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<p>Emerging evidence indicates that gut microbiota-derived metabolites (MDMs) modulate immune and metabolic pathways relevant to type 2 diabetes mellitus (T2DM) inflammation. Short-chain fatty acids (SCFA) primarily acetate, propionate and butyrate from dietary fiber fermentation, which signal through <i>GPR41 (G-protein-coupled receptor 41)</i> and <i>GPR43 (G-protein-coupled receptor 43)</i> expressed on enteroendocrine and immune cells, stimulating <i>GLP-1</i>, <i>PYY</i> and suppressing <i>NF-κB</i>–driven proinflammatory cytokine production. Clinical and experimental studies report that high-fiber or SCFA-enriching interventions can increase circulating SCFAs by approximately 20–50%, reduce serum <i>IL-6</i> and <i>TNF-α</i> levels by 15–40%, and improve indices of insulin sensitivity such as HOMA-IR by 10–30% in T2DM or insulin-resistant subjects. Butyrate also acts as a histone deacetylase inhibitor and activates <i>AMPK/p38</i> pathways to enhance insulin sensitivity. SCFA levels or high-fiber diets improve glycaemic control and reduce inflammation, whereas T2DM is associated with loss of butyrate-producing bacteria. Intestinal <i>FXR</i> activation suppresses gluconeogenesis and lipogenesis, and <i>FXR/TGR5</i> agonists in preclinical models have lowered fasting glucose by 15–35% and attenuated hepatic inflammatory markers. Consistent with these mechanisms, <i>FXR/TGR5</i> agonists improve insulin resistance in rodents and probiotics altering bile acid pools modulate glucose homeostasis via <i>FXR</i> pathways. Clinically, bile acid–based therapies show promise: ursodeoxycholic acid regimens have reduced oxidative stress markers by around 20–30% and improved lipid and glycaemic indices, ursodeoxycholic acid reduced oxidative stress and improved metabolic indices in T2DM patients, and tauroursodeoxycholic acid attenuated inflammatory β-cell damage in diabetic rodent models. Observational studies align with these effects: higher circulating indole propionate is linked to lower T2DM risk, whereas elevated host kynurenine metabolites predict greater diabetes incidence. In contrast, higher trimethylamine N-oxide (TMAO) concentrations correlate with increased vascular inflammation and a higher incidence of cardiometabolic events in diabetic cohorts. Collectively, preclinical and clinical data illustrate that MDMs modulate <i>GPR41/43</i>, <i>FXR/TGR5</i> and <i>AhR</i>-dependent pathways to quell diabetic inflammation and support the development of targeted microbiota- and metabolite-based strategies for mitigating metabolic and inflammatory complications in T2DM.</p>

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The role of microbiota derived metabolites in modulating diabetic inflammation: a systematic review

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Venkatesan Karthick,
  • Rajkumar Thamarai,
  • Singamoorthy Amalraj,
  • Kalimuthu Nagarajan,
  • Ganesan Manimegalai

摘要

Emerging evidence indicates that gut microbiota-derived metabolites (MDMs) modulate immune and metabolic pathways relevant to type 2 diabetes mellitus (T2DM) inflammation. Short-chain fatty acids (SCFA) primarily acetate, propionate and butyrate from dietary fiber fermentation, which signal through GPR41 (G-protein-coupled receptor 41) and GPR43 (G-protein-coupled receptor 43) expressed on enteroendocrine and immune cells, stimulating GLP-1, PYY and suppressing NF-κB–driven proinflammatory cytokine production. Clinical and experimental studies report that high-fiber or SCFA-enriching interventions can increase circulating SCFAs by approximately 20–50%, reduce serum IL-6 and TNF-α levels by 15–40%, and improve indices of insulin sensitivity such as HOMA-IR by 10–30% in T2DM or insulin-resistant subjects. Butyrate also acts as a histone deacetylase inhibitor and activates AMPK/p38 pathways to enhance insulin sensitivity. SCFA levels or high-fiber diets improve glycaemic control and reduce inflammation, whereas T2DM is associated with loss of butyrate-producing bacteria. Intestinal FXR activation suppresses gluconeogenesis and lipogenesis, and FXR/TGR5 agonists in preclinical models have lowered fasting glucose by 15–35% and attenuated hepatic inflammatory markers. Consistent with these mechanisms, FXR/TGR5 agonists improve insulin resistance in rodents and probiotics altering bile acid pools modulate glucose homeostasis via FXR pathways. Clinically, bile acid–based therapies show promise: ursodeoxycholic acid regimens have reduced oxidative stress markers by around 20–30% and improved lipid and glycaemic indices, ursodeoxycholic acid reduced oxidative stress and improved metabolic indices in T2DM patients, and tauroursodeoxycholic acid attenuated inflammatory β-cell damage in diabetic rodent models. Observational studies align with these effects: higher circulating indole propionate is linked to lower T2DM risk, whereas elevated host kynurenine metabolites predict greater diabetes incidence. In contrast, higher trimethylamine N-oxide (TMAO) concentrations correlate with increased vascular inflammation and a higher incidence of cardiometabolic events in diabetic cohorts. Collectively, preclinical and clinical data illustrate that MDMs modulate GPR41/43, FXR/TGR5 and AhR-dependent pathways to quell diabetic inflammation and support the development of targeted microbiota- and metabolite-based strategies for mitigating metabolic and inflammatory complications in T2DM.