Reverse metabolomics for the discovery of chemical structures from humans DOI Creative Commons
Emily C. Gentry, Stephanie L. Collins, Morgan Panitchpakdi

et al.

Nature, Journal Year: 2023, Volume and Issue: 626(7998), P. 419 - 426

Published: Dec. 5, 2023

Abstract Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for public datasets to uncover associations. To demonstrate concept, broadly explored multiple classes metabolites humans, including N -acyl amides, fatty acid esters hydroxy acids, bile conjugated acids. Using repository-scale analysis 1,2 , discovered that some acids associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed cholic Glu, Ile/Leu, Phe, Thr, Trp or Tyr increased Crohn’s disease. Several these related structures affected pathways IBD, such interferon-γ production CD4 + T cells 3 agonism pregnane X receptor 4 . Culture bacteria belonging Bifidobacterium Clostridium Enterococcus genera produced amidates. Because searching repositories has only recently become possible, this approach can now be used general strategy discover other animal ecosystems.

Language: Английский

Inflammatory Bowel Diseases (IBD) and the Microbiome—Searching the Crime Scene for Clues DOI
Mirae Lee, Eugene B. Chang

Gastroenterology, Journal Year: 2020, Volume and Issue: 160(2), P. 524 - 537

Published: Nov. 27, 2020

Language: Английский

Citations

457
Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis DOI Creative Commons
Jie Cai, Lulu Sun, Frank J. Gonzalez

et al.

Cell Host & Microbe, Journal Year: 2022, Volume and Issue: 30(3), P. 289 - 300

Published: March 1, 2022

Language: Английский

Citations

432
Gut microbiome, liver immunology, and liver diseases DOI Open Access
Rui Wang, Ruqi Tang, Bo Li

et al.

Cellular and Molecular Immunology, Journal Year: 2020, Volume and Issue: 18(1), P. 4 - 17

Published: Dec. 14, 2020

Language: Английский

Citations

303
Molecular physiology of bile acid signaling in health, disease, and aging DOI
Alessia Perino, Hadrien Demagny, Laura A. Velázquez‐Villegas

et al.

Physiological Reviews, Journal Year: 2020, Volume and Issue: 101(2), P. 683 - 731

Published: Aug. 13, 2020

Several diseases and conditions have been associated with an uncontrolled rise in bile acid (BA) concentrations. This is often the case when tight feedback regulation of BA synthesis compromised to point that BAs become detrimental. their cognate receptors, farnesoid X receptor (FXR) Takeda G-protein 5 (TGR5), however, exert many beneficial roles as they enable tissues adapt environmental, nutritional, physiological cues. Over last two decades, mimetics targeting FXR, TGR5, or both, proven be efficacious alleviating chronic metabolic inflammatory disorders, such obesity, Type 2 diabetes (T2D), atherosclerosis non-alcoholic steatohepatitis (NASH). While several aspects signaling are still poorly understood, first therapeutics FXR making way into clinic treat liver diseases, primary biliary cholangitis (PBC) NASH. Drugs may, hence, a bright future continuing efforts on studying impact changing pathways humans will translate our emerging knowledge physiology model organisms clinical benefits.

Language: Английский

Citations

300
Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD DOI Creative Commons
Giljae Lee,

Hyun Ju You,

Jasmohan S. Bajaj

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Oct. 5, 2020

Abstract Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort used for external validation. Subjects classified into three subgroups according to histological spectra or fibrosis severity. Significant alterations diversity observed severity non-obese, not obese, subjects. Ruminococcaceae Veillonellaceae the main microbiota Furthermore, stool bile acids propionate elevated, especially subjects significant fibrosis. Fibrosis-related species undergo metagenome sequencing, four representative administered mouse models evaluate their effects on damage. This study provides evidence role pathogenesis,

Language: Английский

Citations

290
Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration DOI Creative Commons
Giovanni Sorrentino, Alessia Perino, Ece Yıldız

et al.

Gastroenterology, Journal Year: 2020, Volume and Issue: 159(3), P. 956 - 968.e8

Published: May 30, 2020

Renewal and patterning of the intestinal epithelium is coordinated by stem cells (ISCs); dietary metabolic factors provide signals to niche that control ISC activity. Bile acids (BAs), metabolites in gut, signal nutrient availability activating G protein-coupled bile acid receptor 1 (GPBAR1, also called TGR5). TGR5 expressed epithelium, but it not clear how its activation affects ISCs regeneration epithelium. We studied role BAs renewal, regulation function mice organoids.We derived organoids from wild-type Tgr5-/- mice, incubated them with or agonist INT-777, monitored morphologic analyses colony-forming assays. disrupted Tgr5 specifically Lgr5-positive (Tgr5ISC-/- mice) analyzed number, proliferation, differentiation flow cytometry, immunofluorescence, organoid Tgr5ISC-/- were given cholecystokinin; we measured effects BA release into lumen on cell renewal. induced colitis administration dextran sulfate sodium; disease severity was determined based body weight, colon length, histopathology analysis biopsies.BAs agonists promoted growth organoids. Administration cholecystokinin resulted acute increased proliferation expression required for homeostatic epithelial renewal fate specification, after induction. developed more severe than without disruption ISCs. INT-777 yes-associated protein (YAP1) upstream regulator SRC. Inhibitors YAP1 SRC prevented activation.BAs promote via ISCs, resulting YAP their target genes. Release endogenous sufficient drives response injury.

Language: Английский

Citations

248
Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level DOI Creative Commons
Douglas J. Kenny, Damian R. Plichta, Dmitry Shungin

et al.

Cell Host & Microbe, Journal Year: 2020, Volume and Issue: 28(2), P. 245 - 257.e6

Published: June 15, 2020

Language: Английский

Citations

220
The microbiome in inflammatory bowel diseases: from pathogenesis to therapy DOI Creative Commons
Sheng Liu, Wenjing Zhao, Ping Lan

et al.

Protein & Cell, Journal Year: 2020, Volume and Issue: 12(5), P. 331 - 345

Published: June 29, 2020

ABSTRACT Inflammatory bowel disease (IBD) has become a global with accelerating incidence worldwide in the 21st century while its accurate etiology remains unclear. In past decade, gut microbiota dysbiosis consistently been associated IBD. Although many IBD-associated have not proven to be cause or an effect of IBD, it is often hypothesized that at least some alteration microbiome protective causative. this article, we selectively reviewed hypothesis supported by both association studies human and pathogenesis biological models. Specifically, potential bacterial pathways species against as well causative We also roles members mycobiome virome Lastly, covered current status therapeutic approaches targeting microbiome, which promising strategy alleviate cure inflammatory disease.

Language: Английский

Citations

197
The Gut Microbiome and Inflammatory Bowel Diseases DOI Open Access
Yue Shan, Mirae Lee, Eugene B. Chang

et al.

Annual Review of Medicine, Journal Year: 2021, Volume and Issue: 73(1), P. 455 - 468

Published: Sept. 23, 2021

Inflammatory bowel diseases (IBD) arise from a convergence of genetic risk, environmental factors, and gut microbiota, where each is necessary but not sufficient to cause disease. Emerging evidence supports bidirectional relationship between disease progression changes in microbiota membership function. Thus, the study microbiome host-microbe interactions should provide critical insights into pathogenesis as well leads for developing microbiome-based diagnostics interventions IBD. In this article, we review most recent advances understanding IBD highlight importance going beyond establishing description association gain mechanistic causes consequences The aims contextualize findings form conceptional frameworks etiopathogenesis future development interventions.

Language: Английский

Citations

192
Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers DOI Creative Commons

Jinzhu Mao,

Dongxu Wang, Junyu Long

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2021, Volume and Issue: 9(12), P. e003334 - e003334

Published: Dec. 1, 2021

The gut microbiome is associated with the response to immunotherapy for different cancers. However, impact of on hepatobiliary cancers receiving remains unknown. This study aims investigate relationship between and clinical anti-programmed cell death protein 1 (PD-1) in patients advanced cancers.Patients unresectable hepatocellular carcinoma or biliary tract who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples collected before during anti-PD-1 treatment analyzed metagenomic sequencing. Significantly differentially enriched taxa prognosis identified. Kyoto Encyclopedia Genes Genomes database MetaCyc further applied annotate explore potential mechanism influencing cancer immunotherapy.In total, 65 included this study. Seventy-four significantly benefit (CBR) group 40 non-clinical (NCB) group. Among these taxa, higher abundance Lachnospiraceae bacterium-GAM79 Alistipes sp Marseille-P5997, which CBR group, achieved longer progression-free survival (PFS) overall (OS) than lower abundance. Higher Ruminococcus calidus Erysipelotichaceae bacterium-GAM147 was also observed better PFS. In contrast, worse PFS OS found Veillonellaceae, NCB Functional annotation indicated that energy metabolism while amino acid metabolism, may modulate addition, immunotherapy-related adverse events affected by diversity relative abundance.We demonstrate Taxonomic signatures responders are effective biomarkers predict immunotherapy, might provide a new therapeutic target immunotherapy.

Language: Английский

Citations

189