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By combining genetic, metagenomic and metabolic data in humans, a recent study has identified causal relationships between the capacity of gut microorganisms to produce short-chain fatty acids, such as butyrate and propionate, and metabolic traits of the host, including insulin response during an oral glucose tolerance test and susceptibility to type 2 diabetes mellitus.

Infections of genotoxic Escherichia coli spread concomitantly with urbanized progression. These bacteria may prompt cell senescence and affect DNA stability, inducing cancer via the production of colibactin, a genotoxin shown capable of affecting host DNA in eukaryotic cells. In this study, we show that the action of colibactin may also be directed against other bacteria of the gut microbiota in which genotoxic E. coli bacteria have been introduced. Indeed, the presence of genotoxic E. coli induced a change in both the structure and function of the gut microbiota. Our data indicate that genotoxic E. coli may use colibactin to compete for gut niche utilization. The genotoxin colibactin produced by resident bacteria of the gut microbiota may have tumorigenic effect by inducing DNA double-strand breaks in host cells. Yet, the effect of colibactin on gut microbiota composition and functions remains unknown. To address this point, we designed an experiment in which pregnant mice were colonized with the following: (i) a commensal Escherichia coli strain, (ii) a commensal E. coli strain plus a genotoxic E. coli strain, (iii) a commensal E. coli strain plus a nongenotoxic E. coli mutant strain unable to produce mature colibactin. Then, we analyzed the gut microbiota in pups at day 15 and day 35 after birth. At day 15, mice that were colonized at birth with the genotoxic strain showed lower levels of Proteobacteria and taxa belonging to the Proteobacteria , a modest effect on overall microbial diversity, and no effect on gut microbiome. At day 35, mice that received the genotoxic strain showed lower Firmicutes and taxa belonging to the Firmicutes , together with a strong effect on overall microbial diversity and higher microbial functions related to DNA repair. Moreover, the genotoxic strain strongly affected gut microbial diversity evolution of pups receiving the genotoxic strain between day 15 and day 35. Our data show that colibactin, beyond targeting the host, may also exert its genotoxic effect on the gut microbiota. IMPORTANCE Infections of genotoxic Escherichia coli spread concomitantly with urbanized progression. These bacteria may prompt cell senescence and affect DNA stability, inducing cancer via the production of colibactin, a genotoxin shown capable of affecting host DNA in eukaryotic cells. In this study, we show that the action of colibactin may also be directed against other bacteria of the gut microbiota in which genotoxic E. coli bacteria have been introduced. Indeed, the presence of genotoxic E. coli induced a change in both the structure and function of the gut microbiota. Our data indicate that genotoxic E. coli may use colibactin to compete for gut niche utilization.

More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10–20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain.

Background The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear. Results Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity ( n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae , Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella , Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient’s mice. In line with the results in humans, transplantation from ‘high ferritin donors’ resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient’s mice. Conclusions Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies. 5HRkabMBtxskC5-wBBcq1w Video abstract

Vδ 1 γδ T cells are key players in innate and adaptive immunity, particularly at mucosal interfaces such as the gut. An increase in circulating Vδ 1 cells has long been observed in people with HIV-1, but remains poorly understood. We performed a comprehensive characterization of Vδ 1 T cells in blood and duodenal intra-epithelial lymphocytes, obtained from endoscopic mucosal biopsies of 15 people with HIV-1 on antiretroviral therapy and 15 HIV-seronegative controls, in a substudy of the ANRS EP61 GALT study (NCT02906137). We deciphered the phenotype, functional profile, single-cell transcriptome and repertoire of Vδ 1 cells and unraveled their relationships with the possible triggers involved, in particular CMV and microbiota. We also assessed whether Vδ 1 T cells may play a role in controlling the HIV-1 reservoir. Vδ 1 T cells were mainly terminally differentiated effectors that clonally expanded in the blood with some trafficking with the gut of people with HIV-1. Most expressed CX3CR1 and displayed a highly cytotoxic profile, but low cytokine production, supported by a transcriptomic shift towards enhanced effector lymphocytes. This expansion was associated with CMV status and markers of occult replication, but also with changes in the duodenal and blood-translocated microbiota. Cytotoxic, but not IFN-γ-producing, Vδ 1 T cells were negatively associated with cell-associated HIV-1 RNA in both the blood and duodenal compartments. The increase in Vδ1 T cells observed in people with HIV-1 has multiple triggers, particularly CMV and microbiota, and may in turn contribute to the control of the HIV-1 reservoir.

By eliciting immune activation in the digestive tract, intestinal pathogens may perturb gut homeostasis. Some gastrointestinal infections can indeed increase the risk of developing post-infectious irritable bowel syndrome (PI-IBS). Intriguingly, the prevalent foodborne parasite Toxoplasma gondii has not been linked to the development of PI-IBS and the impact of this infection on colon homeostasis remains ill-defined. We show in a mouse model that latent T. gondii decreases visceral nociceptive responses in an opioid signaling-dependent manner. Despite the accumulation of Th1 and cytotoxic T cells in the colon of latently infected mice, the selective invalidation of enkephalin gene in T cells ruled out the involvement of T cell-derived enkephalins in hypoalgesia. These findings provide clues about how this widespread infection durably shapes the gut immune landscape and modifies intestinal physiological parameters. They suggest that in contrast to other gut microbes, T. gondii infection could be negatively associated with abdominal pain.

Pattern recognition receptors link metabolite and bacteria‐derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity‐promoting high‐fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2 −/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic‐derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2 −/− mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN‐NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD‐fed NOD2 −/− mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ‐free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes. Synopsis Nutritional and bacterial cues engage the immune system during the chronic inflammation associated with obesity, which could lead to insulin resistance. An intact NOD2‐peptidoglycan sensing system prevents excessive dysbiosis‐related inflammation and insulin resistance during obesity. NOD2 in non‐hematopoietic cells protects against obesity‐induced inflammation and insulin resistance. NOD2 limits accumulation of bacterial markers and inflammation of adipose and liver tissues during obesity. The microbiota of NOD2‐deficient mice contributes to metabolic inflammation and insulin resistance. Graphical Abstract Nutritional and bacterial cues engage the immune system during the chronic inflammation associated with obesity, which could lead to insulin resistance. An intact NOD2‐peptidoglycan sensing system prevents excessive dysbiosis‐related inflammation and insulin resistance during obesity.

Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.

To investigate the role of the intestinal bacterial microbiota in the pathogenesis of calcium oxalate nephrolithiasis in cats, a condition characterized by the formation of kidney stones, it is desirable to identify a sample collection method that accurately reflects the microbiota’s composition. The objective of this study was to evaluate the impact of fecal sample collection methods on the intestinal microbiota composition in two cat populations: healthy cats and kidney stone-diseased cats. The study included eighteen cats from the same colony, comprising nine healthy cats and nine cats with spontaneously occurring presumed calcium oxalate kidney stones. Three fecal collection methods were compared: rectal swabs, the collection of fresh stool, and the collection of stool exposed to ambient air for 24 h. The bacterial microbiota was analyzed through the high-resolution sequencing of the V3–V4 region of the 16S rRNA gene. For all cats, within the same individual, a one-way PERMANOVA analysis showed a significant difference between the rectal swabs and fresh stool (p = 0.0003), as well as between the rectal swabs and stool exposed to ambient air for 24 h (p = 0.0003), but no significant difference was identified between the fresh stool and non-fresh stool (p = 0.0651). When comparing the two populations of cats, this study provides seemingly conflicting results. (1) A principal component analysis (PCA) comparison revealed a significant difference in the bacterial composition between the healthy cats and the cats with kidney stones only when the sample was a fresh fecal sample (p = 0.0037). This finding suggests that the intestinal bacteria involved in the pathogenesis of kidney stones in cats are luminal and strictly anaerobic bacteria. Consequently, exposure to ambient air results in a loss of information, preventing the identification of dysbiosis. For clinical studies, non-fresh stool samples provided by owners does not appear suitable for studying the gut microbiota of cats with kidney stones; fresh stool should be favored. (2) Interestingly, the rectal swabs alone highlighted significant differences in the proportion of major phyla between the two populations. These findings highlight the critical importance of carefully selecting fecal collection methods when studying feline gut microbiota. Combining rectal swabs and fresh stool sampling provides complementary insights, offering the most accurate understanding of the gut microbiota composition in the context of feline kidney stone pathogenesis.

A fat-enriched diet favors the development of gram negative bacteria in the intestine which is linked to the occurrence of type 2 diabetes (T2D). Interestingly, some pathogenic gram negative bacteria are commonly associated with the development of periodontitis which, like T2D, is characterized by a chronic low-grade inflammation. Moreover, estrogens have been shown to regulate glucose homeostasis via an LPS receptor dependent immune-modulation. In this study, we evaluated whether diet-induced metabolic disease would favor the development of periodontitis in mice. In addition, the regulatory role of estrogens in this process was assessed. Four-week-old C57BL6/J WT and CD14 (part of the TLR-4 machinery for LPS-recognition) knock-out female mice were ovariectomised and subcutaneously implanted with pellets releasing either placebo or 17β-estradiol (E2). Mice were then fed with either a normal chow or a high-fat diet for four weeks. The development of diabetes was monitored by an intraperitoneal glucose-tolerance test and plasma insulin concentration while periodontitis was assessed by identification of pathogens, quantification of periodontal soft tissue inflammation and alveolar bone loss. The fat-enriched diet increased the prevalence of periodontal pathogenic microbiota like Fusobacterium nucleatum and Prevotella intermedia, gingival inflammation and alveolar bone loss. E2 treatment prevented this effect and CD14 knock-out mice resisted high-fat diet-induced periodontal defects. Our data show that mice fed with a diabetogenic diet developed defects and microflora of tooth supporting-tissues typically associated with periodontitis. Moreover, our results suggest a causal link between the activation of the LPS pathway on innate immunity by periodontal microbiota and HFD-induced periodontitis, a pathophysiological mechanism that could be targeted by estrogens.