Gut Microbes最新文献

Maternal obesity poses a significant threat to the metabolic profiles of offspring. Microorganisms acquired from the mother early in life critically affect the host's metabolic functions. Natural non-nutritive sweeteners, particularly stevioside (STV), play a crucial role in reducing obesity and affecting gut microbiota composition. Based on this, we hypothesized that maternal STV supplementation could improve the health of mothers and offspring by altering their gut microbiota. Our study found that maternal STV supplementation reduced obesity during pregnancy, decreased abnormal lipid accumulation in offspring mice caused by maternal obesity, and modified the gut microbiota of both dams and offspring, notably increasing the abundance of Lactobacillus apodemi (L. apodemi). Co-housing and fecal microbiota transplant experiments confirmed that gut microbiota mediated the effects of STV on metabolic disorders. Furthermore, treatment with L. apodemi alone replicated the beneficial effects of STV, which were associated with increased thermogenesis. In summary, maternal STV supplementation could alleviate lipid metabolic disorders in offspring by enhancing L. apodemi levels and promoting thermogenic activity, potentially involving changes in bile acid metabolism pathways.

Polyamines are important gut microbial metabolites known to affect host physiology, yet the mechanisms behind their microbial production remain incompletely understood. In this study, we developed a stable isotope-resolved metabolomic (SIRM) approach to track polyamine biosynthesis in the gut microbiome. Viable microbial cells were extracted from fresh human and mouse feces and incubated anaerobically with [U-¹³C]-labeled inulin (tracer). Liquid chromatography-high resolution mass spectrometry analysis revealed distinct ¹³C enrichment profiles for spermidine (SPD) and putrescine (PUT), indicating that the arginine-agmatine-SPD pathway contributes to SPD biosynthesis in addition to the well-known spermidine synthase pathway (PUT aminopropylation). Species differences were observed in the ¹³C enrichments of polyamines and related metabolites between the human and mouse microbiome. By analyzing the fecal metabolomics and metatranscriptomic data from an inflammatory bowel disease (IBD) cohort, we found significantly higher polyamine levels in IBD patients compared to healthy controls. Further investigations using single-strain SIRM and in silico analyses identified Bacteroides spp. as key contributors to polyamine biosynthesis, harboring essential genes for this process and potentially driving the upregulation of polyamines in IBD. Taken together, this study expands our understanding of polyamine biosynthesis in the gut microbiome and will facilitate the development of precision therapies to target polyamine-associated diseases.

Lymphoid tissue-resident commensal bacteria (LRC), a subtype of gut microbiota essential for inflammation-associated carcinogenesis, predominantly attribute to colorectal cancer(CRC), whereas its role was largely unknown. Herein, we found Alcaligenes faecalis (A. faecalis), the main LRC embedded in Peyer's patches, was abundantly enriched in colitis, adenoma, and stage-dependently observed in CRC tissues. Interestingly, A. faecalis alone can not affect intestinal homeostasis, while during colitis, A. faecalis significantly translocated from Peyer's patches to colon, remarkably attenuated immune response abilities of B cells, T cells, and DC cells in PPs, consequently impeded IgA+ B cells homing. Meanwhile, during colitis, the ectopia of A. faecalis in colon tissues, promoted vinculin acetylation by A. faecalis-derived metabolite acetic acid, which impeded intestinal barrier via hindering the binding of vinculin to β-catenin. Our study revealed A. faecalis not only suppress mucosal immune responses via reducing IgA+ B cells in Peyer's patches but also disrupt intestinal barrier via increasing vinculin acetylation, ultimately promoting inflammation-to-cancer transition in CRC.

Diabetic kidney disease (DKD) is a serious healthcare dilemma. Nonetheless, the interplay between the functional capacity of gut microbiota and their host remains elusive for DKD. This study aims to elucidate the functional capability of gut microbiota to affect kidney function of DKD patients. A total of 990 subjects were enrolled consisting of a control group (n = 455), a type 2 diabetes mellitus group (DM, n = 204), a DKD group (n = 182) and a chronic kidney disease group (CKD, n = 149). Full-length sequencing of 16S rRNA genes from stool DNA was conducted. Three findings are pinpointed. Firstly, new types of microbiota biomarkers have been created using a machine-learning (ML) method, namely relative abundance of a microbe, presence or absence of a microbe, and the hierarchy ratio between two different taxonomies. Four different panels of features were selected to be analyzed: (i) DM vs. Control, (ii) DKD vs. DM, (iii) DKD vs. CKD, and (iv) CKD vs. Control. These had accuracy rates between 0.72 and 0.78 and areas under curve between 0.79 and 0.86. Secondly, 13 gut microbiota biomarkers, which are strongly correlated with anthropometric, metabolic and/or renal indexes, concomitantly identified by the ML algorithm and the differential abundance method were highly discriminatory. Finally, the predicted functional capability of a DKD-specific biomarker, Gemmiger spp. is enriched in carbohydrate metabolism and branched-chain amino acid (BCAA) biosynthesis. Coincidentally, the circulating levels of various BCAAs (L-valine, L-leucine and L-isoleucine) and their precursor, L-glutamate, are significantly increased in DM and DKD patients, which suggests that, when hyperglycemia is present, there has been alterations in various interconnected pathways associated with glycolysis, pyruvate fermentation and BCAA biosynthesis. Our findings demonstrate that there is a link involving the gut-kidney axis in DKD patients. Furthermore, our findings highlight specific gut bacteria that can acts as useful biomarkers; these could have mechanistic and diagnostic implications.

Socioeconomic position (SEP) in childhood and beyond may influence the gut microbiome, with implications for disease risk. Studies evaluating the relationship between life-course SEP and the gut microbiome are sparse, particularly among Hispanic/Latino individuals, who have a high prevalence of low SEP. We use the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based cohort study conducted in four field centers in the United States (U.S.), to evaluate the association between life-course SEP and gut microbiome composition. Life-course SEP indicators included parental education (proxy of childhood SEP), current SEP (n = 2174), and childhood (n = 988) and current economic hardship (n = 994). Shotgun sequencing was performed on stool samples. Analysis of Compositions of Microbiomes was used to identify associations of life-course SEP indicators with gut microbiome species and functions. Parental education and current SEP were associated with the overall gut microbiome composition; however, parental education and current education explained more the gut microbiome variance than the current SEP. A lower parental education and current SEP were associated with a lower abundance of species from genus Bacteroides. In stratified analysis by nativity, we found similar findings mainly among foreign-born participants. Early-life SEP may have long-term effects on gut microbiome composition underscoring another biological mechanism linking early childhood factors to adult disease.

Metabolic syndrome is, in humans, associated with alterations in the composition and localization of the intestinal microbiota, including encroachment of bacteria within the colon's inner mucus layer. Possible promoters of these events include dietary emulsifiers, such as carboxymethylcellulose (CMC) and polysorbate-80 (P80), which, in mice, result in altered microbiota composition, encroachment, low-grade inflammation and metabolic syndrome. While assessments of gut microbiota composition have largely focused on fecal/luminal samples, we hypothesize an outsized role for changes in mucus microbiota in driving low-grade inflammation and its consequences. In support of this notion, we herein report that both CMC and P80 led to stark changes in the mucus microbiome, markedly distinct from those observed in feces. Moreover, transfer of mucus microbiota from CMC- and P80-fed mice to germfree mice resulted in microbiota encroachment, low-grade inflammation, and various features of metabolic syndrome. Thus, we conclude that mucus-associated bacteria are pivotal determinants of intestinal inflammatory tone and host metabolism.

Evidence suggests that a healthy gut microbiome is essential for metabolizing dietary phytochemicals. However, the microbiome's role in metabolite production and the influence of gut dysbiosis on this process remain unclear. Further, studies on the relationship among gut microbes, metabolites, and biological activities of phytochemicals are limited. We addressed this knowledge gap using strawberry phytochemicals as a model. C57BL/6J mice were fed a standard diet [C]; strawberry-supplemented diet (~2 human servings) [CS]; strawberry-supplemented diet and treated with antibiotics (to deplete gut microbes) [CSA]; high-fat diet (HFD) [HF]; strawberry-supplemented HFD [HS]; and strawberry-supplemented HFD and treated with antibiotics [HSA] for 12 weeks. First, antibiotic treatment suppressed the production of selected metabolites (CSA vs. CS), and p-coumaric acid was identified as a strawberry-derived microbial metabolite. Second, HFD-induced dysbiosis negatively affected metabolite production (HS vs. HF), and hippuric acid was identified as a microbial metabolite in HFD conditions. Third, dietary strawberries improved HFD-induced vascular inflammation (HS vs. HF). However, antibiotic treatment reduced metabolite production and abolished the vascular effects of strawberries (HSA vs. HS), indicating the importance of gut microbes in mediating the vascular benefits of strawberries via metabolites. Fourth, strawberry supplementation decreased Coprobacillus that was positively associated with vascular inflammation, whereas it increased Lachnospiraceae that was negatively associated with vascular inflammation and positively associated with hippuric acid. Fifth, hippuric acid was negatively associated with vascular inflammation. Our study fills in some pieces of the giant puzzle regarding the influence of gut microbes on the biological activities of phytochemicals. HFD-induced gut dysbiosis negatively impacts metabolite production and a strong association exists among gut microbes, strawberry-derived microbial metabolites, and the vascular benefits of dietary strawberries. Further, our study provides significant proof of concept to warrant future research on the use of strawberries as a nutritional strategy to prevent vascular complications.

Clinical symptoms of Clostridioides difficile infection (CDI) range from diarrhea to pseudomembranous colitis. A major challenge in managing CDI is the high rate of relapse. Several studies correlate the production of CDT binary toxin by clinical strains of C. difficile with higher relapse rates. Although the mechanism of action of CDT on host cells is known, its exact contribution to CDI is still unclear. To understand the physiological role of CDT during CDI, we established two hypoxic relevant intestinal models, Transwell and Microfluidic Intestine-on-Chip systems. Both were challenged with the epidemic strain UK1 CDT⁺ and its isogenic CDT^- mutant. We report that CDT induces mucin-associated microcolonies that increase C. difficile colonization and display biofilm-like properties by enhancing C. difficile resistance to vancomycin. Importantly, biofilm-like microcolonies were also observed in the cecum and colon of infected mice. Hence, our study shows that CDT induces biofilm-like microcolonies, increasing C. difficile persistence and risk of relapse.

Gut bacteria play key roles in intestinal physiology, via the secretion of diversified bacterial effectors. Many of these effectors remodel the host proteome, either by altering transcription or by regulating protein post-translational modifications. SUMOylation, a ubiquitin-like post-translational modification playing key roles in intestinal physiology, is a target of gut bacteria. Mutualistic gut bacteria can promote SUMOylation, via the production of short- or branched-chain fatty acids (SCFA/BCFA). In contrast, several pathogenic bacteria were shown to dampen SUMOylation in order to promote infection. Here, we demonstrate that Staphylococcus warneri, a natural member of the human gut microbiota, decreases SUMOylation in intestinal cells. We identify that Warnericin RK, a hemolytic toxin secreted by S. warneri, targets key components of the host SUMOylation machinery, leading to the loss of SUMO-conjugated proteins. We further demonstrate that Warnericin RK promotes inflammation in intestinal and immune cells using both SUMO-dependent and SUMO-independent mechanisms. We finally show that Warnericin RK regulates the expression of genes involved in intestinal tight junctions. Together, these results highlight the diversity of mechanisms used by bacteria from the gut microbiota to manipulate host SUMOylation. They further highlight that changes in gut microbiota composition may impact intestinal inflammation, by altering the equilibrium between bacterial effectors promoting or dampening SUMOylation.

Diabetes mellitus (DM) is a complex metabolic disease characterized by hyperglycemia. Recently, the incidence of diabetes has increased exponentially, and it is estimated to become the seventh leading cause of global mortality by 2030. Glucagon-like peptide-1 (GLP-1), a hormone derived from the intestine, has been demonstrated to exert remarkable hypoglycemic effects. However, its limitation lies in its short plasma half-life, necessitating the continuous intravenous injection of GLP-1 drugs to achieve efficacy. Here, we engineered Clostridium butyricum to continuously express and deliver GLP-1 (denoted as Cb-GLP-1), and assessed its therapeutic efficacy in type 2 diabetes mellitus (T2DM) mice. We demonstrated that administration of Cb-GLP-1 effectively lowered blood glucose levels, regulated dyslipidemia, and ameliorated hepatic impairment in T2DM mice. Furthermore, Cb-GLP-1 treatment facilitated insulin secretion by retarding islet cell apoptosis and activating the glucagon-like peptide 1 receptor/adenylate cyclase/protein kinase A (GLP-1 R/AC/PKA) signaling pathway. Gut microbiota analysis revealed that Cb-GLP-1 restored gut homeostasis disrupted in T2DM mice, as indicated by the decreased abundance of Lactobacillus and Providencia genera in response to Cb-GLP-1 treatment. Collectively, the intestinal microbiota regulation and hypoglycemic effect of the engineered strain Cb-GLP-1 presents a promising approach for diabetes management.