Mechanisms and key mediators of gut microbiota and type 2 diabetes mellitus: A comprehensive overview

Abstract

The gut microbiota is a major component of the human microbiome, crucial for gastrointestinal function. Dysbiosis of the gut microbiota has been linked to the development, progression, and susceptibility to type 2 diabetes mellitus (T2DM) through energy and fatty acid metabolism, intestinal barrier integrity, glucose homeostasis, insulin sensitivity, and inflammatory pathways. Additional connections have been identified with obesity and the gut-brain axis. Key microbial metabolites include short-chain fatty acids (SCFAs), lipopolysaccharides, secondary bile acids (SBAs), branched-chain amino acids, tryptophan derivatives, trimethylamine N-oxide, imidazole propionate, bioactive peptides, postbiotics, and fasting-induced adipose factor. Individuals with T2DM often exhibit reduced microbial diversity, lower levels of SCFA-producing bacteria, and increased presence of opportunistic, endotoxin-producing gram-negative bacteria. Key microbial genera implicated in T2DM include Clostridium, Bifidobacterium, Akkermansia, Bacteroides, Lactobacillus spp., and members of the Firmicutes phylum. The gut microbiota is shaped by diet, medications, health conditions, genetics, lifestyle, and environmental factors. Despite the complex inter/intra-individual variability of the gut microbiome, robust evidence may emerge through large-scale cohort studies employing deep sequencing and metagenomics. This review provides novel insights into how gut microbiota-derived metabolites influence host physiology, epigenetics and gut-brain axis signaling using comprehensive synthesis of mechanisms, microbial mediators, synergistic factors, and therapeutic modulators in a single context, allowing readers to understand the holistic role of gut microbiota in T2DM pathophysiology. As T2DM is a complex metabolic disorder requiring multidimensional approaches, such integration offers valuable perspective for prevention and therapy. Emerging strategies, including fecal microbiota transplantation (FMT) and bacteriophage therapy, also show promise. A multidisciplinary research agenda, incorporating large-scale cohort studies, omics technologies, and systems biology, is essential to identify causal relationships and personalize interventions.