Gut microbiota modulation of regulatory DNA elements revealed by massively parallel functional characterization
Mol Cell. 2026 Apr 23;S1097-2765(26)00232-7. doi: 10.1016/j.molcel.2026.03.036.
We mapped over 100,000 liver cis-regulatory elements in human hepatocytes under both in vitro and in vivo conditions. Our results reveal that gut microbiota–derived signals, including microbial metabolites, directly regulate liver gene expression by modulating regulatory elements, partly through the KEAP1/NFE2L2 pathway. This study highlights a microbiota-dependent layer of gene regulation in the human liver.
The oral-gut microbiome axis in diabetes mellitus: a systematic review and emerging clinical perspectives
Diabetes Res Clin Pract. 2026 May:235:113232. doi: 10.1016/j.diabres.2026.113232.
Emerging evidence suggests that diabetes mellitus (DM) is influenced by microbial interactions across the oral and gut microbiomes. This review summarizes studies profiling paired oral and gut microbiota in diabetes, showing consistent dysbiosis in both niches. Oral-associated bacteria such as Streptococcus, Prevotella, Fusobacterium, and Porphyromonas were also detected in the gut, suggesting microbial transmission between sites. Shared functional disruptions, including altered short-chain fatty acid and glycine betaine metabolism, were linked to inflammation, insulin resistance, and clinical markers such as HbA1c and fasting glucose. Machine-learning models integrating oral and gut microbiota showed promising diagnostic performance. Overall, the oral-gut microbiome axis may represent a novel target for biomarkers and therapeutic strategies in DM, although longitudinal and interventional studies are still needed.
GPR41 deficiency alters the gut microbiota-bile acid axis, reduces ileal expression of Npc1l1, and attenuates hypercholesterolemia in male mice
Gut Microbes. 2025 Dec 31;17(1):2598957. doi: 10.1080/19490976.2025.2598957.
Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular disease. Short-chain fatty acids (SCFAs), produced by gut bacterial fermentation of dietary fiber, may exert atheroprotective effects through receptors such as GPR41, GPR43, and GPR109A. Using a PCSK9-AAV mouse model of hypercholesterolemia, we found that deficiency of individual SCFA receptors did not significantly alter atherosclerotic plaque burden. However, male Gpr41-/- mice showed reduced adiposity, plasma lipids, altered gut microbiota, increased cecal propionate, and reduced expression of intestinal nutrient transporters. These findings suggest that GPR41 plays an important role in regulating nutrient absorption, lipid metabolism, and gut microbiota composition.
Bacteroides- and Prevotella-enriched gut microbial clusters associate with metabolic risks
Gut Pathogens. 2025 Jul 21;17(1):55. doi: 10.1186/s13099-025-00730-3.
The gut microbiome strongly influences metabolism and immunity, and its disruption is linked to metabolic disorders. In a large-scale Japanese cohort, we used 16S rRNA sequencing to classify gut microbiomes into refined enterotypes and found two high-risk profiles: Bacteroides 2 (B2) and a newly identified Prevotella 2 (P2). Both were associated with reduced diversity, depletion of short-chain fatty acid producers (e.g., Faecalibacterium), and enrichment of opportunistic pathogens. Individuals with these enterotypes showed significantly higher risk of obesity, hypertension, and diabetes. Our findings highlight refined enterotyping as a valuable approach for stratifying metabolic disease risk and guiding early interventions.
Gut microbes modulate the effects of the flavonoid quercetin on atherosclerosis
NPJ Biofilms Microbiomes. 2025 Jan 10;11(1):12. doi: 10.1038/s41522-024-00626-1.
The gut bacterial metabolism of dietary flavonoids produces a variety of phenolic acids, whose contributions to health remain poorly understood. Using gnotobiotic models and metabolomics approaches, we found that gut microbes influences the effects of quercetin on atherosclerosis, potentially mediated by bacterial metabolites derived from the flavonoid.
Gut bacterial metabolism contributes to host global purine homeostasis
Cell Host Microbe. 2023 Jun 14;31(6):1038-1053.e10. doi: 10.1016/j.chom.2023.05.011.
In the paper, we identified gut bacterial taxa spanning multiple phyla, including Bacillota, Fusobacteriota, and Pseudomonadota, that use multiple purines, including uric acid (UA) as carbon and energy sources anaerobically. We found a gene cluster that encodes key steps of anaerobic purine degradation and that is widely distributed among gut-dwelling bacteria. Furthermore, we showed that colonization of gnotobiotic mice with purine-degrading bacteria modulates levels of UA and other purines in the gut and systemically. Thus, gut microbes are important drivers of host global purine homeostasis and serum UA levels, and gut bacterial catabolism of purines may represent a mechanism by which gut bacteria influence health.
Dissecting the impact of dietary fiber type on atherosclerosis in mice colonized with different gut microbial communities
NPJ Biofilms Microbiomes. 2023 Jun 3;9(1):31. doi: 10.1038/s41522-023-00402-7.
Dietary fiber consumption has been linked with improved cardiometabolic health, however, human studies have reported large interindividual variations in the observed benefits. Using germ-free mice with fecal samples from three human donors and diets supplemented with either a mix of 5 fermentable fibers (FF) or non-fermentable cellulose control diet, we found that atheroprotection in response to FF is not universal and is influenced by the gut microbiome.
Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut
Nature Microbiology. 2023 May; 8(3):424-440. doi: 10.1038/s41564-023-01326-w.
The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.
The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass
Gut Microbes. 2022 Jan-Dec;14(1):2050635. doi: 10.1080/19490976.2022.2050635.
Roux-en-Y gastric bypass (RYGB) effectively induces weight loss and improves type-2 diabetes (T2D), but outcomes vary. Given its impact on gut microbiota (GM), we investigated its role in metabolic benefits. In a 5-year study of 100 patients with baseline T2D, hierarchical clustering identified two groups: Severe and Mild T2D cases. Nanopore sequencing revealed that unresolved severe T2D was linked to an enrichment of Bacteroidia, including Phocaeicola dorei, Bacteroides fragilis, and Bacteroides caecimuris. This enrichment was absent in patients with better metabolic outcomes. A separate cohort showed that Bacteroidia overrepresentation was already present preoperatively in severe T2D cases. To explore causality, fecal transplants from 13 patients into mice demonstrated that Severe-donor GM impaired glucose tolerance and insulin sensitivity, independent of body weight. GM sequencing confirmed bacterial feature transfer linked to metabolic dysfunction. These findings highlight the GM’s role in long-term glucose metabolism after RYGB.
The emerging role of gut microbial metabolism on cardiovascular disease
Curr Opin Microbiol. 2019 Aug:50:64-70. doi: 10.1016/j.nib.2019.09.007.
The purpose of this review is to discuss recent progress in our understanding of how gut microbial metabolism of food influences the development of CVD and to outline experimental approaches that can be useful for addressing crucial knowledge gaps in the field.
Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model
Nature Microbiology. 2018 Dec;3(12):1461-1471. doi: 10.1038/s41564-018-0272-x.
Humans with metabolic and inflammatory diseases frequently harbour lower levels of butyrate-producing bacteria in their gut. However, it is not known whether variation in the levels of these organisms is causally linked with disease development and whether diet modifies the impact of these bacteria on health. Here we use germ-free apolipoprotein E-deficient mice colonized with synthetic microbial communities that differ in their capacity to generate butyrate to demonstrate that Roseburia intestinalis interacts with dietary plant polysaccharides to: impact gene expression in the intestine, directing metabolism away from glycolysis and toward fatty acid utilization; lower systemic inflammation; and ameliorate atherosclerosis. Our results illustrate how modifiable diet-by-microbiota interactions impact cardiovascular disease, and suggest that interventions aimed at increasing the representation of butyrate-producing bacteria may provide protection against atherosclerosis.
Fecal Aliquot Straw Technique (FAST) allows for easy and reproducible subsampling: assessing interpersonal variation in TMAO accumulation
Microbiome. 2018 May 18;6(1):91. doi: 10.1186/s40168-018-0458-8.
The Fecal Aliquot Straw Technique (FAST) is a convenient and reproducible method for fecal sample storage and subsampling, preserving viable microbes for microbiome studies. Using a straw, samples can be collected from freshly voided or refrigerated (4°C) feces without freezing. 16S rRNA sequencing confirmed high reproducibility, with minimal taxonomic variation between aliquots. Transplantation into germ-free mice retained ~80% of the donor’s microbiota, with notable interpersonal variation in choline metabolism. FAST enables repeated subsampling without thawing, requiring minimal resources, making it ideal for both laboratory and field research.
Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption
Cell Host Microbe. 2017 Sep 13;22(3):279-290.e7. doi: 10.1016/j.chom.2017.07.021.
Choline is an essential nutrient and methyl donor involved in epigenetic regulation. This study examined how gut microbial choline metabolism affects host biology using a microbial community lacking a key choline-utilizing enzyme. Choline-consuming bacteria competed with the host for choline, reducing plasma and hepatic methyl-donor metabolites and inducing features of choline deficiency. Mice with high levels of these bacteria were more susceptible to metabolic disease under a high-fat diet. Reduced methyl-donor availability also altered DNA methylation patterns and behavior in both adult mice and their offspring. These findings highlight the impact of microbial choline metabolism on host metabolism, epigenetics, and behavior.
Commensal bacteria at the crossroad between cholesterol homeostasis and chronic inflammation in atherosclerosis
Journal of Lipid Research. 2017 Mar;58(3):519-528. doi: 10.1194/jlr.M072165.
Gut microbiota play important roles in atherosclerosis, although the mechanisms remain unclear. Using germ-free and conventionally raised ApoE-/- mice, we found that the absence of gut microbiota increased plasma and hepatic cholesterol levels by altering bile acid metabolism and suppressing hepatic bile acid synthesis. Despite this hypercholesterolemia, germ-free mice showed reduced atherosclerotic lesion formation, likely due to decreased lipopolysaccharide-mediated inflammation. These findings suggest that gut microbiota influence both lipid metabolism and inflammatory pathways involved in atherogenesis.
