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Abstract The human gastrointestinal tract is inhabited by the largest microbial community within the human body consisting of trillions of microbes called gut microbiota. The normal flora is the site of many physiological functions such as enhancing the host immunity, participating in the nutrient absorption and protecting the body against pathogenic microorganisms. Numerous investigations showed a bidirectional interplay between gut microbiota and many organs within the human body such as the intestines, the lungs, the brain, and the skin. Large body of evidence demonstrated, more than a decade ago, that the gut microbial alteration is a key factor in the pathogenesis of many local and systemic disorders. In this regard, a deep understanding of the mechanisms involved in the gut microbial symbiosis/dysbiosis is crucial for the clinical and health field. We review the most recent studies on the involvement of gut microbiota in the pathogenesis of many diseases. We also elaborate the different strategies used to manipulate the gut microbiota in the prevention and treatment of disorders. The future of medicine is strongly related to the quality of our microbiota. Targeting microbiota dysbiosis will be a huge challenge.

Legionella pneumophila, the causative agent of Legionnaires' disease, interacts in the environment with free-living amoebae that serve as replicative niches for the bacteria. Among these amoebae, Acanthamoeba castellanii is a natural host in water networks and a model commonly used to study the interaction between L. pneumophila and its host. However, certain crucial aspects of this interaction remain unclear. One such aspect is the role of oxidative stress, with studies focusing on reactive oxygen species (ROS) production by the host and putting less emphasis on the involvement of the host's antioxidant defenses during the infectious process. In this study, we propose to examine the consequences of infection with L. pneumophila wild-type or with an isogenic ΔdotA mutant strain, which is unable to replicate intracellularly, on A. castellanii. For this purpose, we looked at the host ROS levels, host antioxidant defense transcripts, and metabolites linked to the amoeba's antioxidant defenses. It is known that L. pneumophila WT can block the activation of NADPH oxidase as soon as it enters the macrophage and suppress ROS production compared to ΔdotA mutant strain. In addition, it has been shown in macrophages that L. pneumophila WT decreases ROS at 24 h p.i.; here we confirm this result in amoebae and suggest that this decrease could be partly explained by L. pneumophila differentially regulated host antioxidant defense transcripts at 6 h p.i.. We also explored the metabolome of A. castellanii infected or not with L. pneumophila. Among the 617 metabolites identified, four with reduced abundances during infection may be involved in antioxidant responses. This study suggests that L. pneumophila could hijack the host's antioxidant defenses during its replication to maintain a reduced level of ROS.

For several decades, questions have been raised about the effects of endocrine disruptors (ED) on environment and health. In humans, EDs interferes with hormones that are responsible for the maintenance of homeostasis, reproduction and development and therefore can cause developmental, metabolic and reproductive disorders. Because of their ubiquity in the environment, EDs can adversely impact microbial communities and pathogens virulence. At a time when bacterial resistance is inevitably emerging, it is necessary to understand the effects of EDs on the behavior of pathogenic bacteria and to identify the resulting mechanisms. Increasing studies have shown that exposure to environmental EDs can affect bacteria physiology. This review aims to highlight current knowledge of the effect of EDs on the virulence of human bacterial pathogens and discuss the future directions to investigate bacteria/EDs interaction. Given the data presented here, extended studies are required to understand the mechanisms by which EDs could modulate bacterial phenotypes in order to understand the health risks.

Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL−22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL−22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL−22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.

Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development.In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice.These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.

Bacillus subtilis CU1 is a probiotic strain with beneficial effects on immune health in elderly subjects and diarrhea. Commercialized under spore form, new strategies to improve the germination, fitness and beneficial effects of the probiotic once in the gut have to be explored. For this purpose, functional food ingredients, such as isomaltooligosaccharides (IMOSs), could improve the fitness of Bacillus probiotics. IMOSs are composed of α(1 → 6)- and α(1 → 4)-linked oligosaccharides and are partially indigestible. Dietary IMOSs stimulate beneficial members of intestinal microbiota, but the effect of a combination of IMOSs with probiotics, such as B. subtilis CU1, is unknown. In this study, we evaluate the potential effect of IMOSs in B. subtilis CU1 and identify the metabolic pathways involved. The biochemical analysis of the commercial IMOSs highlights a degree of polymerization (DP) comprised between 1 and 29. The metabolism of IMOSs in CU1 was attributed to an α-glucosidase, secreted in the extracellular compartment one hundred times more than with glucose, and which seems to hydrolyze high DP IMOSs into shorter oligosaccharides (DP1, DP2 and DP3) in the culture medium. Proteomic analysis of CU1 after growth on IMOSs showed a reshaping of B. subtilis CU1 metabolism and functions, associated with a decreased production of lactic acid and acetic acid by two times. Moreover, we show for the first time that IMOSs could improve the germination of a Bacillus probiotic in the presence of bile salts in vitro, with an 8 h reduced lag-time when compared to a glucose substrate. Moreover, bacterial concentration (CFU/mL) was increased by about 1 log in IMOS liquid cultures after 48 h when compared to glucose. In conclusion, the use of IMOSs in association with probiotic B. subtilis CU1 in a synbiotic product could improve the fitness and benefits of the probiotic.