Search Results (499)

Due to the close association between gut microbiota and diabetes, probiotic dairy products have drawn a lot of attention in the development of functional foods with anti-diabetic activity. In this study, 28 type 2 diabetic patients received 10 g of camel milk powder supplemented with Bifidobacterium animalis A6 (BBA6) twice a day, taking camel milk powder as the placebo. After 4 weeks of intervention, there was a significant decrease in fasting blood glucose, serum content of total cholesterol, and pro-inflammatory cytokines (IL-6, MCP-1). And, in the CA group, the level of irisin and osteocrin increased significantly, while the level of osteonectin also increased, but with no significance. For the adipokines, the intervention of CA decreased the adiponectin, resistin, lipocalin-2, and adipsin levels significantly. Gut microbiota analysis suggested a significant enrichment in the relative abundance of Bifidobacterium when compared with patients supplemented with camel milk powder alone. Furthermore, elevated fecal concentrations of glucose-1-phosphate, conduritol b epoxide, D-Arabitol, dehydroascorbic acid, and dl-p-Hydroxyphenyllactic acid, accompanied with a decrease in glycine, N-Acetylisatin, hydroxylamine, caprylic acid, maltotriose, and guaiacol, were found in patients of group CA. Compared with camel milk alone, the adding of BBA6 can significantly decrease fasting blood glucose in type 2 diabetic patients, while also improving dyslipidemia, chronic inflammation, and skeletal muscle functions, indicating the possibility of probiotic camel milk powder as a dietary treatment that targets metabolic syndromes such as diabetes. Full article

(1) Background: Chronic enteropathy (CE) in canines is associated with persistent microbiome dysbiosis, and conventional therapies (e.g., special diets, antimicrobials, and immunosuppressive drugs) are sometimes ineffective. Currently, fecal microbiota transplantation (FMT) has proven successful in treating CE in canines via invasive methods (e.g., enemas or endoscopy) or via oral frozen liquid capsules, which must be stored at −80 °C. However, due to the invasiveness of the administration methods and the storage constraints of the liquid capsules, FMT is not widely used in veterinary clinical practice. (2) Methods: The case of a four-year-old Siberian Husky with a three-year history of CE following canine parvovirus infection received lyophilized FMT capsules for thirty days. Stool samples were collected for metagenomic sequencing and quantification of fecal short-chain fatty acids (SCFAs), both pre- and post-FMT. Blood samples were analyzed using complete blood count (CBC) and biochemical testing. Ultrasound was used to assess the wall thickness of the stomach, duodenum, jejunum, and colon. (3) Results: Post-FMT, improvements in clinical outcomes were observed: fecal scores improved from 6 (unformed stools with mucus) to 2 (formed stool), and body weight increased by 8.3% (from 24.2 kg to 26.2 kg). Abnormal CBC and biochemical parameters were restored to reference ranges, including hematocrit (from 60.6% to 55.7%), hemoglobin (from 208 g/L to 190 g/L), creatinine (from 167 μmol/L to 121 μmol/L), and urea (from 11.9 mmol/L to 7.1 mmol/L). Ultrasound results showed that colonic wall thickness decreased from 0.23 ± 0.03 cm (pathological) to 0.18 ± 0.01 cm (physiological). Metagenomic analysis revealed that microbial richness (operational taxonomic units (OTUs) from 151 to 183) and diversity (Shannon and Simpson indices from 3.16 to 4.8 and from 0.87 to 0.94, respectively) all increased. The microbiota composition of the recipient exhibited a decline in the relative abundance of Firmicutes, falling from 99.84% to 35.62%, concomitant with an increase in Actinobacteria (from 0.08% to 4.78%), indicating a convergence toward a donor-like profile. Fecal SCFAs analysis revealed a 251.4% increase in propionate (from 0.0833 to 0.2929 mg/g) and elevated acetate (from 0.4425 to 0.4676 mg/g). These changes are functionally linked to enriched propanoate metabolism (Z = 0.89) in KEGG pathways. (4) Conclusions: Oral lyophilized FMT capsules resolved clinical signs of CE, enhanced microbial diversity and richness, and restored donor-like abundances of gut microbiota, particularly SCFA-producing taxa. Microbial restructuring increased microbial metabolite output, notably SCFA concentrations, and enriched functional metabolic pathways. Importantly, lyophilized FMT overcomes storage limitations and administration barriers, demonstrating its high clinical viability for treating canine CE. Full article

Eggshell membrane (ESM) is composed of approximately 90% protein. Our previous studies in healthy adults demonstrated that two months of daily ESM intake improved respiratory function, zigzag walking speed, and skin elasticity. The present study aims to address the knowledge gap regarding the in vivo effects of ESM in the context of inflammatory bowel disease (IBD). Proteomic analysis was performed on powdered ESM used as a dietary supplement. To investigate its pharmacokinetics in mice, tritium (³H)-labeled ESM was prepared using the ⁶Li(n,α)³H nuclear reaction. The therapeutic potential of ESM was further examined in a 2.0% dextran sulfate sodium (DSS)-induced murine model of IBD. In addition, fecal samples from both mice and healthy human subjects were analyzed using a modified terminal restriction fragment length polymorphism (T-RFLP) method. Lysozyme C (LYZ) was the most abundant protein (47%), followed by lysyl oxidase (12%) in ESM used in this study. ³H-ESM was mixed with MediGel, and orally administered to mice. Radioactivity levels were measured in blood, organs (duodenum, small intestine, large intestine, liver, kidney, lung, skin), and rectal feces at 0.5, 2, 5, 24, 48, and 72 h post-administration. Radioactivity in feces indicated excretion of undigested components, while systemic distribution suggested potential whole-body effects of ESM. Oral ESM and LYZ significantly alleviated body weight loss, diarrhea, and hematochezia in a DSS-induced murine model of IBD, leading to a significantly lower disease activity index on day 3 and showing a similar trend on day 5. Gut microbiota analysis showed increased Bacteroidales in the DSS group, while the ESM + DSS group maintained levels similar to the control. In humans, a double-blind, randomized controlled trial was conducted to evaluate the effects of ESM on gut microbiota in healthy adults. Participants received either ESM or placebo for 8 weeks. revealed a significant increase in alpha diversity at weeks 1 and 8 in the ESM group (p < 0.05), with between-group differences evident from week 1 (p < 0.01). ESM intake reduced Bacteroides and significantly increased Bifidobacterium and Lactobacillales at weeks 4 and 8. These findings suggest ESM supplementation promotes beneficial modulation of gut microbiota. These findings suggest that ESM, through its major protein components such as LYZ, may serve as a promising dietary intervention for maintaining intestinal health and mitigating inflammation in the context of IBD. Full article

Background: Oral probiotic intake is suggested to have positive effects on skin. We aimed to elucidate the effects of oral Bifidobacterium breve M-16V intake on skin by analyzing facial images, the skin myco/microbiota, and the gut microbiota. Methods: We conducted a randomized, double-blind, placebo-controlled study in Japan. Healthy women aged over 30 years were randomly allocated to either the B. breve (1 × 1010 colony-forming units (CFU)/sachet, two sachets daily) or the placebo group and consumed the corresponding study food for 12 weeks. Facial images were taken at weeks 0, 4, 8, and 12 using VISIA evolution. Stool and skin samples were collected at weeks 0 and 12. The primary outcome was the change in the total VISIA score from baseline. Results: A total of 120 females aged 30–79 years were assigned to the B. breve (n = 59) or placebo (n = 61) group. The total VISIA score worsened in the placebo group at week 8 (p = 0.029) but not in the B. breve group. Compared with that of the placebo group, the VISIA brown spot score of the B. breve group improved at weeks 4 (p = 0.013) and 8 (p = 0.041). The VISIA pore score improved at weeks 4 (p = 0.013), 8 (p = 0.041), and 12 (p = 0.004) within the B. breve group. Genus-level analysis of the gut microbiota revealed a significant increase in Blautia abundance in the B. breve group. The frequency of adverse events was not different between the groups. Conclusions: Oral B. breve M-16V administration may suppress skin deterioration, including the appearance of brown spots, on the faces of adult females. Full article

Due to their high nutritional value and a lower environmental impact, Tenebrio molitor (T. molitor) larvae are regarded as an alternative protein and lipid source in food industries, animal husbandry, and fishery. This study aimed to investigate the effect of ω-3 PUFA intake on the nutritional value and gut microbiota of T. molitor larvae. Tenebrio molitor (T. molitor) larvae were reared with wheat bran at 20–32 °C for 4 weeks to screen for a suitable temperature. EPA ethyl esters (EE), DHA ethyl esters (ED), DHA triglycerides (TG), and krill oil (KO) were supplemented in wheat bran to rear larvae for 4 weeks, and the compositions including moisture, carbohydrates, crude protein, and crude fats were analyzed. Gut microbiome was analyzed using 16S rRNA amplicon sequencing. Larvae reared on wheat bran showed optimal growth at 28 °C. ω-3 PUFA supplements increased crude protein (1.07–1.16 fold) and crude fat (1.12–1.22 fold) contents without affecting survival. Gut microbiota composition shifted significantly in all ω-3 supplemented groups, altering over 10 genera. Bacteria with changed abundance (e.g., Clostridium), known for roles in protein/lipid metabolism, likely contributed to the enhanced nutritional contents. These findings demonstrate the benefits of ω-3 PUFA supplementation in T. molitor rearing and identify associated gut bacteria. Full article

Background: Sustainable, dual-action ergogenic strategies are underexplored; most products target a single pathway and rarely upcycle seafood sidestreams. We therefore tested an upcycled formulation combining grouper bone hydrolysate and Undaria pinnatifida extract (GU) for ergogenic and microbiota effects in mice. We tested the ergogenic and microbiota modulating effects of GU in mice versus a vehicle and a BCAA control. Methods: GU was prepared via enzymatic hydrolysis of marine by-products and administered to male ICR mice for 4 weeks. Mice were divided into five groups (n = 7/group), receiving a vehicle control, a branched-chain amino acid (BCAA) supplement, or GU at three dose levels (1X, 2X, 3X) based on human-equivalent conversion. Exercise performance was assessed via grip strength and treadmill tests. Biochemical markers of fatigue, body composition, and safety indicators were also analyzed. Gut microbiota was evaluated using 16S rRNA sequencing and constrained principal coordinates analysis (CPCoA). Results: Four weeks of GU supplementation significantly enhanced exercise performance [(treadmill time ↑ Δ = 10.2–11.7 min versus vehicle (q ≤ 0.0002), grip strength ↑ Δ = 40.4–48.5 g (q ≤ 0.05)] and lean body mass [FFM ↑ at GU-1X (Δ = +0.80%, q = 0.0123)], surpassing the commercial BCAA control. Biochemical analyses indicated reduced exercise-induced lactate accumulation [(post-exercise lactate ↓ Δ = −2.71/−2.18 mmol·L⁻¹, q = 0.0006)]. Gut microbiota profiling revealed distinct shifts in community composition in GU-treated groups, notably with an increased abundance of beneficial taxa such as Lactobacillus and Muribaculum. These alterations reflect the prebiotic activity of seaweed-derived polysaccharides, promoting a healthier gut microbial profile. Notably, GU improved metabolic markers (aspartate aminotransferase, [AST]; lactate dehydrogenase, [LDH]) without inducing toxicity. Conclusions: These findings indicate that GU functions as a dual-action supplement, coupling amino acid-mediated muscle anabolism with microbiome modulation to enhance physical performance and metabolic health. As an upcycled marine product, it presents a sustainable and effective strategy for exercise support. Future studies should include 90-day safety, mechanistic assays, and a preregistered human pilot. Full article

Background/Objectives: Ulcerative colitis (UC) incidence has risen alarmingly worldwide, posing significant clinical challenges due to limitations of therapeutic efficacy and side effects of current drugs. While Polygonatum kingianum polysaccharides (PKPs) exhibit anti-inflammatory and antioxidant properties, their anti-colitis potential remains unexplored. This study aimed to validate the protective effects of PKPs against dextran sulfate sodium (DSS)-induced colitis and elucidate its mechanisms. Methods: Acute UC was induced in C57BL/6J mice by 3% DSS. PKPs (125 mg/kg) were administered via gavage for 10 days. Integrated approaches included histopathology, tight junction protein (ZO-1/Occludin/Claudin-1) immunohistochemistry, inflammatory/oxidative markers (ELISA), Nrf2 pathway proteins (Western blot), 16S rRNA gut microbiota sequencing, fecal untargeted metabolomics (UHPLC-MS), short-chain fatty acids (SCFAs) analysis and combined analysis. Results: PKPs significantly alleviated colitis phenotypes: reduced weight loss, lowered disease activity index (DAI), and attenuated colon shortening. They restored intestinal barrier integrity by upregulating tight junction proteins and reducing plasma Diamine Oxidase (DAO)/D-lactate (D-Lac)/Endotoxin (ET). PKPs suppressed pro-inflammatory cytokines (TNF-α/IL-1β/IL-6) while elevating IL-10, activated the Nrf2/HO-1/NQO1 antioxidant pathway, and reduced oxidative stress (MDA decreased, SOD/GSH increased). Multi-omics revealed PKPs enriched beneficial bacteria (Blautia, Odoribacter, Rikenellaceae_RC9_gut_group), restored SCFAs (acetate/propionate/butyrate), and modulated metabolic pathways (sphingolipid/linoleic acid metabolism). Conclusions: PKPs ameliorate DSS-induced colitis through multi-target mechanisms: (1) preserving intestinal barrier function, (2) suppressing inflammation and oxidative stress via Nrf2 activation, (3) restoring gut microbiota balance and SCFA production, and (4) regulating host-microbiota metabolic interactions. These findings support PKPs as a promising dietary supplement for UC management. Full article

Galactooligosaccharides (GOS) are a class of prebiotic carbohydrates composed of 2 to 8 galactose units linked together and often terminated with a glucose molecule. GOS have attracted significant attention for their health-promoting properties, including the regulation of gut microbiota, promotion of infant health, immune modulation, laxative effects, and potential metabolic benefits. Widely utilized in functional foods, infant formulas, dairy products, and dietary supplements, GOS occur naturally in human milk and are primarily industrially produced through the enzymatic conversion of lactose. β-Galactosidase is a crucial enzyme in GOS bioproduction, which exhibits dual functions of hydrolysis and transglycosylation. In this investigation, a novel β-galactosidase from Pseudomonas tritici SWRI145 (Pstr β-galactosidase) was characterized. Biochemical characterization revealed that the enzyme exhibits the highest activity at 50 °C and pH 7.5, with a specific activity of 331.9 U/mg against ONPG. Under optimal reaction conditions (40 °C, pH 8.0, 300 g/L lactose, 0.4 mg/mL enzyme), 134.3 g/L GOS were produced, corresponding to 44.8% GOS yield and 80% substrate conversion. LC-MS analysis confirmed that the main products were GOS with degrees of polymerization (DP) ranging from 2 to 4. To our knowledge, this is the first report of a Pseudomonas-derived β-galactosidase with demonstrated GOS synthesis capability, highlighting its potential for industrial application. Full article

An estimated 2.6 billion individuals are currently living with overweight or obesity, and this number is projected to exceed 4 billion by 2035. Consequently, unless this increasing trajectory is effectively addressed, the trend is expected to continue in the coming years. The gut microbiome has emerged as a central regulator of host metabolism and energy homeostasis, making its detailed characterization crucial for the advancement of innovative therapeutic strategies and for elucidating mechanisms underlying metabolic health and disease. This review examines human obesity through the lens of the gut microbiome, providing a comprehensive overview of its role by addressing gut microbiome alterations, microbiome-driven mechanisms, dietary influences, prebiotic effects, microbiome-based therapeutics, and other approaches in the treatment of obesity and related metabolic disorders. The composition of the gut microbiome is altered in obesity and characterized by reduced microbial diversity and inconsistent shifts in dominant bacterial phyla, which collectively contribute to metabolic dysregulation. The gut microbiome influences obesity through multiple mechanisms. These include regulating energy balance and insulin sensitivity via short-chain fatty acids, inducing chronic inflammation, modulating metabolic and appetite genes, altering bile acid signaling, and promoting fat storage by inhibiting fasting-induced adipose factor. Dietary patterns exert a profound influence on gut microbiome composition and function, with plant-based diets conferring protective effects against obesity and its comorbidities. Microbiome-based therapeutics, including probiotics, synbiotics, and fecal microbiota transplantation, have demonstrated potential in modulating key metabolic and inflammatory pathways associated with obesity. As the scientific understanding of the human gut microbiome continues to advance, the integration of microbiome-based therapies into standard clinical practice is poised to become increasingly feasible and therapeutically transformative, particularly for obesity, a complex condition that demands innovative and customized interventions. Full article

As demand for sustainable protein sources grows, edible insects like Tenebrio molitor (yellow mealworm) are gaining attention as functional feed ingredients. This study investigated how dietary inclusion of T. molitor meal affects gut microbiota composition and diversity in laboratory rats. Wistar rats were divided into three diet groups: standard feed, 35% chicken meal, and 35% T. molitor meal. Fecal samples were collected at weeks 4, 6, and 8. Microbial populations were assessed using culture-based methods, and community structure was analyzed at week 9 via Illumina MiSeq 16S rRNA sequencing. Bioinformatic analyses evaluated microbial diversity and predicted functions. Rats fed T. molitor meal showed significantly reduced counts of total aerobic/anaerobic bacteria, fungi, and coagulase-positive staphylococci. Metagenomics revealed a Firmicutes-dominated microbiota, with enrichment of protein- and cholesterol-metabolizing taxa (e.g., Eubacterium coprostanoligenes, Oscillospiraceae, Ruminococcaceae), and a decline in fiber- and mucin-degrading bacteria like Akkermansia and Muribaculaceae. Functional predictions indicated upregulated amino acid metabolism and chitin degradation. Despite compositional shifts, microbial diversity remained stable, with no signs of dysbiosis. These findings suggest that T. molitor meal supports a safe, functional adaptation of gut microbiota to high-protein, chitin-rich diets, supporting its potential use in monogastric animal nutrition. Full article

The prevalence of hyperuricemia with elevated serum uric acid is increasing worldwide. However, the effects of high uric acid on diabetic patients with dyslipidemia and the mechanisms underlying these effects remain unexplored. This study aimed to develop a novel diabetic model of hyperuricemia and dyslipidemia in male hamsters to evaluate the effects of high uric acid on glucolipid metabolism, renal injury and the gut microbiota. Twelve healthy hamsters were randomly divided into two groups and fed with a normal diet and high-fat/cholesterol diet (HFCD), respectively. Twenty-four diabetic hamsters were randomly divided into four groups receiving a normal diet; HFCD; potassium oxonate (PO) treatment (intragastric PO at doses of 350 mg/kg and adenine at doses of 150 mg/kg with 5% fructose water); and PO treatment with HFCD, respectively. After 4 weeks, all animals were dissected for determining serum biochemical indicators, tissue antioxidant parameters, renal pathological changes, target gene expressions, fecal short-chain fatty acids content, and the gut microbiota composition. The results showed that a hamster model with hyperuricemia and dyslipidemia was successively established by the combination of PO treatment and HFCD, in which serum uric acid, glucose, triglyceride and total cholesterol levels reached 499.5 ± 61.96 μmol/L, 16.88 ± 2.81 mmol/L, 119.88 ± 27.14 mmol/L and 72.92 ± 16.62 mmol/L, respectively. PO treatment and HFCD had synergistic effects on increasing uric acid, urea nitrogen, creatinine levels, liver xanthine oxidase activity, plasminogen activator inhibitor-1 and transforming growth factor-β expressions, and the relative abundance of Lleibacterium (p < 0.05); in addition, they caused glomerular mesangial cells and matrix proliferation, protein casts and urate deposition. High uric acid was closely related to decreased antioxidant capacity; decreased renal vascular endothelial growth factor expression; increased acetic acid content; decreased butyric, propanoic, and isobutyric acid levels; decreased Firmicutes to Bacteroidetes ratios (p < 0.05); and altered epithelial integrity and structure of the gut microbiota in diabetic hamsters. The findings indicate that high uric acid affects the glucolipid metabolism, accelerates renal damage, and disrupts the balance of intestinal flora in diabetic animals, which provides a scientific basis for metabolic syndrome prevention and control in diabetes. Full article

Objectives: Alpinia japonica (A. japonica) is traditionally used for digestive disorders, but its hypolipidemic mechanisms remain unclear. This study investigated the lipid-lowering effects of its fruit (SJGS), rhizome (SJGJ), and leaf (SJY) extracts, exploring their bioactive constituents and organ-specific mechanisms. Methods: Sprague Dawley rats (n = 8/group) fed a high-fat diet received SJGS, SJGJ, or SJY (200 mg/kg/day) for 4 weeks. Serum lipids (TC, TG), liver enzymes (AST, ALT), and intestinal barrier markers (DAO) were measured. Gut microbiota (16S rDNA sequencing), hepatic histopathology, and ileal tight junction proteins were analyzed. Transcriptomics and qPCR assessed ileal gene expression. LC-MS identified chemical constituents, while network pharmacology predicted compound-target interactions. Results: All extracts significantly reduced serum TC (↓ 27–33%), TG (↓ 29–38%), AST/ALT (↓ 22–30%), and DAO (↓ 35–42%) versus controls (p < 0.05). They improved hepatic steatosis, enhanced intestinal barrier function, and modulated gut microbiota (↑ α-diversity, ↓ Firmicutes/Bacteroidetes ratio). Transcriptomics revealed PPAR signaling as the core pathway: SJGS/SJGJ downregulated fatty acid oxidation genes (ACSL1, ACOX1, ACADM), while SJY upregulated APOA1 (2.3-fold). LC-MS identified 33–48 compounds/part, with seven shared constituents. Network analysis prioritized three flavonoids (pinocembrin, luteolin, galangin) targeting TNF, AKT1, and PPAR pathways. Conclusions: The findings suggest A. japonica extracts ameliorate hyperlipidemia through distinct mechanisms—SJGS/SJGJ may inhibit fatty acid oxidation, while SJY potentially enhances APOA1-mediated clearance. Shared flavonoids likely contribute to these effects via PPAR signaling, supporting its traditional use. This study provides a scientific basis for the sustainable utilization of A. japonica resources. Full article

Weaning stress in piglets severely restricts swine production efficiency due to growth retardation, immune suppression, and intestinal dysfunction. This study investigated the effects of dietary pyrroloquinoline quinone (PQQ) on 36 weaned piglets (22 ± 1 days old) allocated to six groups (0, 1, 2, 4, 8 and 16 mg/kg PQQ) for 28 days. Results showed that 4–8 mg/kg PQQ improved average daily gain and feed conversion ratio (p < 0.05), enhanced serum immunoglobulin (IgA, IgG) and antioxidant enzyme (T-AOC, SOD, GSH-Px) levels, and reduced inflammatory cytokines (TNF-α, IL-1β, IL-6) (p < 0.05). PQQ modulated gut microbiota, increasing Lactobacillus and Bifidobacterium, and elevated short-chain fatty acid production (p < 0.05). Metabolomic analysis revealed upregulated tricarboxylic acid (TCA) cycle intermediates (citric acid, isocitric acid and malic acid), indicating improved mitochondrial function (p < 0.05). Overall, 4 mg/kg PQQ optimally alleviates weaning stress by enhancing immunity, gut health, and energy metabolism, offering a promising strategy for piglet nutrition. Full article

Acute myeloid leukemia (AML), the most common acute leukemia among adults, poses significant therapeutic challenges due to diagnostic limitations and the frequent development of treatment resistance. While genomics-based approaches have advanced, DNA aberrations do not always reflect the expression levels of genes and proteins, which are more tightly connected to disease phenotypes. Recently, the role of the gut microbiota in AML has gained increasing attention. AML patients often exhibit gut microbiota dysbiosis, which is linked to disease progression and heightened infection risk. Mounting evidence indicates that gut microbiota metabolism influences hematopoiesis and immune function via the “gut-bone marrow axis,” with microbiota composition and diversity significantly affecting treatment outcomes and prognosis. High-throughput sequencing and metabolomics have identified correlations between gut microbiota composition and its metabolic products with AML clinical characteristics, paving the way for new biomarkers in diagnosis and prognosis. Additionally, treatments such as fecal microbiota transplantation (FMT) show promise in enhancing chemotherapy efficacy and improving patient outcomes. This review highlights recent advances in understanding the role of the gut microbiota in AML and explores new perspectives for its diagnosis and treatment. Full article

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. Full article