Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS. Here we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters. In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.

Background: The results of studies investigating the effect of green tea on glucose control and insulin sensitivity in humans are inconsistent.

Emerging evidence suggests that Omega-3 polyunsaturated fatty acids (PUFAs) are essential structural and functional nutrients that significantly influence the composition and function of the gut microbiota, a key mediator of host health. Although evidence suggests that increasing tissue Omega-3 levels through dietary intervention may optimize gut microbiota–host interaction through modulation of composition, metabolite production, and the intestinal mucus barrier, some studies have reported inconsistent findings regarding these protective effects. Studies indicate that a high Omega-6/Omega-3 ratio appears to attenuate the beneficial effects of Omega-3 supplementation on microbial diversity and abundance, while a balanced ratio fosters a more favorable microbiome profile. This review comprehensively highlights the potential effects of differential endogenous Omega-6/Omega-3 ratios on the gut microbiota-modulating capacity of Omega-3 PUFAs, which should be incorporated as a mandatory monitoring indicator in future clinical investigations. These insights provide a new direction for further optimizing the clinical application of Omega-3 PUFAs in chronic disease prevention and treatment.

Hyperglycemia significantly contributes to the development and progression of metabolic diseases. Managing postprandial blood glucose fluctuations is of particular importance for patients with hyperglycemia, but safe and effective means of reducing blood glucose levels are still lacking. Five diets with varying macronutrient ratios and omega-3 fatty acid amounts were tested for their blood glucose-lowering effects in male C57BL/6J mice. The diets with potent blood glucose-lowering effects were further investigated for their underlying mechanisms and their beneficial effects on hyperglycemia models. Mice given the low-carbohydrate, high-protein, and high-omega-3 (LCHP+3) diet exhibited a rapid reduction of the blood glucose levels that remained consistently low, regardless of feeding. These effects were associated with reduced amino acid gluconeogenesis, due to the inhibition of hepatic alanine transaminase (ALT). Furthermore, the LCHP+3 intervention was effective in reducing the blood glucose levels in several disease conditions, including type 1 diabetes mellitus, hormone-induced hyperglycemia, and diet-induced metabolic syndrome. Our findings identify the LCHP+3 diet as a potent blood glucose-lowering diet that suppresses postprandial blood glucose fluctuations through the inhibition of gluconeogenesis and may have great clinical utility for the management of metabolic diseases with hyperglycemia.

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial β-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host–microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.

Alzheimer's disease (AD) is mainly manifested by cognitive dysfunction, accompanied by excessive β-amyloid (Aβ) deposition and neuroinflammation. The regulation of vagus nerve (VN) signal transmission is crucial for influencing the pathological progression of AD and exploring new therapeutic approaches. Two doses of 2′-fucosyllactose (2′-FL, 500 and 1000 mg kg⁻¹) were administered orally to AD model mice. 2′-FL rescued spatial and recognition memory deficits in AD mice. Moreover, 2′-FL reduced Aβ deposition and neuroinflammation. 2′-FL enhances c-Fos expression in the solitary tract nucleus (NTS). This suggested that 2′-FL alleviated AD-related cognition by enhancing VN afferent activity. Vagotomy demonstrated that the alleviation of AD-related cognition by 2′-FL depended on the presence of VN. Moreover, 2′-FL enhanced gut barrier function and alleviated gut inflammation. Notably, 2′-FL also reshaped the gut microbiota composition, increasing the relative abundance of Intestinimonas, Muribaculum, and others. Moreover, 2′-FL promoted the production of short-chain fatty acids (SCFAs). Correlation analysis showed that propionate was highly correlated with other related indicators. After vagotomy, although 2′-FL promoted SCFA production, it did not alleviate cognitive impairment. This suggested that the neuroprotective effect of SCFAs could also be partially dependent on the VN. 2′-FL rescued the cognitive deficits in AD mice, which was partly explained by changes in gut microbial composition, production of SCFAs, and the presence of VN.