Grant Abstract: Dietary-dependent barrier protection by L. rhamnosus GG

Grant Number: 1R01AT013333-01A1
PI Name: Gao
Project Title: Dietary-dependent barrier protection by L. rhamnosus GG

Abstract: Human clinical trials worldwide evaluated probiotic effects in a variety of diseases, resulting in confounding results about the therapeutic efficacy. The uncertainty of probiotic benefits stem from the vastly different patterns in diets, genetics, microbiota, and lifestyle in the human population. In addition, side effects associated with live bacteria have been reported, raising concerns about the safety of probiotics. Thus, the rationale for the mechanistic research into probiotic interactions with host diet, digestive, metabolism, and the microbial system is to identify the group of patients who may receive the most benefit from the probiotic intervention. This MPI research team, consisting of a nutrient physiologist, metabolomic biochemist and a gut biologist, has taken a chemical biology and reductionist approach, and has uncovered two probiotic metabolic pathways that regulate the host gut mucosal homeostasis and tissue repair after injury. In the first pathway, the probiotic bacterium directly produces two structural isomers of nicotinamide metabolites, one of which can be uptake by host cells and used for synthesis of nicotinamide adenine dinucleotide (NAD), a critical cellular coenzyme involved in energy production, DNA repair, and gene expression. In the second pathway, the probiotic species facilitates the degradation and removal of a serum arginine metabolite that is barrier-impairing. These pathways are interlinked as both are driven by the probiotic colonization in mice and by a tryptophan-sufficient diet and both impact the gut barrier integrity. Functional evaluations across mice, human cells and fruit fly demonstrate a conserved protection of gut barrier integrity through these mechanisms. Two aims will use stable isotope tracing to define probiotic’s metabolic impact on NAD turnover and a key NAD-dependent enzyme that has been revealed as a promising target mediating the protection; will employ fly and mouse genetics to dissect regulatory nodes and the cell types mediating the probiotic’s protection; and will utilize mouse disease models, human cell and organoid cultures to elucidate molecular basis on the regulation of intestinal stem cell renewal and epithelial healing. This research is significant as the metabolites under investigation are perturbed in inflammatory bowel disease patients, whose serum or fecal profiles of these molecules can be utilized to guide probiotic intervention. The three PIs have over a decade collaborative record with complementary expertise indispensable for this multidisciplinary project that intersects nutrition, metabolite, microbiota and gut mucosal biology.

Public Health Relevance
PROJECT NARRATIVE: The lack of understanding of which patient population will benefit from probiotic intervention stems from a deficient knowledge of how probiotic bacteria interact then modulate host physiology. This gap has hindered the translational research on probiotics. Using stable isotope tracing, genetics, and functional assays in disease models across species, this project investigates newly uncovered metabolic pathways directly regulated by probiotics.

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