Autophagy: A Novel Mechanism Involved in the Anti-Inflammatory Abilities of Probiotics.

BACKGROUND/AIMS: Deregulation of the complex interaction among host genetics, gut microbiota and environmental factors on one hand and aberrant immune responses on the other hand, are known to be associated with the development of inflammatory bowel disease. Recent studies provided strong evidence that autophagy plays a key role in the etiology of Crohn's disease (CD). Probiotics may exhibit many therapeutic properties, including anti-inflammatory abilities. While successful results have been obtained in ulcerative colitis patients, probiotics remain inefficient in CD for unknown reason. It remains therefore important to better understand their molecular mechanisms of action. METHODS: The activation of autophagy was examined by stimulating bone marrow-derived dendritic cells by the bacteria, followed by confocal microscopy and western blot analysis. The impact of blocking in vitro autophagy was performed in peripheral blood mononuclear cells using 3-methyl adenine or bafilomycin followed by cytokine secretion measurement by ELISA. The role of autophagy in the anti-inflammatory capacities of the bacterial strains was evaluated in vivo using an acute trinitrobenzene sulfonic acid-induced murine model of colitis. The impact of BMDC was evaluated by adoptive transfer, notably using bone marrow cells derived from autophagy-related 16-like 1-deficient mice. RESULTS: We showed that selected lactobacilli and bifidobacteria are able to induce autophagy activation in BMDCs. Blocking in vitro autophagy abolished the capacity of the strains to induce the release of the anti-inflammatory cytokine interleukin-10, while it exacerbated the secretion of the pro-inflammatory cytokine interleukin-1ß. We confirmed in the TNBS-induced mouse model of colitis that autophagy is involved in the protective capacity of these selected strains, and showed that dendritic cells are involved in this process. CONCLUSION: We propose autophagy as a novel mechanism involved in the regulatory capacities of probiotics.

Beneficial metabolic effects of selected probiotics on diet-induced obesity and insulin resistance in mice are associated with improvement of dysbiotic gut microbiota.

Alterations in gut microbiota composition and diversity were suggested to play a role in the development of obesity, a chronic subclinical inflammatory condition. We here evaluated the impact of oral consumption of a monostrain or multi-strain probiotic preparation in high-fat diet-induced obese mice. We observed a strain-specific effect and reported dissociation between the capacity of probiotics to dampen adipose tissue inflammation and to limit body weight gain. A multi-strain mixture was able to improve adiposity, insulin resistance and dyslipidemia through adipose tissue immune cell-remodelling, mainly affecting macrophages. At the gut level, the mixture modified the uptake of fatty acids and restored the expression level of the short-chain fatty acid receptor GPR43. These beneficial effects were associated with changes in the microbiota composition, such as the restoration of the abundance of Akkermansia muciniphila and Rikenellaceae and the decrease of other taxa like Lactobacillaceae. Using an in vitro gut model, we further showed that the probiotic mixture favours the production of butyrate and propionate. Our findings provide crucial clues for the design and use of more efficient probiotic preparations in obesity management and may bring new insights into the mechanisms by which host-microbe interactions govern such protective effects.

Erratum: Rémy et al. Modelling the Impact of Chronic Cigarette Smoke Exposure in Obese Mice: Metabolic, Pulmonary, Intestinal, and Cardiac Issues. Nutrients 2020, 12, 827.

The authors have requested that the following changes be made to their paper [...].

Multiple Selection Criteria for Probiotic Strains with High Potential for Obesity Management.

Since alterations of the gut microbiota have been shown to play a major role in obesity, probiotics have attracted attention. Our aim was to identify probiotic candidates for the management of obesity using a combination of in vitro and in vivo approaches. We evaluated in vitro the ability of 23 strains to limit lipid accumulation in adipocytes and to enhance the secretion of satiety-promoting gut peptide in enteroendocrine cells. Following the in vitro screening, selected strains were further investigated in vivo, single, or as mixtures, using a murine model of diet-induced obesity. Strain Bifidobacterium longum PI10 administrated alone and the mixture of B. animalis subsp. lactis LA804 and Lactobacillus gasseri LA806 limited body weight gain and reduced obesity-associated metabolic dysfunction and inflammation. These protective effects were associated with changes in the hypothalamic gene expression of leptin and leptin receptor as well as with changes in the composition of gut microbiota and the profile of bile acids. This study provides crucial clues to identify new potential probiotics as effective therapeutic approaches in the management of obesity, while also providing some insights into their mechanisms of action.

Lactobacillus reuteri 5454 and Bifidobacterium animalis ssp. lactis 5764 improve colitis while differentially impacting dendritic cells maturation and antimicrobial responses.

Crohn's disease is linked to a decreased diversity in gut microbiota composition as a potential consequence of an impaired anti-microbial response and an altered polarization of T helper cells. Here, we evaluated the immunomodulatory properties of two potential probiotic strains, namely a Bifidobacterium animalis spp. lactis Bl 5764 and a Lactobacillus reuteri Lr 5454 strains. Both strains improved colitis triggered by either 2,4,6-trinitrobenzenesulfonic acid (TNBS) or Citrobacter rodentium infection in mice. Training of dendritic cells (DC) with Lr 5454 efficiently triggered IL-22 secretion and regulatory T cells induction in vitro, while IL-17A production by CD4+ T lymphocytes was stronger when cultured with DCs that were primed with Bl 5764. This strain was sufficient for significantly inducing expression of antimicrobial peptides in vivo through the Crohn's disease predisposing gene encoding for the nucleotide-binding oligomerization domain, containing protein 2 (NOD2). In contrast, NOD2 was dispensable for the impact on antimicrobial peptide expression in mice that were monocolonized with Lr 5454. In conclusion, our work highlights a differential mode of action of two potential probiotic strains that protect mice against colitis, providing the rational for a personalized supportive preventive therapy by probiotics for individuals that are genetically predisposed to Crohn's disease.

Modelling the Impact of Chronic Cigarette Smoke Exposure in Obese Mice: Metabolic, Pulmonary, Intestinal, and Cardiac Issues.

Unhealthy lifestyle choices, such as bad eating behaviors and cigarette smoking, have major detrimental impacts on health. However, the inter-relations between obesity and smoking are still not fully understood. We thus developed an experimental model of high-fat diet-fed obese C57BL/6 male mice chronically exposed to cigarette smoke. Our study evaluated for the first time the resulting effects of the combined exposure to unhealthy diet and cigarette smoke on several metabolic, pulmonary, intestinal, and cardiac parameters. We showed that the chronic exposure to cigarette smoke modified the pattern of body fat distribution in favor of the visceral depots in obese mice, impaired the respiratory function, triggered pulmonary inflammation and emphysema, and was associated with gut microbiota dysbiosis, cardiac hypertrophy and myocardial fibrosis.

Spray-drying process preserves the protective capacity of a breast milk-derived Bifidobacterium lactis strain on acute and chronic colitis in mice.

Gut microbiota dysbiosis plays a central role in the development and perpetuation of chronic inflammation in inflammatory bowel disease (IBD) and therefore is key target for interventions with high quality and functional probiotics. The local production of stable probiotic formulations at limited cost is considered an advantage as it reduces transportation cost and time, thereby increasing the effective period at the consumer side. In the present study, we compared the anti-inflammatory capacities of the Bifidobacterium animalis subsp. lactis (B. lactis) INL1, a probiotic strain isolated in Argentina from human breast milk, with the commercial strain B. animalis subsp. lactis BB12. The impact of spray-drying, a low-cost alternative of bacterial dehydration, on the functionality of both bifidobacteria was also investigated. We showed for both bacteria that the spray-drying process did not impact on bacterial survival nor on their protective capacities against acute and chronic colitis in mice, opening future perspectives for the use of strain INL1 in populations with IBD.