Effects of Gut Microbiome Modulation on Intestinal Inflammation and Arsenic Toxicity with Dietary Administration of Black Raspberries

The human gut microbiome contributes to human health and disease in a significant way. Moreover, its role in transformation and metabolism of xenobiotics has been well recognized. Dietary modulation of the gut microbiome received considerable attention due to the advantages of low toxicity profiles and high patient compliance. However, dietary recommendations to tackle gut microbiota-associated diseases such as intestinal inflammation are usually based on inconclusive or controversial evidence. A therapeutic approach to treat these diseases through gut microbiome modulation is highly desirable. Previous studies showed that arsenic exposure perturbed the gut microbiome and its metabolic functions, which may contribute to its toxicity. Modulation of the gut microbiome could potentially affect arsenic toxicity. The overall objective of this study was to develop and characterize a novel dietary approach based on black raspberries (BRB) for effective modulation of the gut microbiome that pushes the gut microbiome toward a desired state, resulting in protective effects for intestinal inflammation and arsenic toxicity. To accomplish the overall goal of this project, the following specific objectives were pursued: (i) to characterize the taxonomic and functional compositions of the BRB-modulated gut microbiome; (ii) to identify BRB-driven microbiome-derived metabolites that contribute to beneficial health effects; (iii) to determine the functional roles of BRB in mediating intestinal inflammation and arsenic biotransformation/toxicity through gut microbiome modulation. Using a standardized BRB diet and mouse models, we characterized the functional alterations in addition to compositional changes in the gut microbiome upon modulation via dietary administration of BRB. Remarkable changes in the gut microbiome were revealed at both compositional and functional levels with an expected increase of Akkermansia muciniphila in concert with profound impacts on gut microbiome-related functions. Significantly-increased levels of beneficial metabolites and aryl hydrocarbon receptor (AHR) ligands were observed in the BRB-modulated gut microbiome, likely resulting from a combination of microbiome functional changes and unique precursors in BRB. Moreover, application of this modulation approach ameliorated intestinal inflammation in an AHR-dependent manner; and alleviated arsenic toxicity via alterations in related metabolic enzymes and cofactors. These findings provide insights regarding gut microbiome modulation as an attractive therapeutic approach for treatment of microbiome-associated diseases.Doctor of Philosoph