Fecal SCFAs and SCFA‐producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T‐cell activation and advanced disease

Abstract

Background Intestinal microbiota and their metabolites (e.g. short-chain fatty acids (SCFAs)) may influence nonalcoholic fatty liver disease (NAFLD). Objective The objective of this article is to analyze gut bacterial diversity together with fecal SCFA concentrations and immunophenotyping of peripheral blood in histology-proven NAFLD patients. Methods Thirty-two NAFLD patients (14 nonalcoholic fatty liver (NAFL), 18 nonalcoholic steatohepatitis (NASH)) and 27 healthy controls (HCs)) were included in this study. Bacterial communities in feces were profiled by 16S ribosomal RNA gene sequencing of the V3–V4 region. Fecal SCFA levels were analyzed by high-performance liquid chromatography. Fluorescence-activated cell sorting analysis was performed of peripheral blood mononuclear cells. Results NASH patients were characterized by higher abundance of Fusobacteria and Fusobacteriaceae compared to NAFL and HCs. Conforming to our finding that NAFLD patients had higher fecal acetate and propionate levels, taxonomical differences of fecal bacteria were dominated by SCFA-producing bacteria. Higher fecal propionate and acetate levels were associated with lower resting regulatory T-cells (rTregs) (CD4+CD45RA+CD25++) as well as higher Th17/rTreg ratio in peripheral blood as immunological characteristics of NASH patients. Conclusions NASH patients are characterized by a different gut microbiome composition with higher fecal SCFA levels and higher abundance of SCFA-producing bacteria in NAFLD. These changes are associated with immunological features of disease progression. Our data suggest an important role of the intestinal microbiome and immunomodulatory bacterial metabolites in human NAFLD.

Circulating microbiota-derived metabolites: a “liquid biopsy?

“…First, gut microbiota play important roles in modulating host energy balance. In this sense, short-chain fatty acids (SCFAs) are generated by gut microbial fermentation of nondigestible carbohydrates and provide precursors for lipogenesis and gluconeogenesis, mechanisms involved in NAFLD [10]. Probiotics can inhibit small intestinal bacterial overgrowth (SIBO), leading to an improvement in insulin sensitivity in relation to incretin hormones [11] that have been shown diminished in patients with NAFLD [12].…”

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

“…This conclusion is based on two lines of evidence from human and animal, respectively. Although SCFAs are generally regarded as beneficial microbial metabolites for human health, our results, together with several lines of evidence [47, 48, 49, 50] indicate that, like a double-edge sword, excessive SCFA beyond physiological concentration can interfere with biological functioning of host. To the best of our knowledge, this is the first study to show that higher fecal SCFA excretion and circulating SCFA are presented in schizophrenia.…”

Sex differences in gut microbiome in high-fat-diet fed rats.

“…Furthermore, propionic acid was reported to reduce lipogenic enzymes expression in liver, resulting in decreased hepatic triglycerides 39 and prevention of NAFLD by suppressing fatty acid synthesis and oxidative stress 40 . On the other hand, fecal SCFAs concentration in obese volunteers was higher compared with that of lean individuals in human studies, since they provided additional energy to the host 41 , and NAFLD patients had higher fecal propionate levels, which was positively associated with lower resting regulatory T-cells in peripheral blood, as immunological characteristics of NAFLD patients 42 . We have considered that the high concentration of propionic acid in FHFD may partly contribute to the alleviation of liver steatosis in female rats by reducing hepatic lipogenesis and fatty acid uptake.…”