Type 2 diabetes (T2D) is a complex metabolic disease characterized by chronic hyperglycemia due to insulin resistance and inadequate insulin secretion. Beyond the classically implicated organs, emerging evidence highlights the gut as a central player in T2D pathophysiology through its interactions with metabolic organs. The gut hosts trillions of microbes and enteroendocrine cells that influence inflammation, energy homeostasis, and hormone regulation. Disruptions in gut homeostasis (dysbiosis and increased permeability) have been linked to obesity, insulin resistance, and β-cell dysfunction, suggesting multifaceted “Gut-X axes” contribute to T2D development. We aimed to comprehensively review the evidence for gut-mediated crosstalk with the pancreas, endocrine system, liver, and kidneys in T2D. Key molecular mechanisms (incretins, bile acids, short-chain fatty acids, endotoxins, etc.) were examined to construct an integrated model of how gut-derived signals modulate metabolic and inflammatory pathways across organs. We also discuss clinical implications of targeting Gut-X axes and identify knowledge gaps and future research directions. A literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews). Over 150 high-impact publications (original research and review articles from Nature, Cell, Gut, Diabetologia, Lancet Diabetes & Endocrinology, etc.) were screened. Data on gut microbiota, enteroendocrine hormones, inflammatory mediators, and organ-specific outcomes in T2D were extracted. The GRADE framework was used informally to prioritize high-quality evidence (e.g., human trials and meta-analyses) in formulating conclusions. T2D involves perturbations in multiple Gut-X axes. This review first outlines gut homeostasis and T2D pathogenesis, then dissects each axis: (1) Gut–Pancreas Axis: how incretin hormones (GLP-1 and GIP) and microbial metabolites affect insulin/glucagon secretion and β-cell health; (2) Gut–Endocrine Axis: enteroendocrine signals (e.g., PYY and ghrelin) and neural pathways that link the gut with appetite regulation, adipose tissue, and systemic metabolism; (3) Gut–Liver Axis: the role of microbiota-modified bile acids (FXR/TGR5 pathways) and bacterial endotoxins in non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; (4) Gut–Kidney Axis: how gut-derived toxins and nutrient handling intersect with diabetic kidney disease and how incretin-based and SGLT2 inhibitor therapies leverage gut–kidney communication. Shared mechanisms (microbial SCFAs improving insulin sensitivity, LPS driving inflammation via TLR4, and aryl hydrocarbon receptor ligands modulating immunity) are synthesized into a unified model. An integrated understanding of Gut-X axes reveals new opportunities for treating and preventing T2D. Modulating the gut microbiome and its metabolites (through diet, pharmaceuticals, or microbiota therapies) can improve glycemic control and ameliorate complications by simultaneously influencing pancreatic islet function, hepatic metabolism, and systemic inflammation. However, translating these insights into clinical practice requires addressing gaps with robust human studies. This review provides a state-of-the-art synthesis for researchers and clinicians, underlining the gut as a nexus for multi-organ metabolic regulation in T2D and a fertile target for next-generation therapies.

This study investigated the effects of dietary supplementation with Bacillus amyloliquefaciens D1 (B. amyloliquefaciens D1) on growth performance, serum anti-inflammatory cytokines, and intestinal microbiota composition and diversity in bearded chickens. To investigate the effects of Bacillus amyloliquefaciensa and fermented soy milk, 7-day-old broilers were orally fed different doses of Bacillus amyloliquefaciens D1 fermented soy milk for 35 days, with the unfermented soy milk group as the Placebo group. This study found that B. amyloliquefaciens D1 fermented soy milk improved the intestinal microbiota of broilers, significantly increasing the abundance of beneficial bacteria and decreasing the abundance of harmful bacteria in the gut. B. amyloliquefaciens D1 fermented soy milk also significantly reduced the serum lipopolysaccharide (LPS) content. The body weight and daily weight gain of broilers were increased. In conclusion, the results of this study are promising and indicate that supplementing the diets of bearded chickens with B. amyloliquefaciens D1 fermented soy milk has many beneficial effects in terms of maintaining intestinal microbiota balance and reducing inflammation in chickens.

Obesity is closely linked to dyslipidemia, hepatic injury, and chronic inflammation through disturbances in the gut–liver axis. Here, we evaluated the anti-obesity effects of L. rhamnosus (Lacticaseibacillus rhamnosus) CU262 in a high-fat diet (HFD) mouse model and elucidated mechanisms using an integrated multi-omics strategy. Male C57BL/6 mice received CU262 during 12 weeks of HFD feeding. Phenotypes, serum/liver biochemistry, gut microbiota (16S rRNA sequencing), fecal short-chain fatty acids (SCFAs), and hepatic transcriptomes (RNA-seq) were assessed. CU262 significantly attenuated weight gain and adiposity; improved serum TC, TG, LDL-C and HDL-C; lowered ALT/AST and FFA; and mitigated oxidative stress and inflammatory imbalance (↓ IL-6/TNF-α, ↑ IL-10). CU262 restored alpha diversity, reduced the Firmicutes/Bacteroidetes ratio, enriched beneficial taxa (e.g., Akkermansia), and increased acetate and butyrate. Liver transcriptomics showed CU262 reversed HFD-induced activation of cholesterol/steroid biosynthesis and endoplasmic reticulum stress, with downregulation of key genes (Mvk, Mvd, Fdps, Nsdhl, and Dhcr7) and Pcsk9, yielding negative enrichment of steroid and terpenoid backbone pathways and enhancement of oxidative phosphorylation and glutathione metabolism. Correlation analyses linked Akkermansia and SCFAs with improved lipid/inflammatory indices and repression of cholesterol-synthetic and stress-response genes. These findings demonstrate that CU262 alleviates HFD-induced metabolic derangements via microbiota-SCFA-hepatic gene network reprogramming along the gut–liver axis, supporting its potential as a functional probiotic for obesity management.

Background: Probiotics have recently emerged as promising agents in the prevention and treatment of various human diseases. This study investigates the therapeutic potential of Weizmannia coagulans SA9 in the management of type 2 diabetes mellitus (T2DM). Methods: The in vitro antidiabetic activity of W. coagulans SA9 was primarily assessed via its α-glucosidase inhibitory capacity, complemented by metabolomic profiling to identify putative bioactive metabolites. The antidiabetic efficacy was further evaluated in a db/db mouse model, focusing on glucose tolerance, inflammatory biomarkers, and gut microbiota composition. Results: W. coagulans SA9 showed significant inhibitory effects on α-glucosidase and α-amylase, and DNJ and other active substances were detected in its culture supernatant. After 6 weeks of continuous administration, the fasting blood glucose level, glucose tolerance, and inflammation indexes of mice were significantly improved. Beneficial changes in the structure of the intestinal flora occurred after the probiotic intervention, as evidenced by a significant decrease in harmful bacteria (e.g., Aerococcus urinaeequi) and a significant enrichment of beneficial bacteria (e.g., Limosilactobacillus reuteri). Conclusions: W. coagulans SA9 exerts robust antidiabetic effects and holds promise as a novel strategy for the prevention and management of T2DM.