29 results on '"Ahern PP"'
Search Results
2. An exploratory study investigating the impact of the bladder tumor microbiome on Bacillus Calmette Guerin (BCG) response in non-muscle invasive bladder cancer.
- Author
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Knorr J, Lone Z, Werneburg G, Adler A, Agudelo J, Suryavanshi M, Campbell RA, Ericson K, Qiu H, Bajic P, Haber GP, Weight CJ, Ahern PP, Almassi N, Miller AW, and Lee BH
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- Humans, Male, Female, Aged, Retrospective Studies, Middle Aged, Neoplasm Invasiveness, Adjuvants, Immunologic therapeutic use, Treatment Outcome, Administration, Intravesical, Non-Muscle Invasive Bladder Neoplasms, Urinary Bladder Neoplasms microbiology, Urinary Bladder Neoplasms pathology, Urinary Bladder Neoplasms drug therapy, BCG Vaccine therapeutic use, Microbiota
- Abstract
Purpose: Intravesical Bacillus Calmette-Guerin (BCG) is standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). The effect of the bladder microbiome on response to BCG is unclear. We sought to characterize the microbiome of bladder tumors in BCG-responders and non-responders and identify potential mechanisms that drive treatment response., Materials and Methods: Patients with archival pre-treatment biopsy samples (2012-2018) were identified retrospectively. Prospectively, urine and fresh tumor samples were collected from individuals with high-risk NMIBC (2020-2023). BCG response was defined as tumor-free 2 years from induction therapy. Extracted DNA was sequenced for 16S rRNA and shotgun metagenomics. Primary outcomes were species richness (α-diversity) and microbial composition (β-diversity). Paired t-tests were performed for α-diversity (Observed species/Margalef). Statistical analysis for β-diversity (weighted and unweighted UniFrac distances, weighted Bray-Curtis dissimilarity) were conducted through Permanova, with 999 permutations., Results: Microbial species richness (P < 0.001) and composition (P = 0.001) differed between BCG responders and non-responders. Lactobacillus spp. were significantly enriched in BCG-responders. Shotgun metagenomics identified possible mechanistic pathways such as assimilatory sulfate reduction., Conclusion: A compositional difference exists in the tumor microbiome of BCG responders and non-responders with Lactobacillus having increased abundance in BCG responders., Competing Interests: Declaration of competing interest We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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3. Adapting for success: T cell features at tissue sites.
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Ahern PP and Gwyer Findlay E
- Abstract
Competing Interests: None declared.
- Published
- 2024
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4. The NQR Complex Regulates the Immunomodulatory Function of Bacteroides thetaiotaomicron.
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Engelhart MJ, Glowacki RWP, Till JM, Harding CV, Martens EC, and Ahern PP
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- Mice, Humans, Animals, Interleukin-10 metabolism, Mutagenesis, Gastrointestinal Tract, Cytokines metabolism, Bacteroides thetaiotaomicron
- Abstract
The gut microbiome and intestinal immune system are engaged in a dynamic interplay that provides myriad benefits to host health. However, the microbiome can also elicit damaging inflammatory responses, and thus establishing harmonious immune-microbiome interactions is essential to maintain homeostasis. Gut microbes actively coordinate the induction of anti-inflammatory responses that establish these mutualistic interactions. Despite this, the microbial pathways that govern this dialogue remain poorly understood. We investigated the mechanisms through which the gut symbiont Bacteroides thetaiotaomicron exerts its immunomodulatory functions on murine- and human-derived cells. Our data reveal that B. thetaiotaomicron stimulates production of the cytokine IL-10 via secreted factors that are packaged into outer membrane vesicles, in a TLR2- and MyD88-dependent manner. Using a transposon mutagenesis-based screen, we identified a key role for the B. thetaiotaomicron-encoded NADH:ubiquinone oxidoreductase (NQR) complex, which regenerates NAD+ during respiration, in this process. Finally, we found that disruption of NQR reduces the capacity of B. thetaiotaomicron to induce IL-10 by impairing biogenesis of outer membrane vesicles. These data identify a microbial pathway with a previously unappreciated role in gut microbe-mediated immunomodulation that may be targeted to manipulate the capacity of the microbiome to shape host immunity., (Copyright © 2023 by The American Association of Immunologists, Inc.)
- Published
- 2023
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5. Disruption of the Gut Microbiota Confers Cisplatin Resistance in Epithelial Ovarian Cancer.
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Chambers LM, Esakov Rhoades EL, Bharti R, Braley C, Tewari S, Trestan L, Alali Z, Bayik D, Lathia JD, Sangwan N, Bazeley P, Joehlin-Price AS, Wang Z, Dutta S, Dwidar M, Hajjar A, Ahern PP, Claesen J, Rose P, Vargas R, Brown JM, Michener CM, and Reizes O
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- Humans, Female, Mice, Animals, Carcinoma, Ovarian Epithelial drug therapy, Carcinoma, Ovarian Epithelial pathology, Cisplatin therapeutic use, Retrospective Studies, Neoplasm Recurrence, Local drug therapy, Anti-Bacterial Agents pharmacology, Gastrointestinal Microbiome, Ovarian Neoplasms pathology
- Abstract
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity., Significance: Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer. See related commentary by Hawkins and Nephew, p. 4511., (©2022 American Association for Cancer Research.)
- Published
- 2022
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6. A gut microbial metabolite of dietary polyphenols reverses obesity-driven hepatic steatosis.
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Osborn LJ, Schultz K, Massey W, DeLucia B, Choucair I, Varadharajan V, Banerjee R, Fung K, Horak AJ 3rd, Orabi D, Nemet I, Nagy LE, Wang Z, Allende DS, Willard BB, Sangwan N, Hajjar AM, McDonald C, Ahern PP, Hazen SL, Brown JM, and Claesen J
- Subjects
- Humans, Mice, Animals, Polyphenols pharmacology, Obesity metabolism, Diet, High-Fat adverse effects, Flavonoids pharmacology, Gastrointestinal Microbiome physiology, Fatty Liver prevention & control
- Abstract
The molecular mechanisms by which dietary fruits and vegetables confer cardiometabolic benefits remain poorly understood. Historically, these beneficial properties have been attributed to the antioxidant activity of flavonoids. Here, we reveal that the host metabolic benefits associated with flavonoid consumption hinge, in part, on gut microbial metabolism. Specifically, we show that a single gut microbial flavonoid catabolite, 4-hydroxyphenylacetic acid (4-HPAA), is sufficient to reduce diet-induced cardiometabolic disease (CMD) burden in mice. The addition of flavonoids to a high fat diet heightened the levels of 4-HPAA within the portal plasma and attenuated obesity, and continuous delivery of 4-HPAA was sufficient to reverse hepatic steatosis. The antisteatotic effect was shown to be associated with the activation of AMP-activated protein kinase α (AMPKα). In a large survey of healthy human gut metagenomes, just over one percent contained homologs of all four characterized bacterial genes required to catabolize flavonols into 4-HPAA. Our results demonstrate the gut microbial contribution to the metabolic benefits associated with flavonoid consumption and underscore the rarity of this process in human gut microbial communities.
- Published
- 2022
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7. Maltodextrin Consumption Impairs the Intestinal Mucus Barrier and Accelerates Colitis Through Direct Actions on the Epithelium.
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Zangara MT, Ponti AK, Miller ND, Engelhart MJ, Ahern PP, Sangwan N, and McDonald C
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- Animals, Diet, Western, Epithelium pathology, Food Additives, Humans, Mice, Mucus, Polysaccharides, Colitis
- Abstract
Food additives are common components of processed foods consumed in a Western diet. In inflammatory bowel disease patients, some diets that exclude food additives improved clinical disease parameters, suggesting a link between food additives and disease pathogenesis. Food additives also enhanced disease severity in mouse colitis models through incompletely described mechanisms. This study examined the mechanisms by which the food additive maltodextrin (MDX) alters the development of colitis in a murine model. Interleukin-10 knockout (IL10KO) mice were fed diets supplemented with MDX or carboxymethyl cellulose (CMC) to determine their impact on colitis onset and severity; microbiome composition, function, and location; colonic immune cell infiltrates; and mucus layer integrity. Primary IL10KO colonic epithelial monolayers were used to dissect the impact of MDX directly on epithelial differentiation and mucus production. MDX or CMC consumption increased the incidence and severity of colitis, as well as decreased microbiome diversity, altered microbial composition, and decreased fecal acetic acid levels. The number of mucus producing cells were decreased in food additive fed mice and resulted in increased microbial proximity to the intestinal epithelium. Additionally, MDX supplementation resulted in crypt hyperplasia and expansion of the HopX+ injury renewal stem cell niche. In primary intestinal epithelial-derived monolayers devoid of microbes and immune cells, MDX exposure decreased goblet cell number and mucus production in association with downregulated expression of the transcription factor Klf4 , a marker of terminally differentiated goblet cells. These results suggest MDX disrupts the balance of epithelial cell differentiation and proliferation to contribute to disease pathogenesis through direct and indirect actions on the intestinal epithelial barrier., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zangara, Ponti, Miller, Engelhart, Ahern, Sangwan and McDonald.)
- Published
- 2022
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8. Controlled Complexity: Optimized Systems to Study the Role of the Gut Microbiome in Host Physiology.
- Author
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Glowacki RWP, Engelhart MJ, and Ahern PP
- Abstract
The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such "wild mice" therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Glowacki, Engelhart and Ahern.)
- Published
- 2021
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9. Identification of essential genes for Escherichia coli aryl polyene biosynthesis and function in biofilm formation.
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Johnston I, Osborn LJ, Markley RL, McManus EA, Kadam A, Schultz KB, Nagajothi N, Ahern PP, Brown JM, and Claesen J
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- Biological Transport, Biosynthetic Pathways, Gene Expression Regulation, Bacterial, Molecular Structure, Mutation, Oxidation-Reduction, Phenotype, Polyenes chemistry, Biofilms growth & development, Escherichia coli genetics, Escherichia coli metabolism, Escherichia coli Proteins genetics, Escherichia coli Proteins metabolism, Genes, Essential, Polyenes metabolism
- Abstract
Aryl polyenes (APEs) are specialized polyunsaturated carboxylic acids that were identified in silico as the product of the most widespread family of bacterial biosynthetic gene clusters (BGCs). They are present in several Gram-negative host-associated bacteria, including multidrug-resistant human pathogens. Here, we characterize a biological function of APEs, focusing on the BGC from a uropathogenic Escherichia coli (UPEC) strain. We first perform a genetic deletion analysis to identify the essential genes required for APE biosynthesis. Next, we show that APEs function as fitness factors that increase protection from oxidative stress and contribute to biofilm formation. Together, our study highlights key steps in the APE biosynthesis pathway that can be explored as potential drug targets for complementary strategies to reduce fitness and prevent biofilm formation of multi-drug resistant pathogens.
- Published
- 2021
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10. Transcriptional and proteomic insights into the host response in fatal COVID-19 cases.
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Wu M, Chen Y, Xia H, Wang C, Tan CY, Cai X, Liu Y, Ji F, Xiong P, Liu R, Guan Y, Duan Y, Kuang D, Xu S, Cai H, Xia Q, Yang D, Wang MW, Chiu IM, Cheng C, Ahern PP, Liu L, Wang G, Surana NK, Xia T, and Kasper DL
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- Aged, Aged, 80 and over, COVID-19 genetics, COVID-19 immunology, COVID-19 pathology, Colon metabolism, Fatal Outcome, Female, Humans, Lung metabolism, Lung pathology, Lung virology, Male, Middle Aged, Neutrophil Activation, Proteome genetics, SARS-CoV-2 pathogenicity, Viral Load, COVID-19 metabolism, Proteome metabolism, Transcriptome
- Abstract
Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
- Published
- 2020
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11. Combined Prebiotic and Microbial Intervention Improves Oral Cholera Vaccination Responses in a Mouse Model of Childhood Undernutrition.
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Di Luccia B, Ahern PP, Griffin NW, Cheng J, Guruge JL, Byrne AE, Rodionov DA, Leyn SA, Osterman AL, Ahmed T, Colonna M, Barratt MJ, Delahaye NF, and Gordon JI
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- Animals, Bacteria classification, Child, Cholera Toxin pharmacology, Diet, Dietary Supplements, Disease Models, Animal, Germ-Free Life, Humans, Immunity, Mucosal, Immunoglobulin A, Male, Mice, Mice, Inbred C57BL, Mucous Membrane immunology, Probiotics, Cholera, Gastrointestinal Microbiome physiology, Malnutrition, Prebiotics, Vaccination
- Abstract
Undernourished children in low-income countries often exhibit poor responses to oral vaccination. Perturbed microbiota development is linked to undernutrition, but whether and how microbiota changes affect vaccine responsiveness remains unclear. Here, we show that gnotobiotic mice colonized with microbiota from undernourished Bangladeshi children and fed a Bangladeshi diet exhibited microbiota-dependent differences in mucosal IgA responses to oral vaccination with cholera toxin (CT). Supplementation with a nutraceutical consisting of spirulina, amaranth, flaxseed, and micronutrients augmented CT-IgA production. Mice initially colonized with a microbiota associated with poor CT responses exhibited improved immunogenicity upon invasion of bacterial taxa from cagemates colonized with a more "responsive" microbiota. Additionally, a consortium of five cultured bacterial invaders conferred augmented CT-IgA responses in mice fed the supplemented diet and colonized with the "hypo-responsive" community. These results provide preclinical proof-of-concept that diet and microbiota influence mucosal immune responses to CT vaccination and identify a candidate synbiotic formulation., Competing Interests: Declaration of Interests J.I.G. is a co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. N.F.D is an employee of the GSK group of companies and reports ownership of GSK shares and/or restricted GSK shares. GSK and Washington University have filed a joint patent application describing the potential utility of the prebiotic and probiotic formulations., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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12. Understanding immune-microbiota interactions in the intestine.
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Ahern PP and Maloy KJ
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- Animals, Germ-Free Life immunology, Homeostasis immunology, Humans, Intestinal Mucosa immunology, Intestinal Mucosa microbiology, Mice, Models, Animal, Gastrointestinal Microbiome immunology, Host Microbial Interactions immunology, Immunity
- Abstract
The past two decades have seen an explosion in research that aims to understand how the dynamic interplay with the gut microbiota impacts host health and disease, establishing a role for the gut microbiota in a plethora of pathologies. Understanding how health-promoting microbiota are established and how beneficial host-microbiota interactions are maintained is of immense biomedical importance. Despite the enormous progress that has been made, our knowledge of the specific microbiota members that mediate these effects and the mechanisms underlying these interactions is rudimentary. The dearth of information regarding the nature of advantageous host-microbiota interactions, and the factors that cause these relationships to go awry, has hampered our ability to realize the therapeutic potential of the microbiota. Here we discuss key issues that limit current knowledge and describe a path forwards to improving our understanding of the contributions of the microbiota to host health., (© 2019 John Wiley & Sons Ltd.)
- Published
- 2020
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13. Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition.
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Cowardin CA, Ahern PP, Kung VL, Hibberd MC, Cheng J, Guruge JL, Sundaresan V, Head RD, Barile D, Mills DA, Barratt MJ, Huq S, Ahmed T, and Gordon JI
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- Animals, Bacteria drug effects, Cattle, Diet, Disease Models, Animal, Feces microbiology, Gastrointestinal Microbiome drug effects, Humans, Infant, Intestine, Small microbiology, Male, Malnutrition microbiology, Mice, Mice, Inbred C57BL, Signal Transduction drug effects, Bone and Bones drug effects, Germ-Free Life drug effects, Malnutrition drug therapy, Milk, Human metabolism, Oligosaccharides administration & dosage, Osteoblasts drug effects, Osteoclasts drug effects
- Abstract
Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2'-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting., Competing Interests: Conflict of interest statement: D.B. and D.A.M. are cofounders of Evolve Biosystems, a company focused on diet-based manipulation of the gut microbiota. J.I.G. is a cofounder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
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14. Lactobacillus reuteri induces gut intraepithelial CD4 + CD8αα + T cells.
- Author
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Cervantes-Barragan L, Chai JN, Tianero MD, Di Luccia B, Ahern PP, Merriman J, Cortez VS, Caparon MG, Donia MS, Gilfillan S, Cella M, Gordon JI, Hsieh CS, and Colonna M
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Down-Regulation, Germ-Free Life, Indoles metabolism, Intestinal Mucosa immunology, Intestinal Mucosa microbiology, Mice, Mice, Inbred C57BL, Receptors, Aryl Hydrocarbon metabolism, Transcription Factors metabolism, Tryptophan metabolism, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Gastrointestinal Microbiome immunology, Intestine, Small immunology, Intestine, Small microbiology, Limosilactobacillus reuteri immunology
- Abstract
The small intestine contains CD4
+ CD8αα+ double-positive intraepithelial lymphocytes (DP IELs), which originate from intestinal CD4+ T cells through down-regulation of the transcription factor Thpok and have regulatory functions. DP IELs are absent in germ-free mice, which suggests that their differentiation depends on microbial factors. We found that DP IEL numbers in mice varied in different vivaria, correlating with the presence of Lactobacillus reuteri This species induced DP IELs in germ-free mice and conventionally-raised mice lacking these cells. L. reuteri did not shape the DP-IEL-TCR (TCR, T cell receptor) repertoire but generated indole derivatives of tryptophan that activated the aryl-hydrocarbon receptor in CD4+ T cells, allowing Thpok down-regulation and differentiation into DP IELs. Thus, L. reuteri , together with a tryptophan-rich diet, can reprogram intraepithelial CD4+ T cells into immunoregulatory T cells., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2017
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15. Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions.
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Griffin NW, Ahern PP, Cheng J, Heath AC, Ilkayeva O, Newgard CB, Fontana L, and Gordon JI
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- Animals, Bacteria genetics, Caloric Restriction, Feces microbiology, Germ-Free Life, Humans, Male, Mice, Bacteria classification, Bacteria metabolism, Diet, Feeding Behavior, Gastrointestinal Microbiome genetics, Gastrointestinal Tract microbiology
- Abstract
Ensuring that gut microbiota respond consistently to prescribed dietary interventions, irrespective of prior dietary practices (DPs), is critical for effective nutritional therapy. To address this, we identified DP-associated gut bacterial taxa in individuals either practicing chronic calorie restriction with adequate nutrition (CRON) or without dietary restrictions (AMER). When transplanted into gnotobiotic mice, AMER and CRON microbiota responded predictably to CRON and AMER diets but with variable response strengths. An individual's microbiota is connected to other individuals' communities ("metacommunity") by microbial exchange. Sequentially cohousing AMER-colonized mice with two different groups of CRON-colonized mice simulated metacommunity effects, resulting in enhanced responses to a CRON diet intervention and changes in several metabolic features in AMER animals. This response was driven by an influx of CRON DP-associated taxa. Certain DPs may impair responses to dietary interventions, necessitating the introduction of diet-responsive bacterial lineages present in other individuals and identified using the strategies described., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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16. Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes.
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Semenkovich NP, Planer JD, Ahern PP, Griffin NW, Lin CY, and Gordon JI
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- Animals, CD4-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes cytology, Cell Lineage, Chromatin chemistry, Chromatin metabolism, Germ-Free Life, Intestinal Mucosa metabolism, Male, Mice, Mice, Inbred C57BL, Signal Transduction, Enhancer Elements, Genetic, Gastrointestinal Microbiome, Intestines microbiology, Intraepithelial Lymphocytes microbiology
- Abstract
The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ
+ and γδ+ intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages., Competing Interests: The authors declare no conflict of interest.- Published
- 2016
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17. Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition.
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Wagner VE, Dey N, Guruge J, Hsiao A, Ahern PP, Semenkovich NP, Blanton LV, Cheng J, Griffin N, Stappenbeck TS, Ilkayeva O, Newgard CB, Petri W, Haque R, Ahmed T, and Gordon JI
- Subjects
- Animals, Bacteroides fragilis isolation & purification, Bangladesh, Cachexia microbiology, Child, Preschool, Diet, Disease Models, Animal, Feces microbiology, Female, Gene Expression Regulation, Bacterial, Germ-Free Life genetics, Humans, Infant, Male, Mice, Phenotype, Child Nutrition Disorders microbiology, Gastrointestinal Microbiome
- Abstract
To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced bacterial strains cultured from the fecal microbiota of two 24-month-old Bangladeshi children: one healthy and the other underweight. The undernourished donor's bacterial collection contained an enterotoxigenic Bacteroides fragilis strain (ETBF), whereas the healthy donor's bacterial collection contained two nontoxigenic strains of B. fragilis (NTBF). Analyses of mice harboring either the unmanipulated culture collections or systematically manipulated versions revealed that ETBF was causally related to weight loss in the context of its native community but not when introduced into the healthy donor's community. This phenotype was transmissible from the dams to their offspring and was associated with derangements in host energy metabolism manifested by impaired tricarboxylic acid cycle activity and decreased acyl-coenzyme A utilization. NTBF reduced ETBF's expression of its enterotoxin and mitigated the effects of ETBF on the transcriptomes of other healthy donor community members. These results illustrate how intraspecific (ETBF-NTBF) and interspecific interactions influence the effects of harboring B. fragilis., Competing Interests: J.I.G. is co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. The other authors declare that they have no competing interests., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
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18. T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine.
- Author
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Krausgruber T, Schiering C, Adelmann K, Harrison OJ, Chomka A, Pearson C, Ahern PP, Shale M, Oukka M, and Powrie F
- Subjects
- Animals, Disease Models, Animal, Female, Interleukin-17 metabolism, Interleukins metabolism, Male, Mice, Inbred C57BL, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Receptors, Interleukin metabolism, Interleukin-22, CD4-Positive T-Lymphocytes physiology, Colitis immunology, Interleukin-23 metabolism, Intestines immunology, T-Box Domain Proteins metabolism
- Abstract
IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T cells is not required for the induction of colitis or the differentiation of pathogenic Th17 cells but modifies qualitative features of the IL-23-driven colitogenic response by negatively regulating IL-23R expression. Consequently, absence of T-bet leads to unrestrained Th17 cell differentiation and activation characterized by high amounts of IL-17A and IL-22. The combined increase in IL-17A/IL-22 results in enhanced epithelial cell activation and inhibition of either IL-17A or IL-22 leads to disease amelioration. Our study identifies T-bet as a key modulator of IL-23-driven colitogenic responses in the intestine and has important implications for understanding of heterogeneity among inflammatory bowel disease patients.
- Published
- 2016
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19. Analysis of gene-environment interactions in postnatal development of the mammalian intestine.
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Rakoff-Nahoum S, Kong Y, Kleinstein SH, Subramanian S, Ahern PP, Gordon JI, and Medzhitov R
- Subjects
- Animals, Computational Biology, Mice, Mice, Knockout, Receptors, Interleukin-1 genetics, Toll-Like Receptors genetics, Gene-Environment Interaction, Intestines growth & development
- Abstract
Unlike mammalian embryogenesis, which takes place in the relatively predictable and stable environment of the uterus, postnatal development can be affected by a multitude of highly variable environmental factors, including diet, exposure to noxious substances, and microorganisms. Microbial colonization of the intestine is thought to play a particularly important role in postnatal development of the gastrointestinal, metabolic, and immune systems. Major changes in environmental exposure occur right after birth, upon weaning, and during pubertal maturation into adulthood. These transitions include dramatic changes in intestinal contents and require appropriate adaptations to meet changes in functional demands. Here, we attempt to both characterize and provide mechanistic insights into postnatal intestinal ontogeny. We investigated changes in global intestinal gene expression through postnatal developmental transitions. We report profound alterations in small and large intestinal transcriptional programs that accompany both weaning and puberty in WT mice. Using myeloid differentiation factor 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) double knockout littermates, we define the role of toll-like receptors (TLRs) and interleukin (IL)-1 receptor family member signaling in postnatal gene expression programs and select ontogeny-specific phenotypes, such as vascular and smooth muscle development and neonatal epithelial and mast cell homeostasis. Metaanalysis of the effect of the microbiota on intestinal gene expression allowed for mechanistic classification of developmentally regulated genes by TLR/IL-1R (TIR) signaling and/or indigenous microbes. We find that practically every aspect of intestinal physiology is affected by postnatal transitions. Developmental timing, microbial colonization, and TIR signaling seem to play distinct and specific roles in regulation of gene-expression programs throughout postnatal development.
- Published
- 2015
- Full Text
- View/download PDF
20. An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome.
- Author
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Ahmed T, Auble D, Berkley JA, Black R, Ahern PP, Hossain M, Hsieh A, Ireen S, Arabi M, and Gordon JI
- Subjects
- Child, Child Development physiology, Child Nutrition Disorders diagnosis, Child Nutrition Disorders epidemiology, Humans, World Health Organization, Child Nutrition Disorders prevention & control, Gastrointestinal Tract microbiology, Gastrointestinal Tract physiology, Microbiota physiology, Nutrition Policy trends, Nutritional Status physiology
- Abstract
The Sackler Institute for Nutrition Science and the World Health Organization (WHO) have worked together to formulate a research agenda for nutrition science. Undernutrition of children has profound effects on health, development, and achievement of full human capacity. Undernutrition is not simply caused by a lack of food, but results from a complex interplay of intra- and intergenerational factors. Representative preclinical models and comprehensive well-controlled longitudinal clinical studies are needed to further understand the contributions and the interrelationships among these factors and to develop interventions that are effective and durable. This paper summarizes work on mechanisms underlying the varied manifestations of childhood undernutrition and discusses current gaps in knowledge and challenges to our understanding of undernutrition and infection/immunity throughout the human life cycle, focusing on early childhood growth. It proposes a series of basic and clinical studies to address this global health challenge., (© 2014 New York Academy of Sciences.)
- Published
- 2014
- Full Text
- View/download PDF
21. Mining the human gut microbiota for effector strains that shape the immune system.
- Author
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Ahern PP, Faith JJ, and Gordon JI
- Subjects
- Adaptive Immunity, Animals, Feces microbiology, Germ-Free Life immunology, Humans, Immunity, Innate, Mice, T-Lymphocytes, Regulatory immunology, Gastrointestinal Tract microbiology, Immune System immunology, Microbial Consortia immunology, Microbiota immunology
- Abstract
The gut microbiota codevelops with the immune system beginning at birth. Mining the microbiota for bacterial strains responsible for shaping the structure and dynamic operations of the innate and adaptive arms of the immune system represents a formidable combinatorial problem but one that needs to be overcome to advance mechanistic understanding of microbial community and immune system coregulation and to develop new diagnostic and therapeutic approaches that promote health. Here, we discuss a scalable, less biased approach for identifying effector strains in complex microbial communities that impact immune function. The approach begins by identifying uncultured human fecal microbiota samples that transmit immune phenotypes to germ-free mice. Clonally arrayed sequenced collections of bacterial strains are constructed from representative donor microbiota. If the collection transmits phenotypes, effector strains are identified by testing randomly generated subsets with overlapping membership in individually housed germ-free animals. Detailed mechanistic studies of effector strain-host interactions can then be performed., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
22. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice.
- Author
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Faith JJ, Ahern PP, Ridaura VK, Cheng J, and Gordon JI
- Subjects
- Adiposity, Algorithms, Animals, Antigens, CD metabolism, Cecum microbiology, Fatty Acids chemistry, Feces microbiology, Female, Forkhead Transcription Factors genetics, Gastrointestinal Tract microbiology, Humans, Immune System, Integrin alpha Chains metabolism, Male, Metagenome, Mice, Mice, Inbred C57BL, Neuropilin-1 genetics, Phenotype, Systems Biology, T-Lymphocytes, Regulatory immunology, Germ-Free Life, Intestines microbiology, Microbiota physiology
- Abstract
Identifying a scalable, unbiased method for discovering which members of the human gut microbiota influence specific physiologic, metabolic, and immunologic phenotypes remains a challenge. We describe a method in which a clonally arrayed collection of cultured, sequenced bacteria was generated from one of several human fecal microbiota samples found to transmit a particular phenotype to recipient germ-free mice. Ninety-four bacterial consortia of diverse size, randomly drawn from the culture collection, were introduced into germ-free animals. We identified an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells (T(regs)) and expansion of Nrp1(lo/-) peripheral T(regs), as well as strains that modulated mouse adiposity and cecal metabolite concentrations, using feature selection algorithms and follow-up monocolonizations. This combinatorial approach enables a systems-level understanding of microbial contributions to human biology.
- Published
- 2014
- Full Text
- View/download PDF
23. The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation.
- Author
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Yockey LJ, Demehri S, Turkoz M, Turkoz A, Ahern PP, Jassim O, Manivasagam S, Kearney JF, Gordon JI, and Kopan R
- Subjects
- Alleles, Animals, Female, Genotype, Immunoglobulin E blood, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Keratinocytes cytology, Male, Mice, Mice, Knockout, Microbiota, Thymic Stromal Lymphopoietin, Cytokines metabolism, Gene Expression Regulation, Hypersensitivity metabolism, Inflammation metabolism, Skin immunology, Skin microbiology
- Abstract
Evidence is accumulating to suggest that our indigenous microbial communities (microbiota) may have a role in modulating allergic and immune disorders of the skin. To examine the link between the microbiota and atopic dermatitis (AD), we examined a mouse model of defective cutaneous barrier function with an AD-like disease due to loss of Notch signaling. Comparisons of conventionally raised and germ-free (GF) mice revealed a similar degree of allergic skin inflammation, systemic atopy, and airway hypersensitivity. GF mutant animals expressed significantly higher levels of thymic stromal lymphopoietin, a major proinflammatory cytokine released by skin with defective barrier function, resulting in a more severe B-lymphoproliferative disorder that persisted into adulthood. These findings suggest a role for the microbiota in ameliorating stress signals released by keratinocytes in response to perturbation in cutaneous barrier function.
- Published
- 2013
- Full Text
- View/download PDF
24. Metabolic niche of a prominent sulfate-reducing human gut bacterium.
- Author
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Rey FE, Gonzalez MD, Cheng J, Wu M, Ahern PP, and Gordon JI
- Subjects
- Animals, Bromodeoxyuridine, Chondroitin Sulfates administration & dosage, Chondroitin Sulfates metabolism, DNA Primers genetics, DNA Transposable Elements genetics, Desulfovibrio drug effects, Desulfovibrio genetics, Dietary Supplements, Feces microbiology, Gas Chromatography-Mass Spectrometry, Genetic Vectors genetics, Humans, Hydrogen Sulfide metabolism, Mass Spectrometry, Mice, Mutagenesis, Sequence Analysis, DNA, Species Specificity, Chondroitin Sulfates pharmacology, Desulfovibrio growth & development, Desulfovibrio metabolism, Diet, Gastrointestinal Tract microbiology
- Abstract
Sulfate-reducing bacteria (SRB) colonize the guts of ∼50% of humans. We used genome-wide transposon mutagenesis and insertion-site sequencing, RNA-Seq, plus mass spectrometry to characterize genetic and environmental factors that impact the niche of Desulfovibrio piger, the most common SRB in a surveyed cohort of healthy US adults. Gnotobiotic mice were colonized with an assemblage of sequenced human gut bacterial species with or without D. piger and fed diets with different levels and types of carbohydrates and sulfur sources. Diet was a major determinant of functions expressed by this artificial nine-member community and of the genes that impact D. piger fitness; the latter includes high- and low-affinity systems for using ammonia, a limiting resource for D. piger in mice consuming a polysaccharide-rich diet. Although genes involved in hydrogen consumption and sulfate reduction are necessary for its colonization, varying dietary-free sulfate levels did not significantly alter levels of D. piger, which can obtain sulfate from the host in part via cross-feeding mediated by Bacteroides-encoded sulfatases. Chondroitin sulfate, a common dietary supplement, increased D. piger and H2S levels without compromising gut barrier integrity. A chondroitin sulfate-supplemented diet together with D. piger impacted the assemblage's substrate utilization preferences, allowing consumption of more reduced carbon sources and increasing the abundance of the H2-producing Actinobacterium, Collinsella aerofaciens. Our findings provide genetic and metabolic details of how this H2-consuming SRB shapes the responses of a microbiota to diet ingredients and a framework for examining how individuals lacking D. piger differ from those who harbor it.
- Published
- 2013
- Full Text
- View/download PDF
25. Human nutrition, the gut microbiome and the immune system.
- Author
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Kau AL, Ahern PP, Griffin NW, Goodman AL, and Gordon JI
- Subjects
- Animals, Diet trends, Humans, Metagenomics, Milk, Human immunology, Obesity immunology, Obesity microbiology, Gastrointestinal Tract immunology, Gastrointestinal Tract microbiology, Immune System immunology, Metagenome immunology, Nutritional Physiological Phenomena physiology
- Abstract
Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.
- Published
- 2011
- Full Text
- View/download PDF
26. Interleukin-23 drives intestinal inflammation through direct activity on T cells.
- Author
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Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, and Powrie F
- Subjects
- Animals, Cell Proliferation, Cells, Cultured, Colitis pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Interleukin deficiency, Receptors, Interleukin immunology, T-Lymphocytes cytology, Colitis immunology, Interleukin-23 immunology, T-Lymphocytes immunology
- Abstract
Mutations in the IL23R gene are linked to inflammatory bowel disease susceptibility. Experimental models have shown that interleukin-23 (IL-23) orchestrates innate and T cell-dependent colitis; however, the cell populations it acts on to induce intestinal immune pathology are unknown. Here, using Il23r(-/-) T cells, we demonstrated that T cell reactivity to IL-23 was critical for development of intestinal pathology, but not for systemic inflammation. Through direct signaling into T cells, IL-23 drove intestinal T cell proliferation, promoted intestinal Th17 cell accumulation, and enhanced the emergence of an IL-17A(+)IFN-gamma(+) population of T cells. Furthermore, IL-23R signaling in intestinal T cells suppressed the differentiation of Foxp3(+) cells and T cell IL-10 production. Although Il23r(-/-) T cells displayed unimpaired Th1 cell differentiation, these cells showed impaired proliferation and failed to accumulate in the intestine. Together, these results highlight the multiple functions of IL-23 signaling in T cells that contribute to its colitogenic activity., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
27. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
- Author
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Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, and Powrie F
- Subjects
- Animals, Antigens, Ly metabolism, Colitis immunology, Helicobacter Infections immunology, Helicobacter Infections pathology, Helicobacter hepaticus immunology, Helicobacter hepaticus pathogenicity, Interferon-gamma immunology, Interleukin-17 immunology, Irritable Bowel Syndrome immunology, Irritable Bowel Syndrome pathology, Membrane Proteins metabolism, Mice, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Receptors, Interleukin metabolism, Thy-1 Antigens metabolism, Colitis pathology, Immunity, Innate immunology, Interleukin-23 immunology, Intestines immunology, Intestines pathology, Lymphoid Tissue cytology, Lymphoid Tissue immunology
- Abstract
The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-gamma in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-gammat and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-gammat, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.
- Published
- 2010
- Full Text
- View/download PDF
28. The interleukin-23 axis in intestinal inflammation.
- Author
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Ahern PP, Izcue A, Maloy KJ, and Powrie F
- Subjects
- Humans, Inflammatory Bowel Diseases metabolism, Interleukin-17 metabolism, Interleukin-23 metabolism, Intestinal Mucosa metabolism, Signal Transduction immunology, T-Lymphocytes, Helper-Inducer metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Inflammatory Bowel Diseases immunology, Interleukin-17 immunology, Interleukin-23 immunology, Intestines immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Immune responses in the intestine are tightly regulated to ensure host protective immunity in the absence of immune pathology. Interleukin-23 (IL-23) has recently been shown to be a key player in influencing the balance between tolerance and immunity in the intestine. Production of IL-23 is enriched within the intestine and has been shown to orchestrate T-cell-dependent and T-cell-independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17-associated cytokines. Furthermore, IL-23 restrains regulatory T-cell responses in the gut, favoring inflammation. Polymorphisms in the IL-23 receptor have been associated with susceptibility to inflammatory bowel diseases (IBDs) in humans, pinpointing the IL-23 axis as a key, conserved pathway in intestinal homeostasis. In addition to its role in dysregulated inflammatory responses, there is also evidence that IL-23 and the Th17 axis mediate beneficial roles in host protective immunity and barrier function in the intestine. Here we discuss the dual roles of IL-23 in intestinal immunity and how IL-23 and downstream effector pathways may make novel targets for the treatment of IBD.
- Published
- 2008
- Full Text
- View/download PDF
29. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis.
- Author
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Izcue A, Hue S, Buonocore S, Arancibia-Cárcamo CV, Ahern PP, Iwakura Y, Maloy KJ, and Powrie F
- Subjects
- Adoptive Transfer, Animals, Colitis genetics, Forkhead Transcription Factors antagonists & inhibitors, Forkhead Transcription Factors biosynthesis, Forkhead Transcription Factors genetics, Inflammation Mediators metabolism, Interleukin-10 deficiency, Interleukin-10 genetics, Interleukin-23 deficiency, Interleukin-23 genetics, Lymphopenia genetics, Lymphopenia immunology, Lymphopenia metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Regulatory pathology, Transforming Growth Factor beta deficiency, Transforming Growth Factor beta genetics, Colitis immunology, Colitis metabolism, Immune Tolerance genetics, Inflammation Mediators physiology, Interleukin-23 physiology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.
- Published
- 2008
- Full Text
- View/download PDF
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