A recent study published in the Life Metabolism Journal reviewed the relationship between gut microbiota and metabolic disorders focusing on bile acid (BA) metabolism and immunity.
Study: Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions. Image Credit: MeekoMedia/Shutterstock.com
Background
The number of individuals with metabolic syndrome (MetS) has substantially increased over the past decades, given the improvements in living conditions and access to high-calorie diets.
While common metabolic diseases exhibit heterogeneous pathologies, they show common disease-specific abnormalities in the gut microbiota. Gut microbial enzymes metabolize primary BAs into secondary BAs.
BAs impact the pathogenesis of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes (T2D). Low-grade chronic inflammation is a hallmark of metabolic disorders, implying that immune regulation could affect the disease course.
Further, host immunity regulated by intestinal microbiota has been reported to impact several metabolic diseases. The authors reviewed the relationship between gut microbiota and metabolic disorders in the present study.
Gut microbes and metabolic diseases
A growing body of evidence reveals differences in gut microbial composition and metabolic features between healthy individuals and T2D patients. Moreover, an inverse correlation was reported between Akkermansia muciniphila abundance and the presence of diabetes or overweight in murine and human studies.
Administration of A. muciniphila has been reported to improve body weight and liver dysfunction biomarkers in obese and overweight individuals. Poor dietary habits and lifestyle increase the odds of developing obesity, and studies report that widespread antibiotic use can exacerbate obesity, suggesting the role of gut microbes in maintaining body weight.
Evidence shows that the abundance of microbes producing short-chain fatty acids (SCFAs) is associated with obesity. Some studies suggest that SCFAs and microbes producing SCFAs might help ameliorate obesity.
For instance, SCFA-producing Bifidobacterium animalis and A. muciniphila have been reported to improve metabolic indices in obese individuals.
Metabolic diseases and BA metabolism
The Farnesoid X receptor (FXR) is the main regulator of BA homeostasis. Early studies demonstrated that Fxr-null mice fed a standard low-fat diet (LFD) show increased serum cholesterol, triglycerides, liver mass, and peripheral insulin resistance (IR).
While these mice had smaller adipocytes, they were protected from genetically- and high-fat diet (HFD)-induced obesity and associated IR, indicating a crucial role of FXR in diabetes and obesity.
Gut microbiota-derived lithocholic acid activates Takeda G protein-coupled receptor 5 (TGR5). This induces the expression of its gene, leading to higher secretion of glucagon-like peptide 1 (GLP1), thereby improving insulin sensitivity and obesity.
Besides the binding to TGR5 and FXR, BAs can interact with mitochondria and regulate MetS-associated metabolic processes.
Metabolic diseases and immunity
Macrophages are the predominant immune cells infiltrating adipose tissue in obesity. Adipose tissue macrophages (ATMs) in lean animals show the alternatively activated M2 phenotype that is less inflammatory than the classically activated M1 phenotype.
By contrast, pro-inflammatory (M1) ATMs are found in crown-like structures near dying adipocytes in mice with obesity. Cluster of differentiation 4-positive (CD4+) T cells play a crucial role in IR and obesity.
Interferon-gamma (IFNγ)-expressing CD4+ T cells increase in cases of obesity, and deletion of IFNγ ameliorates obesity-induced IR and decreases the infiltration of macrophages in adipose tissue.
Several studies have reported reductions in visceral adipose tissue (VAT) regulatory T (Treg) cells in mice with diet-induced obesity. Similarly, adults with diabetes and obesity show reduced Treg cells in peripheral blood and adipose tissue.
Moreover, obese patients present reduced numbers of natural killer (NK) cells in the peripheral blood. NK cell accumulation has been observed in murine models of obesity.
Altered compositions of the gut microbiota in obesity increase intestinal permeability and, thereby, leakage of microbes and their products. Microbial products induce innate immune responses, resulting in chronic inflammation and metabolic disorders.
Host immune responses can influence the course of T2D and obesity by regulating gut microbes. Gut microbiota-induced disruptions in the intestinal barrier also impact the pathogenesis of NAFLD and non-alcoholic steatohepatitis.
A clinical study observed improved intestinal permeability in NAFLD patients after transplanting fecal microbiota from healthy individuals.
Concluding remarks
The gut microbiota affects host physiological processes, such as metabolism, immunity, and intestinal barrier functions. Elucidating how microbes regulate these host processes can provide better insights into metabolic diseases.
While numerous studies have reported associations of gut microbiota and their metabolites with metabolic diseases, the underlying mechanisms have yet to be defined.
Future work should focus on microbial editing and modifications to treat metabolic disorders.
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