Project description:Healthy aging relies on a symbiotic host–microbiota relationship. The age-associated decline of the immune system can pose a threat in this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can impact host–microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the Tfamfl/flCd4Cre mouse model, we found that T cell failure compromised gut immunity leading to a decrease in T follicular and regulatory T (Treg) cells and an accumulation of highly proinflammatory and cytotoxic T cells. These alterations were associated with intestinal barrier disruption and gut dysbiosis. Microbiota depletion or adoptive transfer of total CD4 T cells or a Treg cell–enriched pool prevented gut barrier dysfunction and mitigated premature inflammaging and senescence, ultimately enhancing healthspan in this mouse model. Thus, a competent CD4 T cell compartment is critical to ensure healthier aging by promoting host–microbiota mutualism and gut barrier integrity.
Project description:Healthy aging relies on a symbiotic host–microbiota relationship. The age-associated decline of the immune system can pose a threat in this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can impact host–microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the Tfamfl/flCd4Cre mouse model, we found that T cell failure compromised gut immunity leading to a decrease in T follicular and regulatory T (Treg) cells and an accumulation of highly proinflammatory and cytotoxic T cells. These alterations were associated with intestinal barrier disruption and gut dysbiosis. Microbiota depletion or adoptive transfer of total CD4 T cells or a Treg cell–enriched pool prevented gut barrier dysfunction and mitigated premature inflammaging and senescence, ultimately enhancing healthspan in this mouse model. Thus, a competent CD4 T cell compartment is critical to ensure healthier aging by promoting host–microbiota mutualism and gut barrier integrity.
Project description:The postnatal period is one of the important windows for developing the gastrointestinal tract's structure-function and associated mucosal immunity. Recent studies suggest a promising contribution of gut microbiota in maintaining host health, immunity, and gut development. However, the function of postnatal gut microbiota dynamics concerning intestinal mucosal development needs to be better understood. To decipher the causal role of gut microbiota on barrier integrity and intestinal epithelium development, we executed an antibiotic-mediated perturbation and tracked the kinetics in postnatal mice. We observed a postnatal age-related impact of antibiotic-mediated gut microbiota perturbation with a substantial decrease in total bacterial load on P14D and also in the barrier integrity and IECs marker. To enhance our knowledge of the mechanisms behind this, we employed a global transcriptomics approach to see the alterations in the mucosal innate immunity and other relevant pathways.
Project description:The intestinal ecosystem is balanced by dynamic interactions between resident and incoming microbes, the gastrointestinal barrier, and the mucosal immune system. However, in the context of inflammatory bowel diseases (IBD) where the integrity of the gastrointestinal barrier is compromised, resident microbes contribute to the development and perpetuation of inflammation and disease. In this context, probiotic bacteria exert beneficial effects enhancing epithelial barrier integrity. However, the mechanisms underlying these beneficial effects are only poorly understood. Here, we comparatively investigated the effects of four probiotic lactobacilli, namely L. acidophilus, L. fermentum, L. gasseri, and L. rhamnosus in a T84 cell epithelial barrier model. Results of DNA-microarray experiments indicating that lactobacilli modulate the regulation of genes encoding in particular adherence junction proteins such as E-cadherin and b-catenin were confirmed by qRT-PCR. Furthermore, we show that epithelial barrier function is modulated by Gram-positive probiotic lactobacilli via their effect on adherence junction protein expression and complex formation. In addition, incubation with lactobacilli differentially influences the phosphorylation of adherence junction proteins and of PKC isoforms such as PKCd which thereby positively modulates epithelial barrier function. Further insight into the underlying molecular mechanisms triggered by these probiotics might also foster the development of novel strategies for the treatment of gastrointestinal diseases (e.g. IBD).
Project description:Dietary lipids favor the growth of the pathobiont Bilophila wadsworthia, but the relevance of this expansion in metabolic syndrome pathogenesis remains unknown. Here, we showed that B. wadsworthia synergize with HFD to promote higher inflammation, intestinal barrier dysfunction and bile acid dysmetabolism, leading to higher glucose dysmetabolism and hepatic steatosis. Host-microbiota transcriptomics analysis unraveled pathways, particularly butanoate metabolism, which may underlie the metabolic effects mediated by B. wadsworthia. Pharmacological suppression of B. wadsworthia-associated inflammation unmasked the bacterium’s intrinsic capacity to induce a negative impact on glycemic control and hepatic function. Finally, the probiotic Lactobacillus rhamnosus CNCM I-3690 was able to limit B. wadsworthia-induced immune and metabolic impairment by limiting its expansion, reducing inflammation and reinforcing intestinal barrier. Our results support a new avenue for interventions against western diet-driven inflammatory and metabolic diseases.
Project description:Dietary lipids favor the growth of the pathobiont Bilophila wadsworthia, but the relevance of this expansion in metabolic syndrome pathogenesis remains unknown. Here, we showed that B. wadsworthia synergize with HFD to promote higher inflammation, intestinal barrier dysfunction and bile acid dysmetabolism, leading to higher glucose dysmetabolism and hepatic steatosis. Host-microbiota transcriptomics analysis unraveled pathways, particularly butanoate metabolism, which may underlie the metabolic effects mediated by B. wadsworthia. Pharmacological suppression of B. wadsworthia-associated inflammation unmasked the bacterium’s intrinsic capacity to induce a negative impact on glycemic control and hepatic function. Finally, the probiotic Lactobacillus rhamnosus CNCM I-3690 was able to limit B. wadsworthia-induced immune and metabolic impairment by limiting its expansion, reducing inflammation and reinforcing intestinal barrier. Our results support a new avenue for interventions against western diet-driven inflammatory and metabolic diseases.
Project description:Enteral immunomodulating nutrition modifies the gastrointestinal microbiota as well as improves the intestinal barrier integrity in patients with gastric and colorectal cancer in the perioperative period. As a consequence, it contributes to the reduction of the incidence of postoperative complications and diarrhea, which is a side effect of anti-cancer treatment often used preoperatively in this group of cancers.
Project description:EGFR targeted anti-cancer therapy induces severe skin toxicities, which affect life quality in patients. The lack of mechanistic details underlying these adverse events hampers their effective management. Here we identified EGFR as the epidermal master-regulator of the ERK pathway, which secures skin barrier integrity upon hair eruption. EGFR deficient epidermis displays a Th2-dominated expression signature and is permissive for excessive microbiota outgrowth. In the absence of EGFR, opening of the follicular ostia during hair eruption allows invasion of commensal microbiota aggravating barrier disruption and initiating an additional Th1 and Th17 response. Chronic folliculitis leads to Staphylococcus aureus dominated dysbiosis, further exacerbating inflammation and expanding barrier defects. Restoration of epidermal ERK signaling via therapeutic FGF7 treatment or transgenic SOS expression rescues skin barrier integrity in the absence of EGFR. These data reveal a gatekeeper function of the EGFR/ERK cascade in hair follicles securing the epidermal barrier around the erupting hair shaft.
Project description:The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). We report the ability of a probiotic bacterial strain in halting neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neuroprotective in C. elegans models of ALS and HD. Our results show that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains, and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are key fatty acid metabolism and mitochondrial b-oxidation genes. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial b-oxidation. L. rhamnosus HA-114 is suitable for human consumption opening the possibility of modifying disease progression by dietary intervention.
Project description:Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infused gut organ cultures with longitudinal microbiota samples collected from therapy-naïve irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet and reinforce the potential feasibility of microbiome based-therapies in IBS.