Intestinal Microbiota Protects against MCD Diet-Induced Steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries, with a continuously rising incidence. Gut-liver communication and microbiota composition have been identified as critical drivers of the NAFLD progression. Hence, it has been shown that microbiota depletion can ameliorate high-fat diet or western-diet induced experimental Non-alcoholic steatohepatitis (NASH). However, its functional implications in the methionine-choline dietary model, remain incompletely understood. Here, we investigated the physiological relevance of gut microbiota in methionine-choline deficient (MCD) diet induced NASH. Experimental liver disease was induced by 8 weeks of MCD feeding in wild-type (WT) mice, either with or without commensal microbiota depletion, by continuous broad-spectrum antibiotic (AB) treatment. MCD diet induced steatohepatitis was accompanied by a reduced gut microbiota diversity, indicating intestinal dysbiosis. MCD treatment prompted macroscopic shortening of the intestine, as well as intestinal villi in histology. However, gut microbiota composition of MCD-treated mice, neither resembled human NASH, nor did it augment the intestinal barrier integrity or intestinal inflammation. In the MCD model, AB treatment resulted in increased steatohepatitis activity, compared to microbiota proficient control mice. This phenotype was driven by pronounced neutrophil infiltration, while AB treatment only slightly increased monocyte-derived macrophages (MoMF) abundance. Our data demonstrated the differential role of gut microbiota, during steatohepatitis development. In the context of MCD induced steatohepatitis, commensal microbiota was found to be hepatoprotective.

Enzyme-mediated depletion of serum l -Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity

“…It is likely that the toxicities and weight loss associated with dietary L-Met restriction result from its effect on the gastrointestinal tract. In earlier studies, maintenance of animals on L-Met-and L-Met/choline-deficient diets, which cause nonalcoholic steatohepatitis, was reported to result in intestinal barrier deterioration, macroscopic shortening of the intestine and intestinal villi, and in gut microbial dysbiosis (57,58). Hepatocellular injury, oxidative stress, and high ALT levels are caused by a significant decrease in liver SAM and GSH in these models (59), which is not surprising given that >75% of the blood supplied to the liver is via the portal vein that collects blood from nearly the entire gastrointestinal tract (60).…”

Trimethylamine N-oxide attenuates high-fat high-cholesterol diet-induced steatohepatitis by reducing hepatic cholesterol overload in rats

“…Another finding of our study is that TMAO restored the diversity of gut commensal bacteria in rats fed a HFHC diet. Gut dysbiosis is a hallmark of NAFLD and NASH, in which reduced diversity of gut bacteria is an important characteristic[25,30]. Gut dysbiosis leads to gut bacteria translocation due to the impaired intestinal barrier and increased production of harmful microbial metabolites such as lipopolysaccharide and endogenous ethanol, which contribute to the pathogenesis and progression of NAFLD and NASH[31].…”

The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases

“…Nevertheless, due to the importance of choline as an essential nutrient, choline-deficient diets may also induce gut microbiota alterations and health problems [ 62 , 63 , 64 , 65 ]. Indeed, a human trial in which the choline intake was controlled demonstrated that the gut microbiota composition changed with dietary choline levels and specific alterations in Gammaproteobacteria , and Erysipelotrichi members were associated with changes in liver fat during choline depletion [ 66 ].…”

“…Choline-deficient diets have also been associated with NASH and may result in obesity and hyperglycemia [ 64 , 65 , 66 , 108 ]. Research indicates the role of choline-deficient diets in intestinal dysbiosis by reducing the microbiota diversity and altering the microbial population representation within the microbiome [ 64 , 65 , 109 ]. Subsequent transplantation of the microbiome of NASH individuals is sufficient in inducing NASH in otherwise healthy individuals [ 65 , 110 ].…”