Modulation de l’association positive entre consommation de viande rouge et risque de cancer par l’anxiété générale dans la cohorte NutriNet-Santé

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Genotoxicity of Escherichia coli Nissle 1917 strain cannot be dissociated from its probiotic activity

International audienceOral administration of the probiotic bacterium Escherichia coli Nissle 1917 improves chronic inflammatory bowel diseases, but the molecular basis for this therapeutic efficacy is unknown. E. coli Nissle 1917 harbors a cluster of genes coding for the biosynthesis of hybrid nonribosomal peptide-polyketide(s). This biosynthetic pathway confers the ability for bacteria to induce DNA double strand breaks in eukaryotic cells. Here we reveal that inactivation of the clbA gene within this genomic island abrogated the ability for the strain to induce DNA damage and chromosomal abnormalities in non-transformed cultured rat intestinal epithelial cells but is required for the probiotic activity of E. coli Nissle 1917. Thus, evaluation of colitis severity induced in rodent fed with E. coli Nissle 1917 or an isogenic non-genotoxic mutant demonstrated the need for a functional biosynthetic pathway both in the amelioration of the disease and in the modulation of cytokine expression. Feeding rodents with a complemented strain for which genotoxicity was restored confirmed that this biosynthetic pathway contributes to the health benefits of the probiotic by modulating its immunomodulatory properties. Our data provide additional evidence for the benefit of this currently used probiotic in colitis but remind us that an efficient probiotic may also have side effects as any other medication

Maternal heme-enriched diet promotes a gut pro-oxidative status associated with microbiota alteration, gut leakiness and glucose intolerance in mice offspring

International audienceMaternal environment, including nutrition and microbiota, plays a critical role in determining offspring's risk of chronic diseases such as diabetes later in life. Heme iron requirement is amplified during pregnancy and lactation, while excessive dietary heme iron intake, compared to non-heme iron, has shown to trigger acute oxidative stress in the gut resulting from reactive aldehyde formation in conjunction with microbiota reshape. Given the immaturity of the antioxidant defense system in early life, we investigated the extent to which a maternal diet enriched with heme iron may have a lasting impact on gut homeostasis and glucose metabolism in 60-day-old C3H/HeN mice offspring. As hypothesized, the form of iron added to the maternal diet differentially governed the offspring's microbiota establishment despite identical fecal iron status in the offspring. Importantly, despite female offspring was unaffected, oxidative stress markers were however higher in the gut of male offspring from heme enriched-fed mothers, and were accompanied by increases in fecal lipocalin-2, intestinal para-cellular permeability and TNF-α expression. In addition, male mice displayed blood glucose intolerance resulting from impaired insulin secretion following oral glucose challenge. Using an integrated approach including an aldehydomic analysis, this male-specific phenotype was further characterized and revealed close covariations between unidentified putative reactive aldehydes and bacterial communities belonging to Bacteroidales and Lachnospirales orders. Our work highlights how the form of dietary iron in the maternal diet can dictate the oxidative status in gut offspring in a sex-dependent manner, and how a gut microbiota-driven oxidative challenge in early life can be associated with gut barrier defects and glucose metabolism disorders that may be predictive of diabetes development

Microbiota dysbiosis induced by defect of paneth cells triggers visceral hypersensitivity in mice

Microbiota dysbiosis induced by defect of paneth cells triggers visceral hypersensitivity in mice. Digestive Disease Week (DDW

Microbiota dysbiosis induced by defect of enteric antimicrobial activity triggers visceral hypersensitivity in young adult mice

Paneth cell-derived antimicrobial peptides like lysozyme provide antibacterial protection and maintain intestinal homeostasis. We aimed to analyze the consequences of altered Paneth cells function on fecal antimicrobial activity, intestinal homeostasis and visceral sensitivity at adulthood. In 50-days old Sox9flox/flox-vil-Cre female mice, absence of Paneth increased fecal population of Enterobacteriaceae associated to visceral hypersensitivity. Daily gavage of conventional adult mice with commensal E. coli, induced visceral hypersensitivity. Occurrence of adverse events during neonatal period impairs intestinal homeostasis establishment. Maternal separation (MS) is a well described rodent model of psychological stress characterized by a decrease of intestinal secretory cells and visceral hypersensitivity mimicking what we observed in Sox9flox/flox-vil-cre mice. We wondered if in this model we also observed a dysbiosis in favor of Enterobacteriaceae. Mice submitted to MS, presented a defect of fecal antimicrobial activity associated with a fecal overgrowth of Enterobacteriaceae. Furthermore, this antimicrobial defect and its consequences on visceral sensitivity were prevented by oral administration of lysozyme. Our results show that a defect of enteric antimicrobial functions leads to microbiota dysbiosis in favor of Enterobacteriaceae responsible for visceral hypersensitivity providing new mechanistic insights in maternal separation-induced visceral hypersensitivit

Le stress de séparation maternelle diminue l’activité antimicrobienne entérique et entraîne une surpopulation bactérienne intestinale responsable de l’hypersensibilité viscérale chez la souris jeune adulte

Le stress de séparation maternelle diminue l’activité antimicrobienne entérique et entraîne une surpopulation bactérienne intestinale responsable de l’hypersensibilité viscérale chez la souris jeune adulte. 33. Réunion annuelle du Club d'Etudes des Cellules Epithéliales Digestives (CECED

Early life stressful events impaired enteric antimicrobial activity and triggered commensal Escherichia coli overgrowth responsible for visceral hypersensitivity in adult mice

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Paneth cell defects induce microbiota dysbiosis In mice and promote visceral hypersensitivity

International audienceSeparation of newborn rats from their mothers induces visceral hypersensitivity and impaired epithelial secretory cell lineages when they are adults. Little is known about the mechanisms by which maternal separation causes visceral hypersensitivity or its relationship with defects in epithelial secretory cell lineages. We performed studies with C3H/HeN mice separated from their mothers as newborns and mice genetically engineered (Sox9flox/flox-vil-cre on C57BL/6 background) to have deficiencies in Paneth cells. Paneth cells deficiency was assessed by lysozyme staining of ileum tissues and lysozyme activity in fecal samples. When mice were 50 days old, their abdominal response to colorectal distension was assessed by electromyography. Fecal samples were collected and microbiota were analyzed using GULDA quantitative PCR. Mice with maternal separation developed visceral hypersensitivity and defects in Paneth cells, as reported from rats, compared to mice without maternal separation. Sox9flox/flox-vil-Cre mice also had increased visceral hypersensitivity compared to control littermate Sox9flox/flox mice. Fecal samples from mice with maternal separation and from Sox9flox/flox-vil-cre mice had evidence for intestinal dysbiosis of the microbiota, characterized by expansion of Escherichia coli. Daily gavage of conventional C3H/HeN adult mice with 109 commensal E. coli induced visceral hypersensitivity. Conversely, daily oral administration of lysozyme prevented expansion of E. coli during maternal separation and visceral hypersensitivity. Mice with defects in Paneth cells (induced by maternal separation or genetically engineered) have intestinal expansion of E. coli leading to visceral hypersensitivity. These findings provide evidence that Paneth cell function and intestinal dysbiosis are involved in visceral sensitivity

Anxiety is a potential effect modifier of the association between red and processed meat consumption and cancer risk: findings from the NutriNet-Santé cohort

International audiencePurpose Red and processed meats are recognized by the International Agency for Research on Cancer as probably carcinogenic and carcinogenic to humans, respectively. Heme iron has been proposed as a central factor responsible for this effect. Furthermore, anxiety affects the intestinal barrier function by increasing intestinal permeability. The objective of this work was to assess how anxiety modifies the association between red and processed meat consumption and cancer risk in the NutriNet-Santé prospective cohort (2009–2019).Methods Using multi-adjusted Cox models in a sample of 101,269 subjects, we studied the associations between the consumption of red and processed meat, the amount of heme iron coming from these meats and overall, colorectal, prostate, and breast cancer risks, overall and separately among participants with and without anxiety.Results An increase in red and processed meat consumption was associated with an increased risk of developing colorectal cancer in the total population (HR for an increase of 50 g/day = 1.18 (1.01–1.37), p = 0.03). After stratification on anxiety, the HR 50 g/day was 1.42 (1.03–1.94, p = 0.03) in anxious participants and 1.12 (0.94–1.33, p = 0.20) in other participants. Similar trends were observed for overall cancer risk. Analyses conducted with heme iron also provided similar results. Conclusions Our results strengthen the existing body of evidence supporting that red and processed meat consumption and heme iron intake are associated with an increased risk of overall and more specifically colorectal cancer, and suggest that anxiety modifies these associations, with an increased risk in anxious participants

Early life stress in mice is a suitable model for Irritable Bowel Syndrome but does not predispose to colitis nor increase susceptibility to enteric infections

International audienceNeonatal period is characterized by an immature intestinal barrier. Scattered evidence suggests that early life stressful events induce long lasting alterations of intestinal homeostasis mimicking Irritable Bowel Syndrome (IBS). Those observations highlighting defect of intestinal barrier by early life stress questioned its potential role as a risk factor for gastrointestinal disorders such as colitis and infections. In this study, we aimed to analyze if maternal separation (MS) in mice gathers IBS main features. We next addressed whether MS could trigger or exacerbate colitis in genetically predisposed mice and/or enhance susceptibility to gastrointestinal infections in wild type mice. MS induced main features of IBS in adult wild type male mice i.e. intestinal hyperpermeability, visceral hypersensitivity, microbiota dysbiosis, bile acid malabsorption and low grade inflammation in intestine associated with a defect of Paneth cells and the ILC3 population. This breach in mucosal barrier functions in adults was associated with a systemic IgG response against commensal E. coli and increased IFNγ secretion by splenocytes. However, in IL10-/- mice, MS did not trigger nor worsen colitis. Furthermore, wild type mice submitted to MS did not show increase susceptibility to gastrointestinal infections (S. Typhimurium, L. monocytogenes or T. gondii) compared to controls. Altogether, our results identify MS in mice as a good experimental model for IBS mimicking all the main features. In addition, early life stress, even though it has long lasting consequences on intestinal homeostasis, does not constitute a facilitating factor to colitis in predisposed individuals nor to gastrointestinal infections in wild type mice