A microbial metabolite remodels the gut-liver axis following bariatric surgery

Chaudhari, Snehal N.; Luo, James; Harris, David A.; Aliakbarian, Hassan; Yao, Lina; Paik, Donggi; Subramaniam, Renuka; Adhikari, Arijit A.; Vernon, Ashley H.; Kılıç, Ayşe; Weiss, Scott T.; Huh, Jun R.; Sheu, Eric G.; Devlin, A. Sloan

doi:10.1016/j.chom.2020.12.004

Cited by 94 publications

(94 citation statements)

References 72 publications

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“…Once differentiated, these cells form a polarized monolayer that mimics the intestinal epithelium, and this system has been previously used to study the effect of metabolites on gut layer integrity (Scott, Fu, & Chang, 2020). Gut permeability was assayed by measuring FITC-Dextran (4 kDa) permeability through the monolayer and quantifying fluorescence in the basolateral chamber (Chaudhari, Harris, et al, 2021). We found that cecal extracts isolated from CDAHFD-fed rats at 48 hours and 1 week induced increased permeability compared to cecal extracts from control rats (Figure 2A).…”

Section: Conjugated Bas Protect Intestinal Epithelial Monolayers From Unconjugated Ba-mediated Damage In Vitromentioning

confidence: 99%

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Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury

Sojoodi

et al. 2021

Preprint

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Background & Aims: While altered host-microbe interactions are implicated in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), specific contributions of microbially derived metabolites remain obscure. We investigated the impact of altered bile acid (BA) populations on intestinal and hepatic phenotypes in a rodent model of NAFLD/NASH. Methods: Wistar rats fed a choline-deficient high-fat diet (CDAHFD) were assessed for altered intestinal permeability after dietary intervention. Cecal and portal venous BA composition were assessed via mass spectrometry. BA-mediated effects on epithelial permeability were assessed using Caco2 epithelial monolayers. Micelle formation was assessed using fluorescent probes and electron microscopy. Bile salt hydrolase (BSH) activity was inhibited with a gut-restricted small molecule in CDAHFD-fed rats and intestinal and hepatic phenotypes were assessed. Results: Increased intestinal permeability and reduced intestinal conjugated BAs were early phenotypes of CDAHFD-fed rats preceding hepatic disease development. Similar intestinal BA pool changes were observed in rats and human NAFLD/NASH patients with progressive disease. Conjugated BAs protected epithelial layers from unconjugated BA-induced damage via mixed micelle formation. The decrease in intestinal conjugated BAs was mediated by increased activity of bacterial BSHs and inhibition of BSH activity prevented the development of pathologic intestinal permeability and hepatic inflammation in the NAFLD/NASH model. Conclusions: Conjugated BAs are important for the maintenance of intestinal barrier function by sequestering unconjugated BAs in mixed micelles. Increased BSH activity reduces intestinal conjugated BA abundance, in turn increasing intestinal permeability and susceptibility to the development of NAFLD/NASH. These findings suggest that interventions that shift the intestinal bile acid pool toward conjugated BAs could be developed as therapies for NAFLD/NASH.

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Section: Conjugated Bas Protect Intestinal Epithelial Monolayers From Unconjugated Ba-mediated Damage In Vitromentioning

confidence: 99%

“…The supernatant was transferred into mass spec vials and injected into the UPLC-MS. Total bile acids were then calculated by adding all detected and measured bile acids. The limits of detection for individual bile acids have been described previously (Chaudhari, Harris, et al, 2021;Chaudhari, Luo, et al, 2021;Yao et al, 2018).…”

Section: Lps Measurement Assaymentioning

confidence: 99%

Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury

Sojoodi

et al. 2021

Preprint

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“…Interestingly, a more recent study showed a gut microbiotadependent pathway by which SG increases liver cholic acid-7sulfate (CA7S) production and subsequent TGR5 signaling and GLP-1 production (53). This authors further demonstrated liver CA7S production was induced by increased lithocholic acid (LCA), a secondary bile acid produced by Clostridia, transported selectively from gut lumen into portal vein, thus illustrating CA7S as a microbiota-dependent metabolite altered by bariatric surgery and is responsible, at least partly, for the metabolic improvement (including MAFLD) of bariatric surgery (54). Notably, these findings were demonstrated by mouse model and requires to be validated in future human study.…”

Section: Bariatric Surgery Bile Acids and Mafldmentioning

confidence: 89%

Mining Gut Microbiota From Bariatric Surgery for MAFLD

Chen

Lee

et al. 2021

Front. Endocrinol.

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The progression of metabolic dysfunction associated fatty liver disease (MAFLD) leads to steatohepatitis, liver fibrosis and hepatocellular carcinoma. Thus far, there have been no FDA-approved medications for MAFLD. Bariatric surgery (BS) has been found to improve insulin resistance, steatohepatitis and liver fibrosis but is not recommended for treating MAFLD due to its invasiveness. Recent studies suggest the improved glucose metabolism after BS is a result of, at least partly, alterations to the gut microbiota and its associated metabolites, including short chain fatty acids and bile acids. It makes sense the improved steatohepatitis and fibrosis after BS are also induced by the gut microbiota that involves in host metabolic modulation, for example, through altering bile acids composition. Given that the gut–liver axis is a path that may harbor unexplored mechanisms behind MAFLD, we review current literatures about disentangling the metabolic benefits of MAFLD after BS, with a focus on gut microbiota. Some useful research tools including the rodent BS model, the multiomics approach, and the human microbiota associated (HMA) mice are presented and discussed. We believe, by taking advantage of these modern translational tools, researchers will uncover microbiota related pathways to serve as potential therapeutic targets for treating MAFLD.

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“…Recent studies have found that obesity has distinct metabolomic fingerprints associated with a shift in the microbiome-derived metabolites. Weight loss surgeries modify this obesity-related metabolomic fingerprint in a way that mimics the metabolome and microbiome associated with healthy or lean persons 52 .…”

Section: Microbiomementioning

confidence: 99%

“…Recently, Chaudhari et al showed in a murine model, that the selective transport of a microbial metabolite, litholytic acid, from the gut to the liver after a SG activates hepatic Vitamin D receptor, thereby inducing expression of bile acid sulfotransferase SULT2A, which produce the antidiabetic molecule CA7s. The CA7s is a gut-restricted TGR5 agonist with antidiabetic properties 52 .…”

Section: Microbiomementioning

confidence: 99%

Manejo de la diabetes tipo 2 con cirugía bariátrica y el papel de la medicina de precisión. Revisión narrativa

Muñoz-Hernandez¹,

Soto-Mota²

2021

ALAD

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Bariatric surgery has become the best treatment for morbid obesity. It has been documented that it achieves higher remission rates of the associated comorbidities when compared with medical treatment. Our objective with this review is provide information about the remission rates of such metabolic alterations with an emphasis on type 2 diabetes mellitus (T2DM), and mainly about how the research on the mechanisms that explain these results have evolved. Initially, the remission mechanisms of conditions such as T2DM were focused on studying the immediate as well as long-term changes of glucose metabolism and the physiology of incretins and hormones of the appetite-satiety axis, concluding that early changes were weight independent and that chronic changes were consequential to sustained weight loss. The possibility of obtaining tissues during the surgery has incorporated the histological, functional, molecular, and genetic study of biopsies from the liver, subcutaneous, and visceral adipose tissue, among others. These new approaches have been combined with methods based on systems biology, to integrate the genetics, transcriptomics, metabolomics, and microbiota with the histological, functional, and molecular findings and their relationship with clinical outcomes. This will likely combine bariatric surgery with precision medicine, favoring a better selection of patients and a more accurate prediction of outcomes.

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A microbial metabolite remodels the gut-liver axis following bariatric surgery

Cited by 94 publications

References 72 publications

Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury

Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury

Mining Gut Microbiota From Bariatric Surgery for MAFLD

Manejo de la diabetes tipo 2 con cirugía bariátrica y el papel de la medicina de precisión. Revisión narrativa

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