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Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation.
Banerjee A, Herring CA, Chen B, Kim H, Simmons AJ, Southard-Smith AN, Allaman MM, White JR, Macedonia MC, Mckinley ET, Ramirez-Solano MA, Scoville EA, Liu Q, Wilson KT, Coffey RJ, Washington MK, Goettel JA, Lau KS
(2020) Gastroenterology 159: 2101-2115.e5
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Chemoreceptor Cells, Crohn Disease, DNA, Bacterial, Disease Models, Animal, Feces, Female, Gastrointestinal Microbiome, Humans, Ileitis, Ileum, Intestinal Mucosa, Male, Mice, Mice, Knockout, Protective Factors, RNA, Ribosomal, 16S, RNA-Seq, Single-Cell Analysis, Succinic Acid
Show Abstract · Added September 17, 2020
BACKGROUND & AIMS - Countries endemic for parasitic infestations have a lower incidence of Crohn's disease (CD) than nonendemic countries, and there have been anecdotal reports of the beneficial effects of helminths in CD patients. Tuft cells in the small intestine sense and direct the immune response against eukaryotic parasites. We investigated the activities of tuft cells in patients with CD and mouse models of intestinal inflammation.
METHODS - We used microscopy to quantify tuft cells in intestinal specimens from patients with ileal CD (n = 19), healthy individuals (n = 14), and TNF mice, which develop Crohn's-like ileitis. We performed single-cell RNA sequencing, mass spectrometry, and microbiome profiling of intestinal tissues from wild-type and Atoh1-knockout mice, which have expansion of tuft cells, to study interactions between microbes and tuft cell populations. We assessed microbe dependence of tuft cell populations using microbiome depletion, organoids, and microbe transplant experiments. We used multiplex imaging and cytokine assays to assess alterations in inflammatory response following expansion of tuft cells with succinate administration in TNF and anti-CD3E CD mouse models.
RESULTS - Inflamed ileal tissues from patients and mice had reduced numbers of tuft cells, compared with healthy individuals or wild-type mice. Expansion of tuft cells was associated with increased expression of genes that regulate the tricarboxylic acid cycle, which resulted from microbe production of the metabolite succinate. Experiments in which we manipulated the intestinal microbiota of mice revealed the existence of an ATOH1-independent population of tuft cells that was sensitive to metabolites produced by microbes. Administration of succinate to mice expanded tuft cells and reduced intestinal inflammation in TNF mice and anti-CD3E-treated mice, increased GATA3 cells and type 2 cytokines (IL22, IL25, IL13), and decreased RORGT cells and type 17 cytokines (IL23) in a tuft cell-dependent manner.
CONCLUSIONS - We found that tuft cell expansion reduced chronic intestinal inflammation in mice. Strategies to expand tuft cells might be developed for treatment of CD.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Fecal metagenomics and metabolomics reveal gut microbial changes after bariatric surgery.
Yu D, Shu XO, Howard EF, Long J, English WJ, Flynn CR
(2020) Surg Obes Relat Dis 16: 1772-1782
MeSH Terms: Bariatric Surgery, Female, Gastric Bypass, Gastrointestinal Microbiome, Humans, Male, Metabolomics, Metagenomics, Middle Aged, Pilot Projects
Show Abstract · Added August 18, 2020
BACKGROUND - Evidence from longitudinal patient studies regarding gut microbial changes after bariatric surgery is limited.
OBJECTIVE - To examine intraindividual changes in fecal microbiome and metabolites among patients undergoing Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
SETTING - Observational study.
METHODS - Twenty patients were enrolled and provided stool samples before and 1 week, 1 month, and/or 3 months after surgery. Shallow shotgun metagenomics and untargeted fecal metabolomics were performed. Zero-inflated generalized additive models and linear mixed models were applied to identify fecal microbiome and metabolites changes, with adjustment for potential confounders and correction for multiple testing.
RESULTS - We enrolled 16 women and 4 men, including 16 white and 4 black participants (median age = 45 years; presurgery body mass index = 47.7 kg/m). Ten patients had Roux-en-Y gastric bypass, 10 had vertical sleeve gastrectomy, and 14 patients provided postsurgery stool samples. Of 47 samples, median sequencing depth was 6.3 million reads and 1073 metabolites were identified. Microbiome alpha-diversity increased after surgery, especially at 3 months. Significant genus-level changes included increases in Odoribacter, Streptococcus, Anaerotruncus, Alistipes, Klebsiella, and Bifidobacterium, while decreases in Bacteroides, Coprocosccus, Dorea, and Faecalibacterium. Large increases in Streptococcus, Akkermansia, and Prevotella were observed at 3 months. Beta-diversity and fecal metabolites were also changed, including reduced caffeine metabolites, indoles, and butyrate.
CONCLUSIONS - Despite small sample size and missing repeated samples in some participants, our pilot study showed significant postsurgery changes in fecal microbiome and metabolites among bariatric surgery patients. Future large-scale, longitudinal studies are warranted to investigate gut microbial changes and their associations with metabolic outcomes after bariatric surgery.
Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.
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10 MeSH Terms
Gut Epithelial Metabolism as a Key Driver of Intestinal Dysbiosis Associated with Noncommunicable Diseases.
Shelton CD, Byndloss MX
(2020) Infect Immun 88:
MeSH Terms: Animals, Colon, Disease Susceptibility, Dysbiosis, Energy Metabolism, Enterobacteriaceae, Gastrointestinal Microbiome, Humans, Intestinal Mucosa, Noncommunicable Diseases, Obesity, Oxidation-Reduction, Risk Assessment, Risk Factors
Show Abstract · Added March 30, 2020
In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent β-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic , regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.
Copyright © 2020 American Society for Microbiology.
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14 MeSH Terms
Maternal microbial molecules affect offspring health.
Ferguson J
(2020) Science 367: 978-979
MeSH Terms: Animals, Child, Child Health, Diet, High-Fat, Female, Gastrointestinal Microbiome, Mice, Obesity, Phenotype, Pregnancy
Added March 3, 2020
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10 MeSH Terms
Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria.
Cevallos SA, Lee JY, Tiffany CR, Byndloss AJ, Johnston L, Byndloss MX, Bäumler AJ
(2019) mBio 10:
MeSH Terms: Aerobiosis, Animals, Carcinogenesis, Colitis, Colorectal Neoplasms, Dextran Sulfate, Escherichia coli, Escherichia coli Infections, Female, Gastrointestinal Microbiome, Mice, Mice, Inbred C57BL, Oxygen, Peptides, Polyketides
Show Abstract · Added March 30, 2020
Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota. One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing , a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.
Copyright © 2019 Cevallos et al.
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15 MeSH Terms
Utilizing Untargeted Ion Mobility-Mass Spectrometry To Profile Changes in the Gut Metabolome Following Biliary Diversion Surgery.
Poland JC, Schrimpe-Rutledge AC, Sherrod SD, Flynn CR, McLean JA
(2019) Anal Chem 91: 14417-14423
MeSH Terms: Anastomosis, Surgical, Animals, Bile Acids and Salts, Bile Ducts, Cholesterol, Chromatography, Liquid, Duodenum, Fatty Acids, Volatile, Feces, Gastrointestinal Microbiome, Ileum, Jejunum, Male, Mass Spectrometry, Mice, Inbred C57BL
Show Abstract · Added December 17, 2019
Obesity and obesity-related disorders are a global epidemic affecting over 10% of the world's population. Treatment of these diseases has become increasingly challenging and expensive. The most effective and durable treatment for Class III obesity (body mass index ≥35 kg/m) is bariatric surgery, namely, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy. These procedures are associated with increased circulating bile acids, molecules that not only facilitate intestinal fat absorption but are also potent hormones regulating numerous metabolic pathways. We recently reported on a novel surgical procedure in mice, termed distal gallbladder bile diversion to the ileum (GB-IL), that emulates the altered bile flow after RYGB without other manipulations of gastrointestinal anatomy. GB-IL improves oral glucose tolerance in mice made obese with high-fat diet. This is accompanied by fat malabsorption and weight loss, which complicates studying the role of elevated circulating bile acids in metabolic control. A less aggressive surgery in which the gallbladder bile is diverted to the proximal ileum, termed GB-IL, also improves glucose control but is not accompanied by fat malabsorption. To better understand the differential effects achieved by these bile diversion procedures, an untargeted ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) method was optimized for fecal samples derived from mice that have undergone bile diversion surgery. Utilizing the UPLC-IM-MS method, we were able to identify dysregulation of bile acids, short-chain fatty acids, and cholesterol derivatives that contribute to the differential metabolism resulting from these surgeries.
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15 MeSH Terms
Gut Microbiome and Response to Cardiovascular Drugs.
Tuteja S, Ferguson JF
(2019) Circ Genom Precis Med 12: 421-429
MeSH Terms: Animals, Bacteria, Biotransformation, Cardiovascular Agents, Gastrointestinal Microbiome, Gastrointestinal Tract, Humans
Show Abstract · Added March 3, 2020
The gut microbiome is emerging as an important contributor to both cardiovascular disease risk and metabolism of xenobiotics. Alterations in the intestinal microbiota are associated with atherosclerosis, dyslipidemia, hypertension, and heart failure. The microbiota have the ability to metabolize medications, which can results in altered drug pharmacokinetics and pharmacodynamics or formation of toxic metabolites which can interfere with drug response. Early evidence suggests that the gut microbiome modulates response to statins and antihypertensive medications. In this review, we will highlight mechanisms by which the gut microbiome facilitates the biotransformation of drugs and impacts pharmacological efficacy. A better understanding of the complex interactions of the gut microbiome, host factors, and response to medications will be important for the development of novel precision therapeutics for targeting CVD.
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7 MeSH Terms
Targeting Gut Microbiome Interactions in Service-Related Gastrointestinal and Liver Diseases of Veterans.
Bajaj JS, Sharma A, Dudeja PK, Collaborators
(2019) Gastroenterology 157: 1180-1183.e1
MeSH Terms: Biomedical Research, Gastroenterology, Gastrointestinal Diseases, Gastrointestinal Microbiome, Humans, Liver Diseases, United States, United States Department of Veterans Affairs, Veterans Health, Veterans Health Services
Added October 29, 2019
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10 MeSH Terms
Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer.
Zhu W, Miyata N, Winter MG, Arenales A, Hughes ER, Spiga L, Kim J, Sifuentes-Dominguez L, Starokadomskyy P, Gopal P, Byndloss MX, Santos RL, Burstein E, Winter SE
(2019) J Exp Med 216: 2378-2393
MeSH Terms: Animals, Colitis, Colorectal Neoplasms, Dextran Sulfate, Dysbiosis, Escherichia coli, Gastrointestinal Microbiome, Interleukin-10, Mice, Neoplasms, Experimental
Show Abstract · Added March 30, 2020
Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited molybdoenzymes and selectively decreased gut colonization with genotoxin-producing and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, -deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.
© 2019 Zhu et al.
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10 MeSH Terms
High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension.
Ferguson JF, Aden LA, Barbaro NR, Van Beusecum JP, Xiao L, Simmons AJ, Warden C, Pasic L, Himmel LE, Washington MK, Revetta FL, Zhao S, Kumaresan S, Scholz MB, Tang Z, Chen G, Reilly MP, Kirabo A
(2019) JCI Insight 5:
MeSH Terms: Adolescent, Adoptive Transfer, Adult, Angiotensin II, Animals, Aorta, Bacteria, Blood Pressure, CD11c Antigen, Colon, Cytokines, Dendritic Cells, Disease Models, Animal, Dysbiosis, Female, Gastrointestinal Microbiome, Humans, Hypertension, Inflammation, Lipids, Lymph Nodes, Male, Mice, Mice, Inbred C57BL, Middle Aged, Myeloid Cells, Peyer's Patches, RNA, Ribosomal, 16S, Sodium Chloride, Sodium Chloride, Dietary, Young Adult
Show Abstract · Added March 3, 2020
Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen presenting cells including dendritic cells (DCs) play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG-adduct formation in myeloid antigen presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high salt diets. In humans and mice, high salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a sub-pressor dose of angiotensin II. Mice fed a high salt diet exhibited increased intestinal inflammation including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG-protein adducts in CD11c+ myeloid cells. Adoptive transfer of fecal material from conventionally housed high salt-fed mice to germ-free mice predisposed them to increased intestinal inflammation and hypertension. These findings provide novel insight into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.
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31 MeSH Terms