ,medicine.symptom ,business ,Clinical psychology - Abstract
ImportanceScreening for anxiety and depression is important but especially difficult during pregnancy. Identification and quantification of the variation of maternal biologic dimensions during the dynamic pregnancy period, e.g. immune and microbiome profiles, have the potential to greatly improve mental heath screening and patient stratification.ObjectiveTo determine if specific immune and microbiome profiles align with features of mental distress during pregnancy.DesignProspective case-control study from two cohorts in US followed from 2017 to 2019 in the second and third trimesters.SettingFor the urban cohort, recruitment from an obstetric clinic; for the suburbian group, recruitment from advertisements in the hospital and surrounding communities.ParticipantsA total of 90 pregnant women from two distinct geographic regions, with contrasting race, age, marital status, education and urban vs suburban settings.ExposuresSelf-reported mental health symptoms (anxiety, preceptions of stress and depression) and sociodemographic characteristics; blood was obtained for cytokine profiles and stool for microbiota analysis.Main Outcomes and MeasuresDimensionality reduction clustered the symptom scores from the three self-report tools. Phenotypes based on these features were then defined.ResultsFactor analysis revealed four features: Burn-out, Low Self-Esteem, Mixed State, and Suicidal/Self-Harm; six phenotypes: severe, with and without suicidal thoughts, depressed with low self-steem, hyperactive, and healthy. Factors and phenotype groups were statistically associated with immune and microbiota profiles and sociodemography. The hyperactive phenotype, despite having low self-reported symptoms, had elevated inflammatory cytokines and a microbiota profile similar to the severe phenotype. Elevated T-helper cell 17 (Th17), inducer of inflammation, is related to anxiety in these cohorts. Variance in socioeconomic factors and and the gut microbiota profile can account for 50% of the variance in phenotype.ConclusionBetter stratification of biological charateristics is essential for understanding complex perinatal mental disorders and can be achieved by including microbiota and immune data. Our preliminary results suggest that variance in microbial and immune factors can describe differences in mental health phenotype, and could be predictive of the women’s current or future risk for future diagnosis. These findings form testable hypotheses for larger longitudinal studies.KEY POINTSQuestionDoes self-reported mental distress in late pregnancy align with specific immune and microbiome patterns?FindingsWe show potential limitations in sole reliance on self-reported symptoms of mental distress in 90 subjects from two prospective cohorts. The most different groups based on symptom-based factors presented statistically similar inflammation and microbiome profiles that may reflect underreporting of mental distress symptoms.MeaningA systems biology approach identified risk immune and microbiome profiles with potential advantages to augment self-report. These biological charateristics high risk for mental distress in pregnancy should be confirmed in larger cohorts and may improve understanding of perinatal mood disorders.
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- 2020
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22. The Binge Eating Genetics Initiative (BEGIN): study protocol
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Cynthia M. Bulik, Tosha Woods Smith, Rachael E. Flatt, Jenna Tregarthen, Laura M. Thornton, Ian M. Carroll, Brian R. Baucom, Jonathan Butner, and Pascal R. Deboeck
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050103 clinical psychology ,lcsh:RC435-571 ,Binge eating ,Psychological intervention ,Mobile application ,Gut flora ,behavioral disciplines and activities ,Feeding and Eating Disorders ,Study Protocol ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Psychiatry ,mental disorders ,Genetics ,medicine ,Humans ,0501 psychology and cognitive sciences ,Microbiome ,Bulimia ,Bulimia Nervosa ,biology ,business.industry ,Bulimia nervosa ,Wearable technology ,05 social sciences ,Feeding Behavior ,medicine.disease ,Precision medicine ,biology.organism_classification ,Psychiatry and Mental health ,Eating disorders ,Etiology ,medicine.symptom ,business ,Binge-Eating Disorder ,030217 neurology & neurosurgery - Abstract
BackgroundThe Binge Eating Genetics Initiative (BEGIN) is a multipronged investigation examining the interplay of genomic, gut microbiota, and behavioral factors in bulimia nervosa and binge-eating disorder.Methods1000 individuals who meet current diagnostic criteria for bulimia nervosa or binge-eating disorder are being recruited to collect saliva samples for genotyping, fecal sampling for microbiota characterization, and recording of 30 days of passive data and behavioral phenotyping related to eating disorders using the appRecovery Recordadapted for the Apple Watch.DiscussionBEGIN examines the interplay of genomic, gut microbiota, and behavioral factors to explore etiology and develop predictors of risk, course of illness, and response to treatment in bulimia nervosa and binge-eating disorder. We will optimize the richness and longitudinal structure of deep passive and active phenotypic data to lay the foundation for a personalized precision medicine approach enabling just-in-time interventions that will allow individuals to disrupt eating disorder behaviors in real time before they occur.Trial registrationThe ClinicalTrials.gov identifier isNCT04162574. November 14, 2019, Retrospectively Registered.
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- 2020
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23. Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner
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Michael Armstrong, Ian M. Carroll, P. Darrell Neufer, Traci Davis, Abrar E. Al-Shaer, Espen E. Spangenburg, Saame Raza Shaikh, Joan Clària, Richard P. Bazinet, Maria J. Torres, William Guesdon, Nichole Reisdorph, Ganesh V. Halade, Anandita Pal, and Kevin Quinn
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Male ,0301 basic medicine ,Metabolite ,medicine.medical_treatment ,White adipose tissue ,Biochemistry ,Receptors, G-Protein-Coupled ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Insulina ,Hyperinsulinemia ,Insulin ,glucose ,Receptor ,Research Articles ,health care economics and organizations ,chemistry.chemical_classification ,0303 health sciences ,Lipidome ,Eicosapentaenoic acid ,3. Good health ,specialized pro‐resolving mediators ,Eicosapentaenoic Acid ,Liver ,Receptors, Chemokine ,lipids (amino acids, peptides, and proteins) ,Biotechnology ,Polyunsaturated fatty acid ,Research Article ,polyunsaturated fatty acids ,medicine.medical_specialty ,insulin ,Adipose Tissue, White ,Linoleic acid ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Hyperinsulinism ,Internal medicine ,Glucose Intolerance ,Genetic variation ,Genetics ,medicine ,Animals ,Obesity ,Molecular Biology ,030304 developmental biology ,business.industry ,diversity outbred mice ,nutritional and metabolic diseases ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Glucose ,chemistry ,Hyperglycemia ,Hiperglucèmia ,Glucosa ,business ,Homeostasis ,030217 neurology & neurosurgery ,030215 immunology - Abstract
Aims Eicosapentaenoic acid (EPA) is consumed in low levels in the western diet. Increased consumption of EPA may prevent impairments in insulin-glucose homeostasis that contribute toward cardiometabolic disorders. Here we investigated how EPA, through the biosynthesis of its downstream metabolites, prevents metabolic impairments driven by diet-induced obesity. Methods and Results Long-term administration of pure EPA ethyl esters to C57BL/6J male mice improved obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Supporting analyses of National Health and Nutrition Examination Survey data revealed fasting glucose levels of obese adults were inversely related to EPA intake in a sex-dependent manner and were dependent on the ratio of linoleic acid to EPA. We next investigated potential mechanisms by which EPA improved hyperinsulinemia and hyperglycemia. 16S rRNA sequencing showed EPA supplementation did not remodel the gut microbiome composition relative to obese mice. Subsequent untargeted and targeted mass spectrometry analyses revealed distinct modifications in the lipidome. Notably, EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in metabolic tissues. Therefore, we probed if administration of the bioactive downstream metabolite of 18-HEPE known as resolvin E1 (RvE1) for four days could reverse hyperinsulinemia and hyperglycemia through RvE1’s receptor ERV1/ChemR23. Additionally, we determined if the metabolic effects of RvE1 were dependent on host genetics. Experiments with obese ERV1/ChemR23 knockout and wild type mice showed that RvE1 mitigated hyperinsulinemia and hyperglycemia in a manner dependent on ERV1/ChemR23. RvE1’s effects on fasting insulin and glucose were not uniform in diversity outbred mice that model human genetic variation. Furthermore, secondary SNP analyses revealed extensive genetic variation in human RvE1- and EPA-metabolizing genes. Conclusions The data suggest increased EPA intake prevents metabolic impairments in obesity through a mechanism mediated by RvE1. The data also underscore the critical need for precision prevention studies that account for host-genetics in the EPA-RvE1 axis. Translational Perspective EPA ethyl esters have attracted significant attention based on findings from the REDUCE-IT trial on cardiovascular disease risk reduction. This study investigated how EPA ethyl esters prevent obesity-induced hyperinsulinemia and hyperglycemia. Our data show that EPA ethyl esters improved murine fasting insulin and glucose levels through the actions of the downstream metabolite known as resolvin E1 (RvE1). Notably, RvE1’s effects on hyperinsulinemia and hyperglycemia were dependent on the host genetic profile. Collectively, these data suggest targeting the EPA-RvE1 pathway may be an effective approach for preventing impairments in insulin-glucose homeostasis in a host genetic dependent manner.
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- 2020
24. Metabolite trajectories across the perinatal period and mental health: A preliminary study of tryptophan-related metabolites, bile acids and microbial composition
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Samantha Meltzer-Brody, Emma Fransson, Shirin Ataei, Anna Plantinga, Kai Xia, Michael C. Wu, Mary Kimmel, Andrea Azcarate-Peril, Ian M. Carroll, Wanting Jin, Rebecca C. Knickmeyer, Hannah Rackers, and Kun Lun
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Adult ,Dietary Fiber ,medicine.drug_class ,Metabolite ,Physiology ,Pilot Projects ,Anxiety ,Biology ,Kynurenic Acid ,Bile Acids and Salts ,Feces ,Behavioral Neuroscience ,chemistry.chemical_compound ,Kynurenic acid ,Pregnancy ,Tandem Mass Spectrometry ,medicine ,Humans ,Kynurenine ,Bile acid ,Depression ,Lachnospiraceae ,Tryptophan ,Fatty Acids, Volatile ,medicine.disease ,Gastrointestinal Microbiome ,Perinatal Care ,Mental Health ,chemistry ,Feasibility Studies ,Female ,Chromatography, Liquid - Abstract
Depression and anxiety during pregnancy and postpartum are common, but affected women differ in timing, trajectories, and extent of symptoms. The objective of this pilot, feasibility study is to analyze trajectories of serotonin and tryptophan-related metabolites, bile acid metabolites, and microbial composition, in relation to psychiatric history and current symptoms across the perinatal period. Serum and fecal samples were collected from 30 women at three times points in the perinatal period and assayed with LC-MS/MS and 16S sequencing respectively. We defined mean trajectories for each metabolite, clustered individuals by metabolite trajectories, tested associations between metabolites, and examined metabolite levels in relation to microbial composition. Findings of note include: (1) changes in kynurenine and the ratio of kynurenic acid to kynurenine from second trimester to third trimester were strongly associated with baseline primary and secondary bile acids. (2) Secondary bile acid UDCA and its conjugated forms were associated with lower bacterial diversity and levels of Lachnospiraceae, a taxa known to produce Short Chain Fatty Acids. (3) History of anxiety was associated with UDCA levels, but history of major depression was not associated with any of the bile acids. (4) There was a trend towards lower dietary fiber for those with history of anxiety or depression. Overall, our results reveal substantial temporal variation in tryptophan-related metabolites and in bile acid metabolites over the perinatal period, with marked inter-individual variability. Trajectories of TRP -related metabolites, primary and secondary bile acids, and the absence or presence of microbes that produce Short Chain Fatty Acids (SCFAs) considered in concert have the potential to differentiate individuals based on perinatal adaptations that may impact mental and overall health.
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- 2022
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25. Intestinal Microbial and Metabolic Alterations Following Successful Fecal Microbiota Transplant for d-Lactic Acidosis
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Ryan J. Elliott, Steven N. Lichtman, Sayanty Roy, Ajay S. Gulati, Emily C. Bulik-Sullivan, Zain Kassam, and Ian M. Carroll
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Short Bowel Syndrome ,0301 basic medicine ,Encephalopathy ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Lactic Acid ,Child ,Acidosis ,business.industry ,Gastrointestinal Microbiome ,Metabolic disorder ,Gastroenterology ,Metabolic acidosis ,Fecal Microbiota Transplantation ,Clostridium difficile ,medicine.disease ,Short bowel syndrome ,Treatment Outcome ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Immunology ,Acidosis, Lactic ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Abstract
Fecal microbiota transplantation (FMT) involves the transfer of stool from a healthy individual into the intestinal tract of a diseased recipient. Although used primarily for recurrent Clostridium difficile infection, FMT is increasingly being attempted as an experimental therapy for other illnesses, including metabolic disorders. D-lactic acidosis (D-LA) is a metabolic disorder that may occur in individuals with short bowel syndrome when lactate-producing bacteria in the colon overproduce D-lactate. This results in elevated systemic levels of D-lactate, metabolic acidosis, and encephalopathy. In this study, we report the successful use of FMT for the treatment of recurrent D-LA in a child who was unresponsive to conventional therapies. Importantly, we also present profiles of the enteric microbiota, as well as fecal D-/L-lactic acid metabolites, before and longitudinally after FMT. These data provide valuable insight into the putative mechanisms of D-LA pathogenesis and its treatment.
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- 2018
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26. A High-Throughput Organoid Microinjection Platform to Study Gastrointestinal Microbiota and Luminal Physiology
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Matthew DiSalvo, M. Andrea Azcarate-Peril, Jason W. Arnold, Leigh Ann Samsa, Ian A. Williamson, Liam T. Gaynor, John F. Rawls, Nancy L. Allbritton, Jordan L. Cocchiaro, Scott T. Magness, and Ian M. Carroll
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0301 basic medicine ,Hepatology ,Gastrointestinal microbiota ,Gastroenterology ,Physiology ,Lumen (anatomy) ,Biology ,Green fluorescent protein ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Human gut ,030220 oncology & carcinogenesis ,Organoid ,lcsh:Diseases of the digestive system. Gastroenterology ,lcsh:RC799-869 ,Microinjection ,Barrier function - Abstract
Background & Aims: The human gut microbiota is becoming increasingly recognized as a key factor in homeostasis and disease. The lack of physiologically relevant in vitro models to investigate host–microbe interactions is considered a substantial bottleneck for microbiota research. Organoids represent an attractive model system because they are derived from primary tissues and embody key properties of the native gut lumen; however, access to the organoid lumen for experimental perturbation is challenging. Here, we report the development and validation of a high-throughput organoid microinjection system for cargo delivery to the organoid lumen and high-content sampling. Methods: A microinjection platform was engineered using off-the-shelf and 3-dimensional printed components. Microinjection needles were modified for vertical trajectories and reproducible injection volumes. Computer vision (CVis) and microfabricated CellRaft Arrays (Cell Microsystems, Research Triangle Park, NC) were used to increase throughput and enable high-content sampling of mock bacterial communities. Modeling preformed using the COMSOL Multiphysics platform predicted a hypoxic luminal environment that was functionally validated by transplantation of fecal-derived microbial communities and monocultures of a nonsporulating anaerobe. Results: CVis identified and logged locations of organoids suitable for injection. Reproducible loads of 0.2 nL could be microinjected into the organoid lumen at approximately 90 organoids/h. CVis analyzed and confirmed retention of injected cargos in approximately 500 organoids over 18 hours and showed the requirement to normalize for organoid growth for accurate assessment of barrier function. CVis analyzed growth dynamics of a mock community of green fluorescent protein– or Discosoma sp. red fluorescent protein-expressing bacteria, which grew within the organoid lumen even in the presence of antibiotics to control media contamination. Complex microbiota communities from fecal samples survived and grew in the colonoid lumen without appreciable changes in complexity. Conclusions: High-throughput microinjection into organoids represents a next-generation in vitro approach to investigate gastrointestinal luminal physiology and the gastrointestinal microbiota. Keywords: Organoid, Microinjection, High-Throughput, Fecal Microbiota, Anaerobic, Barrier Function, High-Content Sampling
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- 2018
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27. A preliminary examination of gut microbiota, sleep, and cognitive flexibility in healthy older adults
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John Gunstad, Amber D. Rochette, James E. Mitchell, Ian M. Carroll, Jason R. Anderson, M. Andrea Azcarate-Peril, Lisa M. Manderino, Leslie J. Heinberg, Christine M. Peat, and Kristine J. Steffen
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0301 basic medicine ,biology ,Cognitive flexibility ,Cognition ,General Medicine ,Lentisphaerae ,biology.organism_classification ,Developmental psychology ,Pittsburgh Sleep Quality Index ,03 medical and health sciences ,Sleep deprivation ,030104 developmental biology ,0302 clinical medicine ,medicine ,Microbiome ,Cognitive decline ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology ,Stroop effect - Abstract
Objectives Inadequate sleep increases the risk for age-related cognitive decline and recent work suggests a possible role of the gut microbiota in this phenomenon. Partial sleep deprivation alters the human gut microbiome, and its composition is associated with cognitive flexibility in animal models. Given these findings, we examined the possible relationship among the gut microbiome, sleep quality, and cognitive flexibility in a sample of healthy older adults. Methods Thirty-seven participants (age 64.59 ± 7.54 years) provided a stool sample for gut microbial sequencing and completed the Pittsburgh Sleep Quality Index and Stroop Color Word Test as part of a larger project. Results Better sleep quality was associated with better Stroop performance and higher proportions of the gut microbial phyla Verrucomicrobia and Lentisphaerae. Stroop Word and Color-Word performance correlated with higher proportions of Verrucomicrobia and Lentisphaerae. Partial correlations suggested that the relationship between Lentisphaerae and Stroop Color-Word performance was better accounted for by sleep quality; sleep quality remained a significant predictor of Color-Word performance, independent of the Lentisphaerae proportion, while the relationship between Lentisphaerae and Stroop performance was non-significant. Verrucomicrobia and sleep quality were not associated with Stroop Word performance independent of one another. Conclusions The current findings suggest a possible relationship among sleep quality, composition of the gut microbiome, and cognitive flexibility in healthy older adults. Prospective and experimental studies are needed to confirm these findings and determine whether improving microbiome health may buffer against sleep-related cognitive decline in older adults.
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- 2017
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28. Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases
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Matthew C. B. Tsilimigras, Ian M. Carroll, Anthony A. Fodor, Elaine M. Glenny, Cynthia M. Bulik, Emily C. Bulik-Sullivan, Eun Young Huh, and Susan C. Kleiman
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Physiology ,Microbial composition ,Microbial dysbiosis ,medicine.disease ,Gastroenterology ,Acute stage ,03 medical and health sciences ,Psychiatry and Mental health ,Clinical Psychology ,Eating disorders ,030104 developmental biology ,0302 clinical medicine ,Anorexia nervosa (differential diagnoses) ,Internal medicine ,medicine ,In patient ,business ,030217 neurology & neurosurgery - Abstract
Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient-specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.
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- 2017
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29. Gut-Brain Interactions: Implications for a Role of the Gut Microbiota in the Treatment and Prognosis of Anorexia Nervosa and Comparison to Type I Diabetes
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Daria, Igudesman, Megan, Sweeney, Ian M, Carroll, Elizabeth J, Mayer-Davis, and Cynthia M, Bulik
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Anorexia Nervosa ,Diabetes Mellitus, Type 1 ,digestive, oral, and skin physiology ,Brain ,Humans ,Prognosis ,Article ,Gastrointestinal Microbiome - Abstract
Through their effects on the intestinal epithelium and immunity, gut microbes and their fermentative byproducts can influence metabolic and psychological health parameters in patients with AN. Integrative therapies that restore gut microbial health may also benefit individuals with conditions in which gut microbial dysbiosis manifests, as in T1D, as individuals in this population experience difficulties with weight stabilization and altered metabolic traits and are vulnerable to developing symptoms of disordered eating. Although the clinical implications of the brain-gut-microbiota axis are not yet fully understood in AN, targeted pro- and antibiotics represent two mechanisms by which augmenting the gut microbiota can serve as an ancillary therapy for lessening severity of bloating and discomfort during treatment. Specifically, antibiotics could be used to eliminate known pathogens that disrupt intestinal integrity, while targeted probiotics may help to restore beneficial species known to promote gut epithelial health. Thus, we conclude that controlled studies investigating use of such novel therapies, including FMT, should be undertaken as part of an interdisciplinary approach to address metabolic and psychological factors that influence acute and long-term health outcomes in AN and T1D. We highlight again that work on the role of the intestinal microbiota in eating disorders is both limited and confined to AN. As is commonly the case, biological research in eating disorders starts with AN before progressing to the other eating disorders presentations. Yet, in many ways, eating disorders are model conditions on in which to explore the gut-brain axis given the centrality of eating and metabolic factors to the illnesses. We encourage investigators to expand on this early work by conducting studies on the other eating disorders (both in youth and adults) to develop a more comprehensive picture of the role that the intestinal microbiota plays in the development and maintenance of and recovery from these debilitating illnesses.
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- 2019
30. Faecal Proteases from Pouchitis Patients Activate Protease Activating Receptor-2 to Disrupt the Epithelial Barrier
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Nathaniel A. Cohen, Sarit Hoffman, Ilya Borovok, Ian M. Carroll, Nitsan Maharshak, Hagit Tulchinsky, and Iris Dotan
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Proteases ,medicine.medical_treatment ,Blotting, Western ,Fluorescent Antibody Technique ,Inflammation ,Pouchitis ,Permeability ,Tight Junctions ,chemistry.chemical_compound ,Feces ,Medicine ,Humans ,Intestinal Mucosa ,Fluorescein isothiocyanate ,Protease ,Tight junction ,Bacteria ,business.industry ,Gastroenterology ,General Medicine ,medicine.disease ,Molecular biology ,Gastrointestinal Microbiome ,chemistry ,Caco-2 ,Pouch ,medicine.symptom ,business ,Peptide Hydrolases - Abstract
Background and Aims The pathogenesis of pouch inflammation may involve epithelial barrier disruption. We investigated whether faecal proteolytic activity is increased during pouchitis and results in epithelial barrier dysfunction through protease activating receptor [PAR] activation, and assessed whether the intestinal microbiome may be the source of the proteases. Methods Faecal samples were measured for protease activity using a fluorescein isothiocyanate [FITC]-casein florescence assay. Caco-2 cell monolayers were exposed to faecal supernatants to assess permeability to FITC-dextran. Tight junction protein integrity and PAR activation were assessed by immunoblot and immunofluorescence. A truncated PAR2 protein in Caco-2 cells was achieved by stable transfection using CRISPR/Cas9 plasmid. PAR2 activation in pouch biopsies was examined using antibodies directed to the N-terminus of the protein. Microbial composition was analysed based on 16S rRNA gene sequence analysis. Results Ten pouchitis patients, six normal pouch [NP] patients and nine healthy controls [HC] were recruited. The pouchitis patients exhibited a 5.19- and 5.35-fold higher faecal protease [FP] activity [p ≤ 0.05] compared to the NP and HC participants, respectively. The genus Haemophilus was positively associated with FP activity [R = 0.718, false discovery rate < 0.1]. Faecal supernatants from pouchitis patients activated PAR2 on Caco-2 monolayers, disrupted tight junction proteins and increased epithelial permeability. PAR2 truncation in Caco-2 abrogated faecal protease-mediated permeability. Pouch biopsies obtained from pouchitis patients, but not from NP patients, displayed PAR2 activation. Conclusions Protease-producing bacteria may increase faecal proteolytic activity that results in pouch inflammation through disruption of tight junction proteins and increased epithelial permeability in a PAR2-dependent manner. This mechanism may initiate or propagate pouch inflammation.
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- 2019
31. The Role of the Gut Microbiota in Sustained Weight Loss Following Roux-en-Y Gastric Bypass Surgery
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Farnaz, Fouladi, Amanda E, Brooks, Anthony A, Fodor, Ian M, Carroll, Emily C, Bulik-Sullivan, Matthew C B, Tsilimigras, Michael, Sioda, and Kristine J, Steffen
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Adult ,Male ,Gastric Bypass ,Middle Aged ,Weight Gain ,Gastrointestinal Microbiome ,Obesity, Morbid ,Mice, Inbred C57BL ,Feces ,Mice ,Weight Loss ,Animals ,Humans ,Female - Abstract
The aim of the study was to investigate the role of the gut microbiota in weight regain or suboptimal weight loss following Roux-en-Y gastric bypass (RYGB).The gut microbiota composition in post-RYGB patients who experienced successful weight loss (SWL, n = 6), post-RYGB patients who experienced poor weight loss (PWL, n = 6), and non-surgical controls (NSC, n = 6) who were age- and BMI-matched to the SWL group (NSC, n = 6) were characterized through 16S rRNA gene sequencing. To further investigate the impact of the gut microbiota on weight profile, human fecal samples were transplanted into antibiotic-treated mice.Orders of Micrococcales and Lactobacillales were enriched in SWL and PWL groups compared to the NSC group. No significant difference was observed in the gut microbiota composition between PWL and SWL patients. However, transfer of the gut microbiota from human patients into antibiotic-treated mice resulted in significantly greater weight gain in PWL recipient mice compared to SWL recipient mice. A few genera that were effectively transferred from humans to mice were associated with weight gain in mice. Among them, Barnesiella was significantly higher in PWL recipient mice compared to SWL and NSC recipient mice.These results indicate that the gut microbiota are at least functionally, if not compositionally, different between PWL and SWL patients. Some taxa may contribute to weight gain after surgery. Future studies will need to determine the molecular mechanisms behind the effects of the gut bacteria on weight regain after RYGB.
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- 2019
32. Molecular characterization of the intestinal microbiota in patients with and without abdominal bloating
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Ian M. Carroll, Ryan Legge, Yehuda Ringel, Tamar Ringel-Kulka, Jaehyoung Kim, and Andrew K. Benson
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Adult ,DNA, Bacterial ,Male ,0301 basic medicine ,Operational taxonomic unit ,medicine.medical_specialty ,Physiology ,Microbiome and Host Interactions ,Biology ,Gastroenterology ,Cohort Studies ,Irritable Bowel Syndrome ,Pathogenesis ,Feces ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Bloating ,RNA, Ribosomal, 16S ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Microbiome ,Irritable bowel syndrome ,Hepatology ,Microbiota ,digestive, oral, and skin physiology ,Gastrointestinal Microbiome ,Abdominal Cavity ,Middle Aged ,medicine.disease ,Intestines ,030104 developmental biology ,Biomarker (medicine) ,Female ,030211 gastroenterology & hepatology ,Dilatation, Pathologic - Abstract
Recent studies have demonstrated differences in the intestinal microbiota between patients with irritable bowel syndrome (IBS) and healthy controls (HC), suggesting a role for the intestinal microbiota in the pathogenesis of IBS. Alterations in the microbiota have also been implicated in the pathogenesis of abdominal bloating, a commonly reported symptom in IBS. We investigated the relationship between the intestinal microbiota, abdominal bloating, and altered bowel patterns in a cohort of patients with IBS and HC. The 16S rRNA gene from fresh fecal samples was amplified and pyrosequenced by using Roche-454 Titanium chemistry. A Core Measurable Microbiome (CMM) was generated for Operational Taxonomic Unit (OTU) detected in >75% of all samples and compositional features of CMM were compared between groups by Linear Discriminant Analysis (LDA). IBS differentiated from HC by LDA using continuous variation in the species/OTUs or the CMM genera. When subcategorized based on bloating symptoms and bowel characteristics, the same subjects were also well differentiated from one another and from HC. ANOVA analysis showed quantitative species/OTU differences between the subgroups including IBS with and without bloating, and subtypes based on bowel characteristics. The clear LDA differentiation and the significant microbial taxa differences between the groups imply a significant association of the microbiota with bloating symptoms and bowel characteristics in IBS. These changes in the microbiota may serve as a biomarker for IBS and its clinical subtypes and suggest a role for the intestinal microbiota in the pathogenesis of the main symptoms of the disorder.
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- 2016
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33. Severe Calorie Restriction Induces Gut Microbiota-Dependent Intestinal Stem Cell Dysfunction
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Cynthia M. Bulik, Nathan Vance, Ian M. Carroll, Elaine M. Glenny, Landeghem Laurianne Van, Scott T. Magness, Melissa Touvron, and Jintong Liu
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Nutrition and Dietetics ,Nutritional Microbiology/Microbiome ,Calorie restriction ,Medicine (miscellaneous) ,Biology ,Refeeding syndrome ,Gut flora ,medicine.disease ,biology.organism_classification ,Epithelium ,Intestinal absorption ,medicine.anatomical_structure ,Immunology ,medicine ,Microbiome ,Stem cell ,Digestion ,Food Science - Abstract
OBJECTIVES: Anorexia nervosa (AN) is a life-threatening illness, primarily characterized by extreme calorie restriction (CR). Given the substantial undernourishment in patients with AN, it is essential to understand the effects of severe CR on the small intestinal epithelium which is the primary tissue responsible for nutrient absorption and is therefore critical for the refeeding process. While we have previously reported that patients with AN harbor an altered intestinal microbiota, it remains unknown whether an AN-associated gut microbial community, induced by a nutrient-deprived environment, impacts intestinal epithelial physiology. METHODS: Conventionally-raised (CONVR) and germ-free (GF) mice were individually housed and placed on a 60% CR (60CR) diet for 9 days. CONVR mice were housed in standard specific-pathogen free conditions while GF mice were bred and housed in sterile isolators to occlude exposure to microorganisms. Mice were injected intraperitoneally with 4 mg/kg 5-ethynyl-2’deoxyuridine (EdU) 90 minutes before necropsy to mark proliferating cells. Intestinal tissue was collected for histology and intestinal crypts were isolated for ex vivo organoid culture. RESULTS: CONVR and GF mice on a 60CR diet lost significant body weight (28%±1 and 24%±1, respectively). 60CR CONVR and GF mice both displayed a significant increase in ISCs (+1.27 ± 0.02-fold and + 1.15 ± 0.05-fold, respectively) yet a significant decrease in proliferating cells (1.7 ± 0.2-fold and 1.7 ± 0.1-fold, respectively) compared to ad libitum controls. Interestingly, ex vivo organoids derived from crypts of CONVR 60CR mice were significantly smaller compared to organoids yielded from control crypts, but, strikingly, no differences in organoid size were observed between GF crypts from either diet group. CONCLUSIONS: While ISC from 60CR CONVR and GF mice exhibited similar features, 60CR GF ISC function was maintained as indicated by the similar organoid growth relative to GF ad libitum controls. These data suggest that severe CR induces ISC dysfunction resulting in impaired de novo generation of digestive epithelial mass, and that these changes are microbiota-dependent. FUNDING SOURCES: National Institutes of Health, North Carolina Translational and Clinical Sciences Institute, NCSU College of Veterinary Medicine, UNC Center for Gastrointestinal Biology and Disease.
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- 2020
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34. Escherichia coliheme oxygenase modulates host innate immune responses
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Jonathan J. Hansen, Sherrie L. Otterbein, Joseph C. Onyiah, Ian M. Carroll, Ronald J. Wong, Nitsan Maharshak, Stephanie Schulz, Hyungjin Sally Ryu, Leo E. Otterbein, Ting Jia Fan, and Scott E. Plevy
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Innate immune system ,Immunology ,Biology ,medicine.disease_cause ,biology.organism_classification ,Microbiology ,Heme oxygenase ,chemistry.chemical_compound ,Immune system ,chemistry ,Virology ,Gene expression ,medicine ,Secretion ,Escherichia coli ,Heme ,Bacteria - Abstract
Induction of mammalian heme oxygenase (HO)-1 and exposure of animals to carbon monoxide (CO) ameliorates experimental colitis. When enteric bacteria, including Escherichia coli, are exposed to low iron conditions, they express an HO-like enzyme, chuS, and metabolize heme into iron, biliverdin and CO. Given the abundance of enteric bacteria residing in the intestinal lumen, our postulate was that commensal intestinal bacteria may be a significant source of CO and those that express chuS and other Ho-like molecules suppress inflammatory immune responses through release of CO. According to real-time PCR, exposure of mice to CO results in changes in enteric bacterial composition and increases E. coli 16S and chuS DNA. Moreover, the severity of experimental colitis correlates positively with E. coli chuS expression in IL-10 deficient mice. To explore functional roles, E. coli were genetically modified to overexpress chuS or the chuS gene was deleted. Co-culture of chuS-overexpressing E. coli with bone marrow-derived macrophages resulted in less IL-12p40 and greater IL-10 secretion than in wild-type or chuS-deficient E. coli. Mice infected with chuS-overexpressing E. coli have more hepatic CO and less serum IL-12 p40 than mice infected with chuS-deficient E. coli. Thus, CO alters the composition of the commensal intestinal microbiota and expands populations of E. coli that harbor the chuS gene. These bacteria are capable of attenuating innate immune responses through expression of chuS. Bacterial HO-like molecules and bacteria-derived CO may represent novel targets for therapeutic intervention in inflammatory conditions.
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- 2015
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35. Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2
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Ryan Balfour Sartor, Melissa Ellermann, Nitsan Maharshak, Michael J. Shanahan, Zorka Djukic, Luke B. Borst, Lance R. Thurlow, Rafal Pawlinski, Ian M. Carroll, Siten Patel, Eun Young Huh, Jeremy Herzog, Roy C. Orlando, Chorlada Paiboonrungruang, and Iris Dotan
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Colon ,Immunology ,Biology ,Microbiology ,Permeability ,Enterococcus faecalis ,Cell Line ,chemistry.chemical_compound ,Intestinal mucosa ,medicine ,Animals ,Humans ,Receptor, PAR-2 ,Gelatinase ,Intestinal Mucosa ,Fluorescein isothiocyanate ,Protease-activated receptor 2 ,Mice, Knockout ,Cellular Microbiology: Pathogen-Host Cell Molecular Interactions ,Intestinal permeability ,Epithelial Cells ,medicine.disease ,biology.organism_classification ,Intestinal epithelium ,Epithelium ,Mice, Inbred C57BL ,Infectious Diseases ,medicine.anatomical_structure ,chemistry ,Gelatinases ,Culture Media, Conditioned ,Parasitology - Abstract
Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis . Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene ( gelE ). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2 −/− ) mice were used to investigate the role of this receptor in E. faecalis -induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2 −/− mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2 −/− mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2 −/− mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2.
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- 2015
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36. Testing in Microbiome-Profiling Studies with MiRKAT, the Microbiome Regression-Based Kernel Association Test
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Jin Zhou, Michael C. Wu, Hua Zhou, Ian M. Carroll, Yehuda Ringel, Michael P. Epstein, Tamar Ringel-Kulka, Hongzhe Li, Jun Chen, and Ni Zhao
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Population ,Biology ,Machine learning ,computer.software_genre ,Polymorphism, Single Nucleotide ,01 natural sciences ,Article ,010104 statistics & probability ,03 medical and health sciences ,Covariate ,Genetics ,Humans ,Genetics(clinical) ,Computer Simulation ,p-value ,Microbiome ,0101 mathematics ,education ,Phylogeny ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Models, Statistical ,business.industry ,Microbiota ,Human microbiome ,High-Throughput Nucleotide Sequencing ,Regression ,Genetics, Population ,Kernel method ,Artificial intelligence ,business ,computer ,Software ,Type I and type II errors - Abstract
High-throughput sequencing technology has enabled population-based studies of the role of the human microbiome in disease etiology and exposure response. Distance-based analysis is a popular strategy for evaluating the overall association between microbiome diversity and outcome, wherein the phylogenetic distance between individuals’ microbiome profiles is computed and tested for association via permutation. Despite their practical popularity, distance-based approaches suffer from important challenges, especially in selecting the best distance and extending the methods to alternative outcomes, such as survival outcomes. We propose the microbiome regression-based kernel association test (MiRKAT), which directly regresses the outcome on the microbiome profiles via the semi-parametric kernel machine regression framework. MiRKAT allows for easy covariate adjustment and extension to alternative outcomes while non-parametrically modeling the microbiome through a kernel that incorporates phylogenetic distance. It uses a variance-component score statistic to test for the association with analytical p value calculation. The model also allows simultaneous examination of multiple distances, alleviating the problem of choosing the best distance. Our simulations demonstrated that MiRKAT provides correctly controlled type I error and adequate power in detecting overall association. “Optimal” MiRKAT, which considers multiple candidate distances, is robust in that it suffers from little power loss in comparison to when the best distance is used and can achieve tremendous power gain in comparison to when a poor distance is chosen. Finally, we applied MiRKAT to real microbiome datasets to show that microbial communities are associated with smoking and with fecal protease levels after confounders are controlled for.
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- 2015
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37. High throughput sequencing reveals distinct microbial populations within the mucosal and luminal niches in healthy individuals
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Yehuda Ringel, Tamar Ringel-Kulka, Nitsan Maharshak, Ian M. Carroll, R. Balfour Sartor, and Elizabeth Ashley Wolber
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Adult ,DNA, Bacterial ,Male ,Microbiology (medical) ,Colon ,Biology ,DNA, Ribosomal ,Microbiology ,DNA sequencing ,Young Adult ,Intestinal mucosa ,RNA, Ribosomal, 16S ,Humans ,Intestinal Mucosa ,Gene ,Feces ,Bacteria ,Microbiota ,Gastroenterology ,Human microbiome ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Middle Aged ,16S ribosomal RNA ,biology.organism_classification ,Gastrointestinal Contents ,Healthy Volunteers ,Gastrointestinal Microbiome ,UniFrac ,Infectious Diseases ,Female ,Research Paper - Abstract
Background: The intestinal microbiota is associated with human health and diseases. The luminal microbiota (LM) and the mucosal-associated microbiota (MAM) are 2 distinct ecosystems with different metabolic and immunological functions. Aim: To characterize the intestinal LM and MAM in humans using high throughput sequencing of the 16S rRNA gene. Methods: Fresh fecal samples and distal colonic mucosal biopsies collected from 24 healthy subjects before (fecal) and during (mucosa) a flexible sigmoidoscopy of an un-prepared bowel. High throughput sequencing of the 16S rRNA gene was used to characterize bacterial communities. Sequences were processed using the QIIME pipeline. Results: LM and MAM populations were significantly different (ANOSIM: R = 0.49, P = 0.001). The LM displayed tighter clustering compared to the MAM (average weighted UniFrac distances 0.27 ± 0.05 vs. 0.43 ± 0.09, P < 0.001, respectively), and showed higher diversity (Shannon diversity index: 4.96 ± 0.37 vs 4.14 ± 0.56, respectively, P < 0.001). The dominant phyla in the LM and MAM were significantly different: Firmicutes (41.4% vs. 29.1%, FDR < 0.0001, respectively), Bacteroidetes (20.2% vs. 26.3%, FDR < 0.05, respectively), Actinobacteria (22% vs. 12.6%, FDR < 0.0001, respectively) and Proteobacteria (9.3% vs. 19.3%, FDR < 0.0001, respectively). The abundance of 56 genera differed significantly (FDR < 0.1) between the 2 niches. All of the genera in the fecal microbiota were present in the MAM while 10 genera were found to be unique to the MAM. Conclusion: The LM and MAM are distinct microbial ecosystems that differ significantly from each other in microbial diversity and composition. These two microbial niches should be investigated independently to better understand the role of the intestinal microbiota in health and disease.
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- 2015
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38. Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases
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Susan C, Kleiman, Elaine M, Glenny, Emily C, Bulik-Sullivan, Eun Young, Huh, Matthew C B, Tsilimigras, Anthony A, Fodor, Cynthia M, Bulik, and Ian M, Carroll
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Adult ,Young Adult ,Anorexia Nervosa ,Adolescent ,mental disorders ,Humans ,Female ,Middle Aged ,Article ,Gastrointestinal Microbiome - Abstract
Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient-specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation. Copyright © 2017 John WileySons, Ltd and Eating Disorders Association.
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- 2017
39. Characterizing and Functionally Defining the Gut Microbiota: Methodology and Implications
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Anthony A. Fodor, Janelle C. Arthur, Jacquelyn Carr, Ian M. Carroll, and Melissa Ellermann
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0301 basic medicine ,Gastrointestinal tract ,biology ,Human gastrointestinal tract ,Disease ,Computational biology ,Gut flora ,Proteomics ,biology.organism_classification ,Bioinformatics ,law.invention ,03 medical and health sciences ,Probiotic ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Metabolomics ,Metagenomics ,law ,medicine ,030211 gastroenterology & hepatology - Abstract
The human gastrointestinal tract contains an abundant and diverse microbial community, which has been shown to significantly impact both homeostasis and multiple disease states. While significant progress has been made in identifying the microbial populations residing in discrete locations from mouth to anus, conventional culturing techniques have been limiting because many of these microbes cannot be cultured. In the last 20 years, however, multiple advanced techniques have emerged to improve efficiency and efficacy in defining these populations. Additionally, these techniques have allowed elucidation of the functional properties of distinct populations. In this chapter, we review the microbial compartments of the gastrointestinal tract, the role of the microbiota in human health and disease, and the advancements in 16S rRNA sequencing, metagenomics, transcriptomics, proteomics, and gnotobiotics that have improved our understanding of the composition and function of gastrointestinal microbial communities. Finally, we briefly discuss the impact of these innovations on our capacity to develop novel pre- and probiotic therapies to modulate human health and treat human disease.
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- 2017
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40. Lactobacillus acidophilusNCFM affects colonic mucosal opioid receptor expression in patients with functional abdominal pain - a randomised clinical study
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Yehuda Ringel, Ian M. Carroll, Christian Jobin, Jason R. Goldsmith, Silvana P. Barros, Tamar Ringel-Kulka, and Olafur S. Palsson
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Abdominal pain ,medicine.medical_specialty ,Hepatology ,business.industry ,medicine.drug_class ,Gastroenterology ,digestive system diseases ,law.invention ,Clinical trial ,Probiotic ,Lactobacillus acidophilus ,Randomized controlled trial ,Opioid ,law ,Opioid receptor ,Internal medicine ,Immunology ,Medicine ,Pharmacology (medical) ,medicine.symptom ,business ,Receptor ,medicine.drug - Abstract
Background In a recent double-blinded clinical trial the probiotic combination of L-NCFM and B-LBi07 reduced bloating symptoms in patients with functional bowel disorder; an effect more evident in those who reported abdominal pain. In mice, L-NCFM but not B-LBi07 induced colonic MOR and CB2 expression and reduced visceral sensitivity.
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- 2014
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41. S115. The Perinatal Gut Microbiome as Possible Biomarker for Psychiatric History
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Hannah Rackers, Rebecca C. Santelli, Megan Barry, Samantha Meltzer-Brody, Mary Kimmel, Ian M. Carroll, Andrea Azcarate-Peril, Anna Plantinga, and Michael C. Wu
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Psychiatric history ,business.industry ,Medicine ,Biomarker (medicine) ,business ,Bioinformatics ,Biological Psychiatry ,Gut microbiome - Published
- 2019
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42. Gut feelings: A role for the intestinal microbiota in anorexia nervosa?
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Lisa M. Tarantino, Cynthia M. Bulik, Susan C. Kleiman, and Ian M. Carroll
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Clinical trial ,Psychiatry and Mental health ,Psychotherapist ,Feeling ,Anorexia nervosa (differential diagnoses) ,media_common.quotation_subject ,mental disorders ,MEDLINE ,Psychology ,Dropout (neural networks) ,media_common ,Clinical psychology - Abstract
Anorexia nervosa (AN) continues to perplex, and new lenses with which to view the disorder are essential to advancing understanding and enhancing treatment. Although a fundamental first step in treatment, few clinical trials exist that explore how best to renourish individuals with AN, and treatment approaches typically are based on clinical opinion or guidelines.1 Moreover, gastrointestinal effects of refeeding are uncomfortable, distressing, and painful, resulting in low treatment acceptance and high dropout.
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- 2015
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43. Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome
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Ian M. Carroll, Tamar Ringel-Kulka, Young Hyo Chang, Yehuda Ringel, Temitope O. Keku, Christopher D. Packey, and Ryan Balfour Sartor
- Subjects
Adult ,DNA, Bacterial ,Diarrhea ,Male ,medicine.medical_specialty ,Colon ,Physiology ,Biology ,Gastroenterology ,Neuroregulation and Motility ,Irritable Bowel Syndrome ,Pathogenesis ,Feces ,fluids and secretions ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Intestinal Mucosa ,Irritable bowel syndrome ,Hepatology ,Middle Aged ,medicine.disease ,Molecular analysis ,Microbial biodiversity ,Etiology ,Metagenome ,Female ,Molecular Fingerprinting ,medicine.symptom - Abstract
Alterations in the intestinal microbiota have been suggested as an etiological factor in the pathogenesis of irritable bowel syndrome (IBS). This study used a molecular fingerprinting technique to compare the composition and biodiversity of the microbiota within fecal and mucosal niches between patients with diarrhea-predominant IBS (D-IBS) and healthy controls. Terminal-restriction fragment (T-RF) length polymorphism (T-RFLP) fingerprinting of the bacterial 16S rRNA gene was used to perform microbial community composition analyses on fecal and mucosal samples from patients with D-IBS ( n = 16) and healthy controls ( n = 21). Molecular fingerprinting of the microbiota from fecal and colonic mucosal samples revealed differences in the contribution of T-RFs to the microbiota between D-IBS patients and healthy controls. Further analysis revealed a significantly lower (1.2-fold) biodiversity of microbes within fecal samples from D-IBS patients than healthy controls ( P = 0.008). No difference in biodiversity in mucosal samples was detected between D-IBS patients and healthy controls. Multivariate analysis of T-RFLP profiles demonstrated distinct microbial communities between luminal and mucosal niches in all samples. Our findings of compositional differences in the luminal- and mucosal-associated microbiota between D-IBS patients and healthy controls and diminished microbial biodiversity in D-IBS fecal samples further support the hypothesis that alterations in the intestinal microbiota may have an etiological role in the pathogenesis of D-IBS and suggest that luminal and mucosal niches need to be investigated.
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- 2011
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44. Alterations in the Intestinal Microbiota and Functional Bowel Symptoms
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Ian M. Carroll and Yehuda Ringel
- Subjects
medicine.medical_specialty ,biology ,business.industry ,Probiotics ,Intestinal physiology ,Gastroenterology ,Colonic Diseases, Functional ,medicine.disease ,biology.organism_classification ,digestive system ,United States ,Anti-Bacterial Agents ,Gastrointestinal Tract ,Irritable Bowel Syndrome ,stomatognathic diseases ,Internal medicine ,Lactobacillus ,Colonic Diseases ,Prevalence ,medicine ,Animals ,Humans ,business ,Irritable bowel syndrome - Abstract
Functional gastrointestinal disorders (FGIDs) are highly prevalent in Western countries yet no single mechanism or etiological agent that initiates IBS has been identified. Current research has implicated the intestinal microbiota with FGIDs. This article reviews the available literature/data regarding the intestinal microbiota and FGIDS. The possible relationships between the intestinal microbiota and the intestinal function and functional bowel symptoms are discussed.
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- 2009
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45. The Intestinal Microbiota in Acute Anorexia Nervosa and During Renourishment: Relationship to Depression, Anxiety, and Eating Disorder Psychopathology
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Ian M. Carroll, Lisa M. Tarantino, Emily C. Bulik-Sullivan, Hunna J. Watson, Susan C. Kleiman, Cynthia M. Bulik, and Eun Young Huh
- Subjects
Adult ,DNA, Bacterial ,medicine.medical_specialty ,Anorexia Nervosa ,Adolescent ,Gut–brain axis ,Physiology ,Firmicutes ,Anxiety ,Methanobrevibacter ,Anorexia nervosa ,digestive system ,Ribotyping ,Article ,Feces ,Young Adult ,Surveys and Questionnaires ,mental disorders ,Ruminococcus ,medicine ,Humans ,Psychiatry ,Applied Psychology ,Depression (differential diagnoses) ,Bacteroidetes ,Depression ,digestive, oral, and skin physiology ,Case-control study ,Convalescence ,Feeding Behavior ,medicine.disease ,Gastrointestinal Microbiome ,Psychiatry and Mental health ,Eating disorders ,Affect ,Lactobacillus ,Mood ,Case-Control Studies ,Body Composition ,Female ,medicine.symptom ,Psychology ,Psychopathology - Abstract
Objective The relevance of the microbe-gut-brain axis to psychopathology is of interest in anorexia nervosa (AN), as the intestinal microbiota plays a critical role in metabolic function and weight regulation. Methods We characterized the composition and diversity of the intestinal microbiota in AN, using stool samples collected at inpatient admission (T1; n = 16) and discharge (T2; n = 10). At T1, participants completed the Beck Depression and Anxiety Inventories and the Eating Disorder Examination-Questionnaire. Patients with AN were compared with healthy individuals who participated in a previous study (healthy comparison group; HCG). Genomic DNA was isolated from stool samples, and bacterial composition was characterized by 454 pyrosequencing of the 16S rRNA gene. Sequencing results were processed by the Quantitative Insights Into Microbial Ecology pipeline. We compared T1 versus T2 samples, samples from both points were compared with HCG (n = 12), and associations between psychopathology and T1 samples were explored. Results In patients with AN, significant changes emerged between T1 and T2 in taxa abundance and beta (between-sample) diversity. Patients with AN had significantly lower alpha (within-sample) diversity than did HCG at both T1 (p = .0001) and T2 (p = .016), and differences in taxa abundance were found between AN patients and HCG. Levels of depression, anxiety, and eating disorder psychopathology at T1 were associated with composition and diversity of the intestinal microbiota. Conclusions We provide evidence of an intestinal dysbiosis in AN and an association between mood and the enteric microbiota in this patient population. Future directions include mechanistic investigations of the microbe-gut-brain axis in animal models and association of microbial measures with metabolic changes and recovery indices.
- Published
- 2015
46. Adherent-Invasive Escherichia coli Production of Cellulose Influences Iron-Induced Bacterial Aggregation, Phagocytosis, and Induction of Colitis
- Author
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Rita Tamayo, Ian M. Carroll, Melissa Ellermann, Eun Young Huh, Bo Liu, and R. Balfour Sartor
- Subjects
Male ,Phagocytosis ,Iron ,Immunology ,Biology ,medicine.disease_cause ,Microbiology ,Bacterial Adhesion ,Proinflammatory cytokine ,Mice ,medicine ,Extracellular ,Escherichia coli ,Macrophage ,Animals ,Humans ,Secretion ,Cellulose ,Escherichia coli Infections ,Cellular Microbiology: Pathogen-Host Cell Molecular Interactions ,Macrophages ,Biofilm ,Colitis ,Interleukin-12 ,Interleukin 10 ,Infectious Diseases ,Parasitology ,Female - Abstract
Adherent-invasive Escherichia coli (AIEC), a functionally distinct subset of resident intestinal E. coli associated with Crohn's disease, is characterized by enhanced epithelial adhesion and invasion, survival within macrophages, and biofilm formation. Environmental factors, such as iron, modulate E. coli production of extracellular structures, which in turn influence the formation of multicellular communities, such as biofilms, and bacterial interactions with host cells. However, the physiological and functional responses of AIEC to variable iron availability have not been thoroughly investigated. We therefore characterized the impact of iron on the physiology of AIEC strain NC101 and subsequent interactions with macrophages. Iron promoted the cellulose-dependent aggregation of NC101. Bacterial cells recovered from the aggregates were more susceptible to phagocytosis than planktonic cells, which corresponded with the decreased macrophage production of the proinflammatory cytokine interleukin-12 (IL-12) p40. Prevention of aggregate formation through the disruption of cellulose production reduced the phagocytosis of iron-exposed NC101. In contrast, under iron-limiting conditions, where NC101 aggregation is not induced, the disruption of cellulose production enhanced NC101 phagocytosis and decreased macrophage secretion of IL-12 p40. Finally, abrogation of cellulose production reduced NC101 induction of colitis when NC101 was monoassociated in inflammation-prone Il10 −/− mice. Taken together, our results introduce cellulose as a novel physiological factor that impacts host-microbe-environment interactions and alters the proinflammatory potential of AIEC.
- Published
- 2015
47. 280 The Beneficial Impact of Rifaximin on Systemic and Intestinal Inflammation and Ammonia Occurs Even Without Microbiota: More Than an Antibiotic
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Oliver Fiehn, Chunhua Jiao, Ian M. Carroll, Patrick M. Gillevet, Daejoong Kang, Hajime Takei, Hiroshi Nittono, Jasmohan S. Bajaj, Genta Kakiyama, Masoumeh Sikaroodi, Jin Yang, Sili Fan, Jeremy Herzog, Naga S. Betrapally, William M. Pandak, R. Balfour Sartor, Phillip B. Hylemon, and Huiping Zhou
- Subjects
chemistry.chemical_compound ,Hepatology ,chemistry ,medicine.drug_class ,Intestinal inflammation ,business.industry ,Antibiotics ,Gastroenterology ,medicine ,business ,Rifaximin ,Microbiology - Published
- 2016
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48. Mo1928 Caspase-11 Exacerbates Acute, but Not Chronic, Experimental Colitis in a Microbiota-Dependent Manner
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Diana Arsene, Jonathan J. Hansen, Ting-Jia Fan, Ian M. Carroll, and Sandrine Tchaptchet
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Hepatology ,Dependent manner ,business.industry ,Gastroenterology ,Cancer research ,Medicine ,Experimental colitis ,Caspase-11 ,business - Published
- 2016
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49. P-193 A Distinct Microbiome Signature Characterizes Patients with Penetrating and Fistulizing Crohnʼs Disease
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Terrence S. Furey, Daniel N. Frank, Ryan Balfour Sartor, Reza Rahbar, Nur M Shahir, Hans H Herfarth, Timothy S. Sadiq, Shehzad Z. Sheikh, Rodney D. Newberry, Ian M. Carroll, and Mark J. Koruda
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Gastroenterology ,Immunology and Allergy ,030211 gastroenterology & hepatology ,Disease ,Microbiome ,Biology ,Bioinformatics ,Signature (topology) - Published
- 2016
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50. Fine-Structure Molecular Typing of Irish Helicobacter pylori Isolates and Their Genetic Relatedness to Strains from Four Different Continents
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Niyaz Ahmed, Sarah M. Beesley, Ian M. Carroll, Cyril J. Smyth, Colm A. Ó. Moráin, Aleem Ahmed Khan, and Sheikh Ghousunnissa
- Subjects
Microbiology (medical) ,Serotype ,congenital, hereditary, and neonatal diseases and abnormalities ,Genotype ,India ,Biology ,Polymerase Chain Reaction ,Humans ,CagA ,Serotyping ,Genotyping ,Genotyping Techniques ,Phylogeny ,DNA Primers ,Genetics ,Polymorphism, Genetic ,Helicobacter pylori ,Phylogenetic tree ,Molecular epidemiology ,Bacteriology ,South America ,bacterial infections and mycoses ,Pathogenicity island ,Europe ,Africa ,DNA Transposable Elements ,Ireland ,Gene Deletion - Abstract
Genotyping of 74 Irish Helicobacter pylori isolates was performed at four different loci ( vacA signal sequence and mid-region, insertion-deletion polymorphisms at the 3′ end of the cag pathogenicity island, and cagA ). The predominant vacA alleles and insertion-deletion motifs suggest an ancestral relationship between Irish isolates and either specific East Asian or Northern European strains. In addition, fluorescent amplified fragment length polymorphism-PCR genotyping and phylogenetic analysis of 32 representative Irish H. pylori isolates and 22 isolates from four different continents demonstrated that the Irish H. pylori isolates examined were weakly clonal and showed some association with both European and Asian isolates. These three genotyping techniques show that Irish H. pylori isolates have distinctive features that may have evolved in this insular European population.
- Published
- 2003
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