Obesity is associated with a chronic low-grade inflammation affecting metabolic changes and organ dysfunction. Impairment of the intestinal epithelial barrier (IEB) and alterations in gut microbiota are considered to contribute to this phenotype by largely undefined mechanisms. Here, we used a diet-induced obesity model in rats to investigate the early interplay between a high-fat diet (HFD), gut microbiota composition, metabolic stool contents and IEB regeneration. Male Wistar rats received either a high-fat diet or a low-fat diet (LFD) ad libitum. HFD feeding resulted in weight gain and impaired oral glucose tolerance. Impairment of IEB function was evident by augmented lipopolysaccharide levels in the blood and reduced expression of junctional proteins Claudin-3, 4, and Desmoglein-2 in colonic samples of HFD rats. 16S-rRNA marker-gene sequencing of colonic microbiota revealed decreased phylogenetic diversity in HFD rats and significant alterations in microbial community composition. Detailed analysis revealed that content from HFD rats impaired intestinal epithelial regeneration in organoid assays. Metabolomic profiling identified uridine monophosphate/uridine diphosphate (UMP/UDP) metabolites as strongly enriched in HFD samples. UDP emerged as a key metabolite mediating impaired epithelial regeneration through P2Y6 receptor signaling, as pharmacological inhibition of P2Y6 with antagonist MRS2578 attenuated both UDP- and HFD-induced loss of epithelial regeneration. In summary, these data demonstrate that the diet-dependent stool metabolite UDP compromises intestinal epithelial repair via P2Y6 receptor signaling in early obesity. These findings link impaired epithelial regeneration to the onset of obesity-associated low-grade inflammation.
An emerging focus in microbiome science is on changes to people’s microbiomes following immigration, particularly to so-called Western countries, such as the USA, Canada, and Australia. Moving to these regions has been linked to microbiome changes that may increase immigrants’ susceptibility to health problems, including obesity and Inflammatory Bowel Disease. The term “Westernization” (and adjacent terminology) is frequently used to describe changes in diet, lifestyle, and built environment – and the consequent microbiome shifts – associated with immigration. However, what Westernization means in this context, and whether it is an appropriate descriptor, is often unclear. The purpose of this article is to provide a review of the diverse meanings associated with the terms “West”, “Western”, “Westernization” (and similar) across microbiome-related research and broader uses. We argue that these terms can obscure the specific structural, environmental, and cultural factors shaping microbiome changes. We discuss the consequences of this imprecision and provide recommendations for future research. Avoiding oversimplified conclusions about what impacts immigrants’ microbiome and health can contribute to more accurate targets for public health interventions for these groups in the long term.
The human gut microbiome undergoes changes across the lifespan and has been implicated in age-related decline. The symbol digit modalities test (SDMT) is a measure of information processing speed and is sensitive to mild cognitive impairment. Here, we assessed SDMT scores and fecal shotgun metagenomics in older individuals from the Imageomics cohort (n = 867) and performed fecal microbiota transplantation (FMT) from human donors to male C57BL/6 mouse recipients. In mice, we evaluated cognitive performance using the Morris water maze (MWM) and measured neurone density, fecal shotgun metagenomics, hippocampal metabolomics, and cortical gene expression to identify microbial-derived functional properties related to cognitive performance. In humans, both microbial species composition and functional profiles were associated with cognitive performance. FMT from high-SDMT donors improved cognitive performance and increased neuronal density in recipient mice compared with FMT from low-SDMT donors. In both humans and mice, higher cognitive performance was associated with arginine and proline metabolism and pterin-related pathways. In mice receiving microbiota from high-SDMT donors, cortical gene expression showed enrichment of dopamine receptor pathways and reduced dopamine reuptake and catecholamine biosynthesis. Our findings highlight the potential role of the gut microbiome in cognitive performance among older individuals, particularly information processing speed, and identify potential mechanisms involving alterations in arginine and pterin metabolism. Integrating human and mouse data supports a model in which microbiota-associated metabolic remodeling influences cognitive performance.
Obesity is a major global health challenge, necessitating safe and effective therapies. Although probiotics are promising for obesity management, research has focused on bacteria, leaving non-Saccharomyces yeasts underexplored. Here, we investigated the anti‑obesity mechanisms of Rhodotorula mucilaginosa DM2025, isolated from the healthy murine gut. To test whether benefits depend on viable cells, high‑fat diet‑fed mice received either live yeast or its cell‑free supernatant, followed by integrated physiological, genomic, and metabolomic analyzes. Live yeast, but not supernatant, significantly reduced body weight gain, improved serum lipids, and was associated with activation of brown adipose tissue thermogenesis (upregulated PPARγ, PGC1α, UCP1). Though the supernatant lowered total cholesterol, it failed to affect weight or thermogenic genes, indicating cholesterol‑lowering and weight reduction are distinct processes. Live cells were enriched in propionate, indole, and carotenoid‑related metabolites, with genomic support for their biosynthesis. Live yeast reshaped the gut mycobiome, promoting Basidiomycota/Rhodotorula dominance; this fungal restructuring was absent in HFD controls. These findings suggest that R. mucilaginosa DM2025 anti‑obesity efficacy relies on the continuous metabolic activity of live cells, producing thermogenesis‑associated metabolites that may contribute to BAT activation. Additionally, physical cholesterol binding to the yeast cell surface provides a complementary cholesterol‑reduction mechanism. Thus, R. mucilaginosa DM2025 represents a promising live probiotic candidate for obesity intervention.
The gut microbiota is increasingly recognized as a regulator of host lipid metabolism, yet the specific strains and effector metabolites driving hyperlipidemia remain poorly defined. Here, we identified Ruminococcus gnavus (R. gnavus) as a candidate contributor to cholesterol-related dyslipidemia and delineated its metabolic mechanism. Comparing individuals with high versus normal TC/LDL-C (HTL vs NTL) in both normal-weight and overweight populations, we found that fecal R. gnavus was enriched in HTL individuals regardless of BMI stratum, a finding validated by species-specific qPCR in an independent cohort (n = 488). Administering R. gnavus to mice fed a normal or high-fat diet induced alterations in circulating lipids and liver function markers, accompanied by hepatic steatosis. Hepatic transcriptomics and targeted bile acid profiling converged on bile acid metabolism: R. gnavus downregulated key hepatic genes (Cyp7a1, Cyp8b1, Ldlr, and Ppara) and elevated isochenodeoxycholic acid (isoCDCA) levels both in vivo and in vitro. In vitro, R. gnavus directly converted chenodeoxycholic acid (CDCA) to isoCDCA. Clinically, serum isoCDCA was elevated in HTL individuals in an independent cohort (n = 1,137) and was positively associated with TC, TG, and LDL-C. Functionally, oral isoCDCA supplementation reproduced key lipid disturbances in mice, and isoCDCA downregulated lipid metabolism genes and promoted lipid accumulation in hepatocytes; heterologous expression of R. gnavus hydroxysteroid dehydrogenases conferred isoCDCA-producing capacity on E. coli and elevated circulating TC and LDL-C in colonized mice. These findings nominate isoCDCA as a microbial effector metabolite linking R. gnavus to hepatic lipid dysregulation and identify the R. gnavus–isoCDCA axis as a potential target for the prevention and treatment of hyperlipidemia.
