Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression

Nimer, Nisreen; Choucair, Ibrahim; Wang, Zeneng; Nemet, Ina; Li, Lin; Gukasyan, Janet; Weeks, Taylor L.; Alkhouri, Naim; Zein, Nizar N.; Tang, W.H. Wilson; Fischbach, Michael A.; Brown, J. Mark; Allayee, Hooman; Dasarathy, Srinivasan; Gogonea, Valentin; Hazen, Stanley L.

doi:10.1016/j.metabol.2020.154457

Cited by 91 publications

(83 citation statements)

References 45 publications

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“…Torres et al were able to demonstrate a relationship between stool bile acids profile and microbiota composition in patients with PSC associated to IBD compared to patients suffering from IBD alone, thus suggesting an effect of bile acids on the microbiota composition of PSC patients ( 21 ). Similar findings have been made with circulating bile acids from NAFLD and NASH patients ( 66 , 67 ). Moreover, in a mouse model of high fat-diet (HFD), the presence of hydrophobic bile acids is correlated with liver inflammation and bacteria dysbiosis, and promotes carcinogenesis ( 68 ).…”

Section: Gut-derived Metabolites and Molecular Pathwayssupporting

confidence: 86%

Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases

et al. 2021

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The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.

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Section: Gut-derived Metabolites and Molecular Pathwayssupporting

confidence: 86%

Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases

et al. 2021

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“…Circulating TCA and GCA, along with both CDCA conjugates, were also elevated in biopsy-proven MAFLD as well as NASH patients [81]. In line with the previous observations, Nimer et al recently described that in a cohort of NAFLD patients, plasma TCA and GCA are positively associated with increasing grades of inflammation and fibrosis, respectively [82]. Interestingly, despite the fact that bile acid measurements in liver tissue revealed characteristic changes during MAFLD to NASH progression, reported outcomes were quite contradictory [83,84].…”

Section: Mafld-associated Alterations In Bile Acid Metabolism In Mice and Humanssupporting

confidence: 64%

Role of bile acids in inflammatory liver diseases

et al. 2021

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Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

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“…Bile acids (BAs) are a class of microbially modified metabolites that have been implicated as potential causal agents in the pathophysiology of NAFLD/NASH [12][13][14] . BAs are steroidal products synthesized from cholesterol in the liver and are present in high concentrations in the intestine.…”

Section: Introductionmentioning

confidence: 99%

“…While changes in serum BA profiles have been reported to correlate with disease severity in NAFLD/NASH patients, the mechanistic contribution of specific BA populations to the pathogenesis of disease has not been well elucidated [12][13][14] . Previous work has demonstrated that exposure of epithelial monolayers to certain hydrophobic BAs, including unconjugated BAs, leads to increased intestinal permeability in vitro and may contribute to the development of intestinal inflammation and disruption of intestinal homeostasis in vivo 18,19 .…”

Section: Introductionmentioning

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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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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Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression

Cited by 91 publications

References 45 publications

Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases

Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases

Role of bile acids in inflammatory liver diseases

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

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