Modulation of the intestinal microbiome can alter in insulin sensitivity
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page264-265
2025-12-10
27
Beyond these seminal studies implicating bacterial LPS as an initiating factor in impaired glucose metabolism, direct modulation of the intestinal microbiota also affects indices of glucose homeostasis. Use of antibiotic treatment over periods ranging from two to eight weeks in genetically modified phenotypically obese mice (ob/ob) and in diet- induced obesity models modulates the gut microbial composition, reduces the level of endotoxaemia, and elicits improvements in indices of glucose metabolism. Further, a growing number of studies also support the potential for probiotic supplements to have positive effects on glucose metabolism. Single- strain probiotic supplements administered over 14 weeks of high- fructose feeding and over eight weeks in a diabetic rat model were associated with lower fasting glucose and insulin and improved glucose clearance following a glucose tolerance test, and lower fasting insulin and homeostatic model assessment for insulin resistance (HOMA- IR), respectively. Similarly, in high- fat fed mice, improved glucose clearance after glucose tolerance tests has been reported following Lactobacillus single- strain probiotic supplementation over 5 and 10 weeks, and also in response to dual- and multistrain supplements. Collectively, these data support the potential for modulation of the intestinal microbiota to mediate improvements in insulin sensitivity.
Findings from antibiotic studies have yet to be widely replicated in humans in the context of glucose metabolism. A recent meta- analysis assessing the impacts of antibiotics on metabolic status in adults with obesity includes just two placebo- controlled trials, with effects that are largely unclear. The effects of probiotic supplementation have also been assessed in a series of human clinical studies. While not all probiotic supplementation trials have been able to demonstrate definitive benefits on glycaemia, early positive findings included improved insulin sensitivity fol lowing four weeks of probiotic supplementation in a cohort of adults with overweight (n = 45) and a range of glucose tolerance. In addition, two trials from the same laboratory report reductions in fasting glucose, fasting insulin, and HOMA- IR in a cohort of overweight adults and in otherwise healthy young adults following six weeks of probiotic supplementation. A series of recent meta- analyses also support modest, but beneficial, effects of probiotics on measures of glycaemic metabolism in individuals with type 2 diabetes; however, selection of specific strains likely to have the greatest efficacy is unresolved.
The application of faecal microbial transplantation as a further strategy for modulation of the gut microbiota in obesity and metabolic disease is of growing interest. However, there remain few human clinical studies assessing indices of metabolic health as primary outcomes. An early study involving men with metabolic syndrome administered either an autologous gut micro biota duodenal infusion (n = 9) or an allogenic gut microbiota duodenal infusion from healthy lean donors (n = 9) and reported improvements in peripheral insulin sensitivity and a trend towards reduced endogenous glucose production six weeks following allogenic infusion only. A subsequent investigation from the same team, also involving men with obesity and metabolic syn drome (n = 38) and utilizing a similar design reported that improvements in peripheral insulin sensitivity observed at 6 weeks were not maintained at 18 weeks, and noted that low baseline microbial diversity was predictive of positive metabolic responses among recipients of faecal microbial transplantation.
Microbial metabolites may be key mediators linking the gut microbiota and insulin signalling pathways. Serum metabolite sig natures, specifically increased abundance of branched- chain amino acids (BCAAs), which are unable to be synthesized by humans and therefore must be obtained from the diet or derived from microbial metabolism, have been associated with insulin resistance in two independent studies. In a series of follow- up experiments utilizing a high- fat fed murine model, the authors of one study demonstrated that challenging mice with Prevotella copri, a species identified as synthesizing BCAAs, over three weeks resulted in increased circulating BCAA concentrations and exacerbated insulin resistance. Another metabolite, imidazole propionate, which is a byproduct of the microbial metabolism of dietary histidine, was also found at higher circulating concentrations in individuals with type 2 diabetes and was associated with severity of insulin resistance. Interestingly, in a murine model, administration of imidazole propionate impaired glucose tolerance independent of changes in insulin concentrations; subsequent in vitro experiments revealed alterations in phosphorylation of the insulin receptor substrate (IRS) and activation of the mechanistic target of rapamycin complex (mTORC1) in response to imidazole propionate. These insights provide early evidence of a causal link between the gut microbiota and alterations in insulin signal ling pathways.
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