Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

Nature, Journal Year: 2019, Volume and Issue: 569(7758), P. 655 - 662

Published: May 29, 2019

Abstract Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. colitis are complex diseases that heterogeneous at the clinical, immunological, molecular, genetic, microbial levels. Individual contributing factors have been focus of extensive research. As part Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles host activity during (up 24 time points each; in total 2,965 stool, biopsy, blood specimens). Here present results, provide a comprehensive view functional dysbiosis gut microbiome inflammatory activity. We demonstrate characteristic increase facultative anaerobes expense obligate anaerobes, as well disruptions transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, short-chain fatty acids), levels antibodies serum. Periods were also marked by increases temporal variability, with taxonomic, functional, biochemical shifts. Finally, integrative analysis identified microbial, biochemical, central this dysregulation. The study’s infrastructure resources, data, available through Bowel Disease Multi’omics Database ( http://ibdmdb.org ), most description date activities diseases.

Language: Английский

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Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2017, Volume and Issue: 15(2), P. 111 - 128

Published: Oct. 11, 2017

Language: Английский

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Consequences of bile salt biotransformations by intestinal bacteria

Gut Microbes, Journal Year: 2016, Volume and Issue: 7(1), P. 22 - 39

Published: Jan. 2, 2016

Emerging evidence strongly suggest that the human "microbiome" plays an important role in both health and disease. Bile acids function as detergents molecules promoting nutrient absorption intestines hormones regulating metabolism. regulate metabolism via activation of specific nuclear receptors (NR) G-protein coupled (GPCRs). The circulating bile acid pool composition consists primary produced from cholesterol liver, secondary formed by gut bacteria. various biotransformation carried out bacteria appear to structure microbiome host physiology. Increased levels are associated with diseases GI system. Elucidating methods control humans may lead a reduction some major gall bladder colon.

Language: Английский

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Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives

Hepatology, Journal Year: 2016, Volume and Issue: 65(1), P. 350 - 362

Published: June 30, 2016

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic cardiometabolic mortality. The rapidly increasing prevalence of this its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent progression advanced fibrosis or cirrhosis cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at extrahepatic tissues regulate lipid carbohydrate metabolic pathways well energy homeostasis. Activation modulation acid receptors, such the farnesoid X receptor TGR5, transporters, ileal apical sodium-dependent transporter, appear affect insulin sensitivity NAFLD/NASH pathogenesis multiple levels, these hold promise therapies. present review, we summarize current available data on relationships NAFLD potential therapeutically targeting bile-acid-related address growing world-wide disease. (Hepatology 2017;65:350-362).

Language: Английский

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Bile acids and the gut microbiota: metabolic interactions and impacts on disease

Nature Reviews Microbiology, Journal Year: 2022, Volume and Issue: 21(4), P. 236 - 247

Published: Oct. 17, 2022

Language: Английский

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Review: microbial transformations of human bile acids

Microbiome, Journal Year: 2021, Volume and Issue: 9(1)

Published: June 14, 2021

Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition. While the liver is responsible for production of primary bile acids, microbes modify these compounds into myriad forms that greatly increase their diversity biological function. Since early 1960s, have been known to transform human four distinct ways: deconjugation amino glycine or taurine, dehydroxylation, dehydrogenation, epimerization cholesterol core. Alterations chemistry secondary linked several diseases, such as cirrhosis, inflammatory bowel disease, cancer. In addition previously transformations, a recent study has shown members our microbiota are also able conjugate representing new set "microbially conjugated acids." This finding influences mammalian gut, but effects on host physiology microbial dynamics mostly unknown. review focuses discoveries investigating mechanisms explores chemical may exist acid structures light discovery conjugations. Video Abstract.

Language: Английский

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Regulation of Intestinal Barrier Function by Microbial Metabolites

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2021, Volume and Issue: 11(5), P. 1463 - 1482

Published: Jan. 1, 2021

The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics gut microbiota remain to be explored in various health and disease conditions. Microbiota generate variety metabolites from dietary products influence functions. Since are produced close proximity epithelium, presumably they have significant impact on barrier function immune goal this review is discuss recent advances regulation intestinal function. While mechanisms action these only beginning emerge, mainly point small group shared pathways control Amidst expanding technology broadening knowledge, exploitation beneficial their restore balance will likely prove an extremely useful remedial tool. SummaryGut proximal regulate numerous responsive activities. Current article highlights area as well potential translational applications regulating disorders. Gut Humans microbes coevolved over millions years, thereby contributing interdependency physiological activities.1Li M. Wang B. Zhang Rantalainen S. Zhou H. Y. Shen J. Pang X. Wei Chen Lu Zuo Su Qiu Jia W. Xiao C. Smith L.M. Yang Holmes E. Tang Zhao G. Nicholson J.K. Li L. Symbiotic modulate metabolic phenotypes.Proc Natl Acad Sci U S A. 2008; 105: 2117-2122Crossref PubMed Scopus (755) Google Scholar Diverse interactive associations cells lead mild severe cellular molecular responses depending status Deciphering underlying relationship between community provides unique opportunity utilize prevent treat disorders maintain overall health. Increasing culture-independent omic-based technologies such biomarker sequencing, metagenomics, metatranscriptomics, metaproteomics, metabolomics facilitated discovery novel microbiota2Oh Byrd A.L. Deming Conlan Program N.C.S. Kong H.H. Segre J.A. Biogeography individuality shape skin metagenome.Nature. 2014; 514: 59-64Crossref (442) Scholar, 3Lynch S.V. Pedersen O. microbiome disease.N Engl J Med. 2016; 375: 2369-2379Crossref (879) 4Human Microbiome Project CStructure, diversity healthy microbiome.Nature. 2012; 486: 207-214Crossref (5255) 5Eckburg P.B. Bik E.M. Bernstein C.N. Purdom Dethlefsen Sargent Gill S.R. Nelson K.E. Relman D.A. Diversity flora.Science. 2005; 308: 1635-1638Crossref (4674) with pathophysiology.6Kamada N. G.Y. Inohara Nunez Control pathogens pathobionts by microbiota.Nat Immunol. 2013; 14: 685-690Crossref (662) 7Ha C.W. Lam Y.Y. A.J. Mechanistic links dynamics, functions health.World Gastroenterol. 20: 16498-16517Crossref 8Wu Tremaroli V. Backhed F. Linking diseases: systems biology perspective.Trends Endocrinol Metab. 2015; 26: 758-770Abstract Full Text PDF (87) 9Claesson M.J. Jeffery I.B. Conde Power S.E. O'Connor Cusack Harris H.M. Coakley Lakshminarayanan O'Sullivan Fitzgerald G.F. Deane Harnedy K. O'Mahony D. van Sinderen Wallace Brennan Stanton Marchesi J.R. A.P. Shanahan Hill Ross R.P. O'Toole P.W. composition correlates diet elderly.Nature. 488: 178-184Crossref (1618) (∼1012–1013) play important role homeostatic leading activities both disease. significantly separates internal organs harmful entities including microorganisms, luminal antigens, proinflammatory factors. Intestinal compromised (barrier dysfunction) several conditions increased translocation bacteria, endotoxins, other inflammatory mediators. dysfunction associated systemic response resulting aggravation diseases. Recent studies shown correlation bowel (IBD), irritable syndrome (IBS), celiac also strongly correlated autoimmune, inflammatory, diseases diabetes, obesity, atherosclerosis, heart failure, hypertension, food allergies, cancer.10Gopalakrishnan Helmink B.A. Spencer Reuben Wargo cancer, immunity, cancer immunotherapy.Cancer Cell. 2018; 33: 570-580Abstract (267) Scholar,11Martini Krug S.M. Siegmund Neurath M.F. Becker Mend your fences: epithelial its mucosal immunity disease.Cell Mol Gastroenterol Hepatol. 2017; 4: 33-46Abstract It has been reported external factors like alcohol, nonsteroidal anti-inflammatory drugs, specific can directly alter pathogenesis diseases.12Elamin Masclee Troost Pieters H.J. Keszthelyi Aleksa Dekker Jonkers Ethanol impairs humans through mitogen activated protein kinase signaling: combined vivo vitro approach.PLoS One. 9e107421Crossref (24) 13Utzeri Usai P. Role non-steroidal drugs permeability nonalcoholic fatty liver disease.World 23: 3954-3963Crossref 14Berkes Viswanathan V.K. Savkovic S.D. Hecht enteric pathogens: effects tight junction barrier, ion transport, inflammation.Gut. 2003; 52: 439-451Crossref (394) imbalance (microbial dysbiosis) linked immature system, wide spectrum intestinal, hepatic, neurological disorders.15Bjarnason I. MacPherson Hollander permeability: overview.Gastroenterology. 1995; 108: 1566-1581Abstract (744) 16Leclercq Matamoros Cani P.D. Neyrinck A.M. Jamar Starkel Windey Verbeke de Timary Delzenne N.M. permeability, gut-bacterial dysbiosis, behavioral markers alcohol-dependence severity.Proc 111: E4485-E4493Crossref (339) 17Gonzalez-Gonzalez Diaz-Zepeda Eyzaguirre-Velasquez Gonzalez-Arancibia Bravo Julio-Pieper Investigating animal models disease.Front Physiol. 9: 1962Crossref (5) 18Frank D.N. St Amand Feldman R.A. Boedeker E.C. Harpaz Pace N.R. Molecular-phylogenetic characterization imbalances diseases.Proc 2007; 104: 13780-13785Crossref (2631) Studies revealed fecal transplantation (FMT) hosts positively reversal, especially those stemming IBD, IBS, disease, Clostridium difficile infections.19Moayyedi Surette M.G. Kim P.T. Libertucci Wolfe Onischi Armstrong Marshall Kassam Z. Reinisch Lee C.H. Fecal induces remission patients active ulcerative colitis randomized controlled trial.Gastroenterology. 149: 102-109.e6Abstract (706) Scholar,20Kim Gadani Abdul-Baki Mitre R. recurrent infection: retrospective single-center chart review.JGH Open. 2019; 3: 4-9Crossref (9) One major metabolism components generation physiology function.21Maurice C.F. Haiser Turnbaugh P.J. Xenobiotics gene expression microbiome.Cell. 152: 39-50Abstract (468) restoration separate cell functions.22Singh Chandrashekharappa Bodduluri Baby B.V. Hegde Kotla N.G. Hiwale A.A. Saiyed T. Patel Vijay-Kumar Langille M.G.I. Douglas G.M. Cheng Rouchka Waigel S.J. Dryden G.W. Alatassi H.G. Haribabu Vemula P.K. Jala V.R. Enhancement integrity metabolite Nrf2 pathway.Nat Commun. 10: 89Crossref (108) 23Ewaschuk J.B. Diaz Meddings Diederichs Dmytrash Backer Looijer-van Langen Madsen K.L. Secreted bioactive Bifidobacterium infantis enhance function.Am Physiol Gastrointest Liver 295: G1025-G1034Crossref (359) 24Anderson R.C. Cookson McNabb W.C. Park McCann Kelly W.J. Roy N.C. Lactobacillus plantarum MB452 enhances increasing levels genes involved formation.BMC Microbiol. 2010; 316Crossref (210) Detailed yet elucidated, but knowledge concerning system gradually. Exploiting tool against In review, we how reinforce via bi-directional interactions cells. Further, treatment strategies mitigate composed 3 main interlinked/interdependent layers physical bacterial intrusion lumen. These include mucus layer, layer formed continuous sheet cells, third, forms system. acts immunological defense viruses, environmental toxins. selectively permeable allow for essential nutrients, electrolytes, amino acids, short-chain acids (SCFAs), sugars, water, select lumen into circulation. single interspersed functionally specialized differentiated enterocytes, Paneth goblet tuft enteroendocrine microfold which together form polarized monolayer separation lamina propria (Table 1). Among these, present intestine, whereas intestine colon, reviewed previously.25Peterson L.W. Artis cells: regulators homeostasis.Nat Rev 141-153Crossref (1145) 26Okumura Takeda Roles maintenance homeostasis.Exp 49: e338Crossref 27Allaire J.M. Crowley Law H.T. Chang S.-Y. Ko H.-J. Vallance epithelium: central coordinator immunity.Trends 39: 677-696Abstract (159) layer28Corfield interaction human.Microorganisms. 6: 78Crossref Scholar,29Corfield Carroll Myerscough Probert C.S. Mucins Biosci. 2001; D1321-D1357Crossref different types distinct roles maintaining homeostasis.Table 1Cell Types Barrier Their FunctionCell typesRole functionEnterocytes (small colon)•Responsible junctional complexes.•Nutrient absorption metabolization.•Balance shedding.•Secretion antimicrobial agents.•Changes expression/localization proteins permeability.Paneth intestine)•Source AMPs.•Directly sense critical homeostasis.•Paneth triggers inflammation dysfunction.•Lack leads necrotizing enterocolitis mice.Goblet intestine)•Produce release MUCs, forming glycoprotein barrier.•Lack MUC2 or O-glycan N-glycosylation susceptibility colitis.Tuft colon)•Secrete IL-25 IL-13 type 2 innate lymphoid (ILC2) promote hyperplasia mucin production.•Detect helminth infection expulse.Enteroendocrine colon)•Secret hormones GLP-2.•GLP-2 TJ ZO-1 occludin attenuates TNF-α–induced changes colon cells.•GLP-2 wound healing TGF-β–dependent manner.M intestine)•Antigen uptake.•M damage, during chronic elevates uptake microorganisms amplifying condition dysfunction.AMP, peptide; GLP-2, glucagon-like peptide-2; M cell, cell; MUC, mucin; TGF-β, transforming growth factor beta; TJ, junction; TNF-α, tumor necrosis alpha. Open table new tab AMP, (IECs) selective penetration electrolytes while simultaneously excluding pathogen-associated pattern, toxins, foreign antigens.30Kunzelmann Mall Electrolyte transport mammalian colon: implications disease.Physiol Rev. 2002; 82: 245-289Crossref Enterocytes connect each adhesive make up (TJ) proteins, adherens (AJ) gap desmosomes 2).31Niessen C.M. Tight junctions/adherens junctions: basic structure function.J Invest Dermatol. 127: 2525-2532Abstract (410) Scholar,32Groschwitz K.R. Hogan S.P. function: pathogenesis.J Allergy Clin 2009; 124 (quiz 21–22): 3-20Abstract (766) complexes not mechanically secure extracellular interactions, intracellular adaptor protein–mediated within Epithelial tightly paracellular (space cells) transcellular (through cell) posttranslational modifications proteins.33Van Itallie Anderson Claudins transport.Annu 2006; 68: 403-429Crossref (837) 34Fung K.Y.Y. Fairn G.D. W.L. Transcellular vesicular endothelial challenges opportunities.Traffic. 19: 5-18Crossref (47) 35Shigetomi Ikenouchi Regulation post-translational membrane proteins.J Biochem. 163: 265-272Crossref (0) located apical side belt-like ring at lateral membrane. consist 50 crucial cell-to-cell adhesion health.36Chiba Osanai Murata Kojima Sawada Transmembrane junctions.Biochim Biophys Acta. 1778: 588-600Crossref (276) Some tetraspan single-span transmembrane link cytoskeletal proteins.37Schulzke J.D. Fromm meets function.Ann N Y Sci. 1165: 1-6Crossref (1) (OCLN), claudin (CLDN), tricellulin molecules proteins.38Furuse Hirase Itoh Nagafuchi Yonemura Tsukita Occludin: integral localizing junctions.J Cell Biol. 1993; 123: 1777-1788Crossref (1975) 39Furuse Fujita Hiiragi Fujimoto Claudin-1 -2: junctions no sequence similarity occludin.J 1998; 141: 1539-1550Crossref (1554) 40Ikenouchi Furuse Sasaki Tricellulin constitutes tricellular contacts cells.J 171: 939-945Crossref (535) 41Garrido-Urbani Bradfield P.F. Imhof dynamics: (JAMs).Cell Tissue Res. 355: 701-715Crossref (64) Other zonula occludens (ZO) (ZO-1, ZO-2, ZO-3) scaffold proteins. postsynaptic density protein-95/Drosophila disc large suppressor/ZO-1 (PDZ) binding domains plaque (eg, F-actin) complex.42Odenwald M.A. Choi Kuo W.T. Singh Sailer Fanning A.S. Turner scaffolding coordinates actomyosin specializations vivo.J Biol Chem. 293: 17317-17335Abstract (20) seals generally when anastomose adjacent based size/charge space. Adherence primarily contribute mechanical structures, properties, extensively elsewhere.43Garcia-Hernandez Quiros Nusrat claudins: homeostasis inflammation.Ann 1397: 66-79Crossref (104) 44Laukoetter Bruewer complex.Curr Opin 22: 85-89Crossref (173) 45Buckley disease.Cold Spring Harb Perspect A02931Crossref (110) 46Farkas A.E. Pharmacological targeting inflamed barrier.Curr Pharm Des. 5400-5414Crossref (3) 47Choi Yeruva Contributions barriers disease.Exp 358: 71-77Crossref (29) 48Zuo targets effectors homeostasis.Cell 2020; 327-340Abstract ScholarTable 2Structural Components Cells FunctionStructural componentsJunctional proteinsExamples dysfunctionTight proteinsZO, occludin, claudins, tricellulin, JAM•IFN-γ TNF-α mediated organization ZO-1, claudin-1, claudin-4, occluding, JAM-A downregulate function.•Downregulation claudin-3, claudin-5, claudin-8 claudin-2 MLCK phosphorylation function.Adherens proteinsCadherins, catenins•Downregulated E-cadherin–catenin complex mediates impairment barrier.DesmosomeDesmoglein, desmocollins•Desmoglein (Dsg2) deficiency loss integrity.Gap junctionsConnexin•Connexin-43 plays intercellular communication vesicles, tunneling nanotubes junctions.IFN-γ, interferon gamma; JAM, molecules; MLCK, myosin light-chain kinase; alpha; ZO, occludens. IFN-γ, disruption AJ, causing dysregulated translocation/transportation mediators, potentially manifests inflammation. Increased further perpetuates permeability. following sections describe altered state Defective combination dysregulation tract–related limited drug-induced toxicity, cancer. occurs apoptosis/enterocyte death, degradation, due TJs. independently regulated consequences other. section describes responsible dysfunction. As described previous sections, was solutes water cross TJs size charge selectivity: pore pathway48Zuo 49Turner disease.Nat 799-809Crossref (1727) 50Anderson Van Physiology junction.Cold 1: a002584Crossref (563) leak pathway.48Zuo Scholar,51Buschmann M.M. Rajapakse Raleigh D.R. Lingaraju Zha Abbott McAuley Breskin L.A. Wu Weber C.R. Occludin OCEL-domain required macromolecular flux.Mol 24: 3056-3068Crossref (94) pathway exclusively excludes diameter ≤8 Å high-conductance route. CLDN-2 CLDNs 10a, 10b, 15, 16, 17 were pathway. contrast pathway, allows macromolecule flux exclusion limit ∼100 lower conductance.51Buschmann believed (MLCK), where constitutively sufficient increase pathway–dependent vivo.52Shen Black E.D. Witkowski Lencer W.I. Guerriero Schneeberger E.E. Myosin light chain regulates remodeling structure.J 119: 2095-2106Crossref (308) Scholar,53Su Clayburgh Nalle S.C. Sullivan E.A. Abraham Targeted causes activation contributes development experimental colitis.Gastroenterology. 136: 551-563Abstract (273) OCLN, pathway.54Yu McCarthy K.M. Francis S.A. McCormack Lai Rogers Lynch R.D. Knockdown phenotypic alterations cells.Am 288: C1231-C1241Crossref (239) discussions published.48Zuo Scholar,49Turner 9

Language: Английский

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Microbial modulation of cardiovascular disease

Nature Reviews Microbiology, Journal Year: 2018, Volume and Issue: 16(3), P. 171 - 181

Published: Jan. 8, 2018

Language: Английский

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Gut microbiota derived metabolites in cardiovascular health and disease

Protein & Cell, Journal Year: 2018, Volume and Issue: 9(5), P. 416 - 431

Published: May 1, 2018

Trillions of microbes inhabit the human gut, not only providing nutrients and energy to host from ingested food, but also producing metabolic bioactive signaling molecules maintain health elicit disease, such as cardiovascular disease (CVD). CVD is leading cause mortality worldwide. In this review, we presented gut microbiota derived metabolites involved in including trimethylamine-N-oxide (TMAO), uremic toxins, short chain fatty acids (SCFAs), phytoestrogens, anthocyanins, bile lipopolysaccharide. These play critical roles maintaining a healthy function, if dysregulated, potentially causally linked CVD. A better understanding function dynamics holds great promise toward mechanistic predicative biomarker discoveries precise interventions.

Language: Английский

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Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease

PLoS ONE, Journal Year: 2016, Volume and Issue: 11(5), P. e0151829 - e0151829

Published: May 20, 2016

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM) and bile acids (BA) suggest that dysbiosis may be accompanied an altered acid homeostasis, which in turn can contribute to the metabolic dysregulation seen NAFLD. This study sought examine BA homeostasis patients with NAFLD relate IM data. Methods was a prospective, cross-sectional of adults biopsy-confirmed (non-alcoholic liver: NAFL or non-alcoholic steatohepatitis: NASH) healthy controls (HC). Clinical laboratory data, stool samples 7-day food records were collected. Fecal profiles, serum markers synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4) signalling, as well composition assessed. Results 53 subjects included: 25 HC, 12 16 NASH. Levels total fecal BA, cholic (CA), chenodeoxycholic (CDCA) higher NASH compared HC (p<0.05 for all comparisons). primary secondary ratio (p = 0.004), but conjugated unconjugated BAs not different groups. Bacteroidetes Clostridium leptum counts decreased subset after adjusting body mass index weight-adjusted calorie intake 0.028 p 0.030, respectively). C. positively correlated lithocholic (LCA) (r 0.526, 0.003) inversely CA -0.669, p<0.0001) CDCA - 0.630, p<0.0001). FGF19 levels groups 0.114). Conclusions In NAFLD, associated renders them at increased risk hepatic injury.

Language: Английский

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