Gut Microbes最新文献

Aging is a key contributor of morbidity and mortality during acute viral pneumonia. The potential role of age-associated dysbiosis on disease outcomes is still elusive. In the current study, we used high-resolution shotgun metagenomics and targeted metabolomics to characterize SARS-CoV-2-associated changes in the gut microbiota from young (2-month-old) and aged (22-month-old) hamsters, a valuable model of COVID-19. We show that age-related dysfunctions in the gut microbiota are linked to disease severity and long-term sequelae in older hamsters. Our data also reveal age-specific changes in the composition and metabolic activity of the gut microbiota during both the acute phase (day 7 post-infection, D7) and the recovery phase (D22) of infection. Aged hamsters exhibited the most notable shifts in gut microbiota composition and plasma metabolic profiles. Through an integrative analysis of metagenomics, metabolomics, and clinical data, we identified significant associations between bacterial taxa, metabolites and disease markers in the aged group. On D7 (high viral load and lung epithelial damage) and D22 (body weight loss and fibrosis), numerous amino acids, amino acid-related molecules, and indole derivatives were found to correlate with disease markers. In particular, a persistent decrease in phenylalanine, tryptophan, glutamic acid, and indoleacetic acid in aged animals positively correlated with poor recovery of body weight and/or lung fibrosis by D22. In younger hamsters, several bacterial taxa (Eubacterium, Oscillospiraceae, Lawsonibacter) and plasma metabolites (carnosine and cis-aconitic acid) were associated with mild disease outcomes. These findings support the need for age-specific microbiome-targeting strategies to more effectively manage acute viral pneumonia and long-term disease outcomes.

Roux-en-Y gastric bypass (RYGB) results in glucose-lowering in patients with type 2 diabetes mellitus (T2DM) and may be associated with increased intestinal glucose excretion. However, the contribution of intestinal glucose excretion to glycemic control after RYGB and its underlying mechanisms are not fully elucidated. Here, we confirmed that intestinal glucose excretion significantly increased in obese rats after RYGB, which was negatively correlated with postoperative blood glucose levels. Moreover, we also found that the contribution of Biliopancreatic limb length, an important factor affecting glycemic control after RYGB, to the improvement of glucose metabolism after RYGB attributed to the enhancement of intestinal glucose excretion. Subsequently, we further determined through multiple animal models that intestinal glucose excretion is physiological rather than pathological and plays a crucial role in maintaining glucose homeostasis in the body. Finally, we employed germ-free mice colonized with fecal samples from patients and rats to demonstrate that enhanced intestinal glucose excretion after RYGB is directly modulated by the surgery-induced changes in the gut microbiota. These results indicated that the gut microbiota plays a direct causal role in the hypoglycemic effect of RYGB by promoting intestinal glucose excretion, which may provide new insights for developing gut microbiota-based therapies for T2DM.

Liver cancer is usually diagnosed at an advanced stage and is the third most common cause of cancer-related death worldwide. In addition to the lack of effective treatment options, resistance to therapeutic drugs is a major clinical challenge. The gut microbiota has recently been recognized as one of the key factors regulating host health. The microbiota and its metabolites can directly or indirectly regulate gene expression in the liver, leading to gut-liver axis dysregulation, which is closely related to liver cancer occurrence and the treatment response. Gut microbiota disturbance may participate in tumor progression and drug resistance through metabolite production, gene transfer, immune regulation, and other mechanisms. However, systematic reviews on the role of the gut microbiota in drug resistance in liver cancer are lacking. Herein, we review the relationships between the gut microbiota and the occurrence and drug resistance of hepatocellular carcinoma, summarize the emerging mechanisms underlying gut microbiota-mediated drug resistance, and propose new personalized treatment options to overcome this resistance.

Roseburia intestinalis is one of the most abundant and important butyrate-producing human gut anaerobic bacteria that plays an important role in maintaining health and is a potential next-generation probiotic. We investigated the pangenome of 16 distinct strains, isolated over several decades, identifying local and time-specific adaptations. More than 50% of the genes in each individual strain were assigned to the core genome, and 77% of the cloud genes were unique to individual strains, revealing the high level of genome conservation. Co-carriage of the same enzymes involved in carbohydrate binding and degradation in all strains highlighted major pathways in carbohydrate utilization and reveal the importance of xylan, starch and mannose as key growth substrates. A single strain had adapted to use rhamnose as a sole growth substrate, the first time this has been reported. The ubiquitous presence of motility and sporulation gene clusters demonstrates the importance of these phenotypes for gut survival and acquisition of this bacterium. More than half the strains contained functional, potentially transferable, tetracycline resistance genes. This study advances our understanding of the importance of R. intestinalis within the gut ecosystem by elucidating conserved metabolic characteristics among different strains, isolated from different locations. This information will help to devise dietary strategies to increase the abundance of this species providing health benefits.

Evidence suggests a tumor-suppressive effect of the intake of yogurt, which typically contains Bifidobacterium. We hypothesized that long-term yogurt intake might be associated with colorectal cancer incidence differentially by tumor subgroups according to the amount of tissue Bifidobacterium. We utilized the prospective cohort incident-tumor biobank method and resources of two prospective cohort studies. Inverse probability weighted multivariable Cox proportional hazards regression was used to assess differential associations of yogurt intake with the incidence of colorectal carcinomas subclassified by the abundance of tumor tissue Bifidobacterium. During follow-up of 132,056 individuals, we documented 3,079 incident colorectal cancer cases, including 1,121 with available tissue Bifidobacterium data. The association between long-term yogurt intake and colorectal cancer incidence differed by Bifidobacterium abundance (P heterogeneity = 0.0002). Multivariable-adjusted hazard ratios (HRs) (with 95% confidence intervals) in individuals who consumed ≥2 servings/week (vs. <1 serving/month) of yogurt were 0.80 (0.50-1.28) for Bifidobacterium-positive tumor and 1.09 (0.81-1.46) for Bifidobacterium-negative tumor. This differential association was also observed in a subgroup analysis of proximal colon cancer (P heterogeneity = 0.018). Long-term yogurt intake may be differentially associated with the incidence of proximal colon cancer according to Bifidobacterium abundance, suggesting the antitumor effect of yogurt intake on the specific tumor subgroup.

The gut microbiome's pivotal role in health and disease is well established. SARS-CoV-2 infection often causes gastrointestinal symptoms and is associated with changes of the microbiome in both human and animal studies. While hamsters serve as important animal models for coronavirus research, there exists a notable void in the functional characterization of their microbiomes with metaproteomics. In this study, we present a workflow for analyzing the hamster gut microbiome, including a metagenomics-derived hamster gut microbial protein database and a data-independent acquisition metaproteomics method. Using this workflow, we identified 32,419 protein groups from the fecal microbiomes of young and old hamsters infected with SARS-CoV-2. We showed age-specific changes in the expressions of microbiome functions and host proteins associated with microbiomes, providing further functional insight into the interactions between the microbiome and host in SARS-CoV-2 infection. Altogether, this study established and demonstrated the capability of metaproteomics for the study of hamster microbiomes.

Gut microbiota-derived butyrate plays a vital role in attenuating hepatocellular carcinoma (HCC) in murine models. However, the precise molecular mechanisms by which butyrate exerts its effects are largely undefined. Plasma short-chain fatty acids (SCFAs) were quantitatively measured by using gas chromatography-mass spectrometry (GC-MS) to access their association with HCC prognosis. Tumor-infiltrating immune cells were characterized by flow cytometry. The interactions between butyrate and natural killer (NK) cells were studied using in vitro assays, including migration, cytotoxic degranulation, and co-culture experiments. In vivo validation was conducted through neutralization experiments. The molecular pathways regulated by butyrate were further investigated by employing RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). A positive correlation was observed between elevated plasma butyrate levels and improved prognosis in HCC patients. Notably, butyrate inhibited tumor progression by enhancing NK cell infiltration into tumor tissues. Mechanistically, butyrate stimulated cytokine secretion, notably significantly enhancing the production of the chemokine CXCL11, thereby facilitating NK cell infiltration. Gene Set Enrichment Analysis (GSEA) of hepatic tumor cell lines revealed that the chemokine signaling and NK cell-mediated cytotoxicity pathways were upregulated following butyrate stimulation. Furthermore, transcriptomic and epigenomic analyses showed that exposure to butyrate induced de novo chromatin accessibility and enhancer remodeling, regulated by STAT family transcription factors. Our study demonstrated that butyrate was able to enhance the expression of CXCL11. This is likely attributed to chromatin remodeling, and then promoting NK cell infiltration and exerting effective anti-tumor effects on HCC.

Appendectomy has been associated with reduced risk of developing ulcerative colitis (UC) or experiencing flares after diagnosis, suggesting the appendix may play a role in UC pathogenesis. Given its function in microbial homeostasis and gut immunity, we investigated the relationship between mucosal microbiota and immune environment of the appendix in UC. Appendix tissue was collected from 85 patients undergoing surgery for UC, acute appendicitis (APA) or colon cancer (CC). Immunophenotyping of dendritic cells (DC), macrophages and T lymphocytes was performed using flow cytometry. Microbiota composition was analyzed via 16S rRNA gene amplicon sequencing. Although alpha diversity did not differ between UC and non-UC appendices, beta diversity indicated significant compositional differences. Five bacterial species (Actinomyces hyovaginalis, Mogibacterium sp. Fusobacterium sp. Pseudoramibacter eubacterium, and Streptococcus anginosus) were significantly reduced in the UC appendix compared to APA. However, no species were associated with UC disease activity. In contrast, UC patients showed a significantly higher frequency of activated DCs (CD1a⁺ HLAdr⁺ CD86⁺). DC activation levels correlated with daily stool frequency and T-cell activation. These findings suggest that the appendix may contribute to UC pathogenesis through immune, rather than microbial, mechanisms - supporting a role for dendritic cell-mediated T-cell priming in colonic inflammation.

Radiation-induced gastrointestinal (GI) toxicity can be a major cause of morbidity in patients undergoing abdominal radiotherapy. There is an unmet need for treatments to ameliorate GI toxicity. Estrogen-related receptor alpha (ESRRA), a protein involved in the regulation of inflammation and autophagy, is widely expressed across human tissues. Our recent findings on ESRRA's significant contribution to intestinal homeostasis and inflammation control in inflammatory bowel disease inspired us to investigate its potential role in radiation-induced gastrointestinal injury. esrra^-/- mice showed distinct gut microbiota composition and increased susceptibility to abdominal irradiation with significant alteration of microbiota and increased intestinal inflammation. B. vulgatus reversed gut pathology in esrra^-/- mice by improving intestinal barrier function, reducing inflammation, and restoring the expression of Tfeb and its downstream genes. Additionally, in patients treated with abdominal radiotherapy, decreased ESRRA expression in rectal tissues correlated with increased IL-6 expression and radiation induced diarrhea. Our findings indicate that ESRRA contributes to intestinal homeostasis through gut enrichment of B. vulgatus.

Alcohol-associated liver disease (ALD) is a prevalent global health issue primarily caused by excessive alcohol consumption. Recent studies have highlighted the gut-liver axis's protective role against ALD, mainly through gut microbiota. However, the precise mechanism remains ill-defined. Our results showed a significant reduction in Lachnospiraceae bacterium in the gut microbiota of ALD patients and ethanol (EtOH)-fed mice, as revealed by 16S rDNA sequencing. Supplementation with Lachnospiraceae bacterium strains in mice significantly reduced inflammation, hepatic neutrophil infiltration, oxidative stress, and improved gut microbiota and intestinal permeability. Multi-omics analysis identified N-Acetyl-glutamic acid (NAG) as the most significantly altered metabolite following Lachnospiraceae bacterium supplementation, with levels positively correlated to Lachnospiraceae bacterium colonization. NAG treatment exhibited significant protective effects in EtOH-exposed hepatocyte cell lines and EtOH-fed mice. Mechanistically, NAG confers hepatoprotection against ALD by activating the KEAP1-NRF2 pathway, inhibiting ferroptosis. Notably, the protective effects of NAG were reversed by the NRF2 inhibitor. In conclusion, oral supplementation with Lachnospiraceae bacterium mitigates alcohol-induced liver damage both in vivo and in vitro by inhibiting ferroptosis through NAG-mediated activation of the KEAP1-NRF2 pathway. Lachnospiraceae bacterium may serve as promising probiotics for future clinical applications.