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Chemotherapy treatment is associated with acute behavioral side effects (fatigue, anorexia) that significantly reduce patient quality of life and are dose-limiting, thereby increasing mortality (Kidwell et al., 2014). Disruptions to gut homeostasis (diarrhea, constipation, microbial dysbiosis) are also observed in patients receiving chemotherapy. In non-oncological patients, facets of mental health (fatigue, anxiety, depression) correlate with alterations in the gut microbiome, suggestive of a contribution of the gut in CNS disease etiology. The potential gut-to-brain pathway is poorly understood in patients receiving chemotherapy. Our prior studies have demonstrated a correlation between chemotherapy treatment, gut changes, peripheral and central inflammation, and behavioral symptoms in mice. Here we aimed to determine the extent to which chemotherapy-associated gut manipulations modulate the behavioral and biological consequences of chemotherapy. We measured sickness behaviors, peripheral and central inflammatory mediators, and anxiety in conventional or germ-free female mice: 1) cohabitating with mice of the opposite treatment group, 2) pre-treated with broad-spectrum antibiotics, or 3) given an intra-gastric gavage of gut content from chemotherapy-treated mice. In cohabitation studies, presumed coprophagia promoted body mass recovery, however strong associations with inflammation and behavior were not observed. Reduction of gut microbial alpha diversity via antibiotics did not prevent chemotherapy-associated side effects, however the relative abundances of the genera Tyzzerella, Romboutsia, and Turicibacter correlated with circulating inflammatory (IL-1β) and behavioral outcomes (lethargy, anxiety-like behavior). A gut microbiota transplant from chemotherapy-treated mice decreased central locomotion in open field testing, increased circulating CXCL1, and increased hippocampal Il6 and Tnfa in germ-free mice compared to germ-free mice that received a transplant from vehicle-treated mice. Taken together, these data provide further evidence that the gut microbiota likely contributes to the development of chemotherapy-associated side effects. This work has significant implications in the future treatment of anxiety in patients, and warrants future studies using microbe-based treatment options.

Robert M Jaggers,1 Damon J DiSabato,2,3 Brett R Loman,1 Danica Kontic,1 Kyle D Spencer,1,4,5 Jacob M Allen,1 Jonathan P Godbout,2,3 Ning Quan,6 Tamar L Gur,2,7 Michael T Bailey1,2,8 1Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA; 2Institute for Behavioral Medicine Research, Columbus, OH, 43210, USA; 3Department of Neuroscience, The Ohio State University, Columbus, OH, 43210, USA; 4Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA; 5Graduate Partnership Program, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, OH, USA; 6Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA; 7Department of Psychiatry, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; 8Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USACorrespondence: Michael T Bailey, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, W410, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH, 43205, USA, Tel +1 614-722-2764, Email Michael.bailey2@nationwidechildrens.orgPurpose: Commensal microbes are impacted by stressor exposure and are known contributors to cognitive and social behaviors, but the pathways through which gut microbes influence stressor-induced behavioral changes are mostly unknown. A murine social stressor was used to determine whether host–microbe interactions are necessary for stressor-induced inflammation, including neuroinflammation, that leads to reduced cognitive and social behavior.Methods: C57BL/6 male mice were exposed to a paired fighting social stressor over a 1 hr period for 6 consecutive days. Y-maze and social interaction behaviors were tested following the last day of the stressor. Serum cytokines and lipopolysaccharide binding protein (LBP) were measured and the number and morphology of hippocampal microglia determined via immunohistochemistry. Intestinal mucous thickness and antimicrobial peptide expression were determined via fluorescent staining and real-time PCR (respectively) and microbial community composition was assessed using 16S rRNA gene amplicon sequencing. To determine whether the microbiota or the LBP receptor (CD14) are necessary for stressor-induced behavioral changes, experiments were performed in mice treated with a broad-spectrum antibiotic cocktail or in CD14−/− mice.Results: The stressor reduced Y-maze spontaneous alternations, which was accompanied by increased microglia in the hippocampus, increased circulating cytokines (eg, IL-6, TNF-α) and LBP, and reduced intestinal mucus thickness while increasing antimicrobial peptides and cytokines. These stressor-induced changes were largely prevented in mice given broad-spectrum antibiotics and in CD14−/− mice. In contrast, social stressor-induced alterations of social behavior were not microbe-dependent.Conclusion: Stressor-induced cognitive deficits involve enhanced bacterial interaction with the intestine, leading to low-grade, CD14-dependent, inflammation.Keywords: social defeat, stress, microbiome, microglia, cytokines, neuroinflammation, mucus barrier

Chemotherapy treatment negatively affects the nervous and immune systems and alters gastrointestinal function and microbial composition. Outside of the cancer field, alterations in commensal bacteria and immune function have been implicated in behavioral deficits; however, the extent to which intestinal changes are related to chemotherapy-associated behavioral comorbidities is not yet known. Thus, this study identified concurrent changes in behavior, central and peripheral immune activation, colon histology, and bacterial community structure in mice treated with paclitaxel chemotherapy. In paclitaxel-treated mice, increased fatigue and decreased cognitive performance occurred in parallel with reduced microglia immunoreactivity, increased circulating chemokine expression (CXCL1), as well as transient increases in pro-inflammatory cytokine/chemokine (Il-1β, Tnfα, Il-6, and Cxcl1) gene expression in the brain. Furthermore, mice treated with paclitaxel had altered colonic bacterial community composition and increased crypt depth. Relative abundances of multiple bacterial taxa were associated with paclitaxel-induced increases in colon mass, spleen mass, and microglia activation. Although microbial community composition was not directly related to available brain or behavioral measures, structural differences in colonic tissue were strongly related to microglia activation in the dentate gyrus and the prefrontal cortex. These data indicate that the chemotherapeutic paclitaxel concurrently affects the gut microbiome, colonic tissue integrity, microglia activation, and fatigue in female mice, thus identifying a novel relationship between colonic tissue integrity and behavioral responses that is not often assessed in studies of the brain-gut-microbiota axis.

Background: Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Methods: Conventionally-raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. Findings: RNA sequencing of IECs isolated from conventionally-reared (CONV-R) mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3g, Reg3b) transcriptional profile as a result of Str. This response occurred concomitant to thinning of the mucus layer and signs of systemic endotoxemia. In contrast to their CONV-R counterparts, IECs from GF mice exhibited no detectable transcriptional changes in response to Str. Still, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased Dual Oxidase-2 [DUOX2]), indicating a priming event by host stress signals. Stress-induced increase in colonic DUOX2 in CONV-R mice paralleled changes to catalase positive bacteria and luminal catalase activity, evidencing Str-mediated disruptions in gut microbiota function through excessive IEC ROS production. Interpretation: Social stress disrupts colonic epithelial cells and mucosal integrity, a response dependent on an intact microbiota and endogenous stress signal priming. Funding: This work was supported by a Ruth L. Kirschstein National Research Service T32DE014320 to J. Allen, NIH grant AT006552-01A1 to M. Bailey, and internal funding from the Abigail Wexner Research Institute at Nationwide Children’s Hospital to J. Allen and M. Bailey. Declaration of Interest: The authors report no competing interests. Ethical Approval: All animals used in this study were approved by the IACUC at Nationwide Children’s Hospital.

Increasing scientific attention is focused on the gut-brain axis, including the ability of the gastrointestinal (GI) tract to modulate central nervous system function. Changes in the intestinal microbiome can influence affective-like behavior, cognitive performance, fatigue, and sleep in rodents and humans. Patients with cancer who are receiving chemotherapy experience similar negative behavioral changes and concurrent GI symptoms. These chemotherapy comorbidities can be long-lasting and may reduce patients' quality of life and motivation to comply with treatment. This review summarizes the clinical and preclinical evidence supporting a role for the intestinal microbiome in mediating behavioral comorbidities through peripheral immune activation in patients with cancer who are receiving chemotherapy. In addition, evidence suggesting that targeted modification of the intestinal microbiome during cancer treatment could ameliorate associated behavioral comorbidities is reviewed.

OBJECTIVES: High-fiber dietary patterns are associated with cardiovascular health and intestinal microbiome composition. Caregivers influence diets of children, affecting dyadic health and microbiomes. The objectives of this study were to evaluate the relationship between changes in caregiver diet quality and caregiver and child: 1) systolic blood pressure (SBP) and 2) fecal bacteriome composition. METHODS: Caregiver-child (age 8–9 years) dyads were randomized to either a 10-week high-fiber diet intervention (fruits, vegetables, and whole grains) or control. Caregiver diet quality (30-day FFQs and Healthy Eating Index (HEI)), and caregiver and child SBP and fecal samples were collected pre- and post-intervention. Fecal bacteriomes were analyzed via 16S rRNA gene amplicon sequencing. HEI and SBP were tested via 2-way ANOVA. Bacteriome differentials (i.e., ratio of amplicon sequence variants (ASVs) with related relative abundances) associated with HEI were identified via Songbird and Qurro. Caregiver HEI was used to guide differential assembly in caregiver bacteriomes and as a proxy for child diet quality to guide differential assembly in child bacteriomes. Pearson correlations assessed inter-data relationships. RESULTS: Complete data were collected from 19 caregivers and 16 children. Intervention caregivers increased total (T) HEI (+4.4 vs − 1.7 points, P = 0.047) and whole grain (WG) HEI component scores (+1.7 vs 0 points, P = 0.014) compared to control. WG-HEI was correlated with caregiver SBP (r = −0.37, P = 0.046). T-HEI was correlated with caregiver and child T-HEI bacteriome differentials (r = 0.36, P = 0.027 and r = 0.57, P = 0.001). WG-HEI correlated with caregiver and child WG-HEI bacteriome differentials (r = 0.45, P = 0.013 and r = 0.60, P

Context Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent and underdiagnosed comorbidity of many chronic diseases that is associated with altered intestinal bacterial communities. This association has prompted research into alternative treatments aimed at modulating intestinal microbiota. Given the novelty of these treatments, scarce evidence regarding their effectiveness in clinical populations exists. Objective This meta-analysis sought to systemically review and quantitatively synthesize evidence on prebiotic, probiotic, and synbiotic therapies for patients with NAFLD in randomized controlled trials. Data sources PRISMA guidelines ensured transparent reporting of evidence. PICOS criteria defined the research question for the systematic review. A systematic keyword search in PubMed and EMBASE identified 25 studies: 9 assessed prebiotic, 11 assessed probiotic, and 7 assessed symbiotic therapies for a total of 1309 patients. Data extraction Basic population characteristics, the primary variables of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (utilized for NAFLD diagnosis), and the secondary variables of body mass index (BMI), gamma-glutamyl transferase (γ-GT), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglyceridges (TAG) were extracted. Pooled effect sizes of these variables were calculated by meta-analysis. No publication bias was identified using Begg's and Egger's tests or Cochrane bias assessment tool. Results Meta-analysis indicated that microbial therapies significantly reduced BMI (-0.37 kg/m2; 95% confidence interval [CI], -0.46 to -0.28; P

Background Reduced nutrient intake is common in patients after hospitalization, contributing to increased risk for readmission and mortality. Oral nutrition supplements can improve nutrition status and clinical outcomes, but intake of food is prioritized by clinicians. This study examines the impact of a high‐protein oral nutrition supplement (S‐ONS) on nutrient intake post discharge. Methods In a subset of patients (14 S‐ONS and 16 placebo) from the NOURISH (Nutrition effect On Unplanned ReadmIssions and Survival in Hospitalized patients) trial, 24‐hour dietary recalls were conducted on 3 randomly selected days during the weeks of 30, 60, and 90 days post discharge. Nutrient intake was estimated using Nutrition Data System for Research software. Adequate energy and protein intake were defined as 30 kcal/kg/d and 1.2 g/kg/d, respectively. Dietary Reference Intakes (DRIs) were used for other nutrients. Results Less than half of patients met the requirements for energy, protein, and 12 micronutrients from food intake alone during the study. Energy and protein intakes from food were not diminished relative to placebo. Considering nutrient intake from both food and S‐ONS, 50% and 71% of patients receiving S‐ONSs met energy and protein goals respectively at 90 days (compared with 29% and 36%, in the placebo group), and 100% met the DRI for total carbohydrate, iron, phosphorus, copper, selenium, thiamin, and riboflavin at all time points, all of which were consumed at higher amounts vs placebo. Conclusion Three months of S‐ONS consumption increases intake of numerous nutrients without decreasing nutrient intake from food in older malnourished adults post discharge.

Recent evidence indicates that the gut microbiome can influence brain and behavior, including cognition. Approximately one-third of cancer survivors report cognitive impairments after receiving chemotherapy. Many of these cancer patients also experience adverse effects on their gut, including diarrhea and vomiting, along with a shift in community structure of their natural gut microbiota. However, very little is known about the potential role of the gut microbiome in the enduring and prevalent consequences of chemotherapy on the brain and cognitive function. The present hypothesis is that chemotherapy shifts composition in the gut microbiota, leading to neuroinflammation and cognitive impairments. Here, half of the adult Balb/c female mice received 6 doses of paclitaxel chemotherapy (30 mg/kg; i.p.; every other day); the others received vehicle (n = 5–10/group). Immediately or 2 weeks after chemotherapy, cognition was assessed by fear conditioning and tissues were collected to assess neuroinflammation and 16S fecal microbial profiles. These preliminary data suggest that chemotherapy treatment impaired cued conditioning and decreased diversity of fecal microbial taxa (marked by increased abundance of Turicibacter species), which was correlated with brain inflammatory markers. Paclitaxel also increased gut and spleen masses, while altering transcript expression of genes necessary for paclitaxel excretion in both the brain and the colon. These results suggest that the gut microbiota may exert indirect effects of chemotherapy on the brain, thereby potentiating behavioral comorbidities.

Current population-based methods for assessing dietary intake, including food frequency questionnaires, food diaries, and 24-h dietary recall, are limited in their ability to objectively measure food intake. Digital photography has been identified as a promising addition to these techniques but has rarely been assessed in self-serve settings. We utilized digital photography to examine university students' food choices and consumption in a self-serve dining hall setting. Research assistants took pre- and post-photos of students' plates during lunch and dinner to assess selection (presence), servings, and consumption of MyPlate food groups. Four coders rated the same set of approximately 180 meals for inter-rater reliability analyses; approximately 50 additional meals were coded twice by each coder to assess intra-rater agreement. Inter-rater agreement on the selection, servings, and consumption of food groups was high at 93.5%; intra-rater agreement was similarly high with an average of 95.6% agreement. Coders achieved the highest rates of agreement in assessing if a food group was present on the plate (95-99% inter-rater agreement, depending on food group) and estimating the servings of food selected (81-98% inter-rater agreement). Estimating consumption, particularly for items such as beans and cheese that were often in mixed dishes, was more challenging (77-94% inter-rater agreement). Results suggest that the digital photography method presented is feasible for large studies in real-world environments and can provide an objective measure of food selection, servings, and consumption with a high degree of agreement between coders; however, to make accurate claims about the state of dietary intake in all-you-can-eat, self-serve settings, researchers will need to account for the possibility of diners taking multiple trips through the serving line.

The objective of this study was to examine the relationship between microbial composition, gene abundance, and corresponding short-chain fatty acid (SCFA) concentration in piglets with SBS fed pre- and/or probiotics. We hypothesized that prebiotic consumption would increase the abundance of butyrogenic bactria, butyryl-CoA transferase DNA (BCoAT), and butyrate concentration while attenuating acetogens, acetyl-CoA synthase DNA (ACS), and acetate concentration. Neonatal piglets (n=70) underwent 80% jejunoileal resection and placement of a jugular catheter. Piglets received 80% parenteral and 20% enteral nutrition (EN) for 1, 3, or 7 days (d). Control piglets (CON) received unsupplemented EN, prebiotic (PRE) 10 g short-chain fructooligosaccharides/L EN (scFOS), probiotic (PRO) 1E9 CFU LGG, and synbiotic (SYN) scFOS + LGG. BCoAT was increased by PRE on ileal mucosa at 7d and by PRO in ileal lumen at 3d and 7d (p=0.05). PRE increased butyrate concentration vs CON independent of time (p=0.05). However, BCoAT ab...