MITIGATING ANTIBIOTIC-INDUCED MICROBIOME DISRUPTION WITH WHOLE GRAINS

In this application, we propose to determine if agriculturally-important whole grains can protect the microbiome from antibiotic-induced disruption and reduce associated morbidity.There is now a strong consensus that the gut microbiome is a key determinant of host physiology and health. It is also clear that perturbing this community can have vastly negative health consequences. Perhaps the two factors that can have the most impact on the composition of the microbiome are diet and antibiotic treatment. Dietary fiber is considered one of the most important determinants of microbiome activity and composition, such that reducing the content of fiber in the diet can rapidly disrupt microbiome homeostasis. This disruption, termed dysbiosis, is associated with many negative health outcomes. Antibiotic treatment has an equal, if not more powerful, capacity to induce dysbiosis that may contribute to numerous complications, including Clostridiodes difficile colitis, fungal infections, and other superinfections. In addition to these acute complications, long-term impacts on microbial homeostasis have been associated with or linked to multiple chronic conditions, including obesity, autoimmune diseases, diabetes, and neuropsychiatric conditions.While significant work has been done to define the impacts of diet and antibiotics on microbiome composition and health outcomes separately, studies have not tested these two perturbations together. Recent data from our group indicate that the metabolic activity of the murine microbiome is a key determinant of antibiotic-induced microbiome disruption and that dietary fiber has the potential to provide prebiotic protection to this community during treatment. This preliminary work utilized purified fibers as the prebiotic. However, humans and animals do not consume fiber in purified form, but as part of plant-derived whole foods that contain a mixture of macronutrients; these include polysaccharides and monosaccharides, as well as phytochemicals, minerals, and vitamins. Thus, in this application, we will profile the impact of milled whole grains on the composition of the murine microbiome and its response to antibiotics. We will focus on three key commodity grains with high fiber content: nixtamalized field corn, whole grain wheat, and whole grain oats.To determine if supplementing the diet with whole grains can reduce antibiotic-mediated microbiome disruption, we will feed mice a low fiber fully-defined base diet or a diet designed to replicate a typical western diet. We will then supplement these diets with whole grains or purified polysaccharides. We will then track the impacts of these additives on antibiotic-induced microbiome perturbation and recovery with the goal of identifying grains that provide protection during these two periods. In addition to profiling taxonomic impacts, we will also analyze the transcriptional changes in microbiome members induced by supplementation and antibiotic therapy. Based on our preliminary data with pure fibers, we hypothesize that supplementation with some of these grains will reduce the detrimental impact of antibiotics on the microbiome and promote recovery after treatment. We also propose that this protection will be associated with improved host health indicators, such as gut barrier function, reduced inflammatory response, and elevated protection from enteric pathogens. This hypothesis will be tested in the following self-contained objectives.Objective 1) Profile the impact of whole grains in comparison to purified polysaccharides on antibiotic-induced changes in composition and transcriptional responses of the murine microbiome.O.1A) Utilize a low-fiber purified diet as the base.O.1B) Utilize a western-style diet as the base.Objective 2) Determine the impacts of additive delivery timing on antibiotic-induced perturbation and recovery. Whole grain additives be supplemented at different times throughout the experimental timeframe. O.2A) Additive concurrently during antibiotic treatment.O.2B) Additive exclusively during recovery after antibiotic treatment.Objective 3) Profile the impacts of microbiome protective additives on antibiotic-induced perturbations to host physiology.O.3A) Determine impacts on mucosal integrity by profiling mucosal thickness, intestinal permeability, and Muc2 expression.O.3B) Determine impacts of protective additives on pathogen susceptibility by tracking enteric infections with select pathogens.