Modulation of microbiome function by host-derived noncoding small RNA

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Summary: A number of studies have reported changes in the composition of microbiota in diseases such as metabolic syndrome, inflammatory bowel diseases, hypertension, Asthma, cardiovascular diseases, rheumatoid arthritis, cancer and infection. Some of these links have been shown to be causative of diseases by using specific bacteria introduced into pre-clinical models. For example, we showed that the human clinical isolate C. jejuni (C. jejuni) 81-176 promote development of colitis-associated colorectal cancer through the production of cytolethal distending toxin (cdt) (He Z et al. Gut. 2019; 68(2) 289-300). Importantly, mice colonized with C. jejuni 81-176 had a significantly different microbial gene expression profile compared to C. jejuni lacking the toxin cdtB group, and different microbial communities as measured by 16S rDNA sequencing (He Z et al. Gut. 2019; 68(2):289-300). In addition, we demonstrated that the intestinal microbiota prevents C. jejuni-induced intestinal inflammation in ex-GF Il10-/- mice, through bile acid metabolism (Sun X et al. Gastroenterology. 2018;154(6):1751-1763). Thus, disruption of microbial composition and function may be an important aspect of disease mediated by enteropathogenic microorganisms. The mechanism implicated in maintaining a healthy host-microbiota balance is complex and included production of host-derived anti-microbial peptides, mucus barrier and immunoglobulin secretion among others. Recent findings from our laboratory suggest that human intestinal microbiota obtained from healthy or colorectal tissues altered expression of mammalian-derived fecal small RNAs such as miRNA, with some miRNAs preferentially targeting bacteria genes as predicted by bioinformatic approach (Tomkovich S et al. mSystems. 2020; 5(1)). Many of these miRNAs were predicted to target bacterial genes implicated in regulating motility, secretion, outer membrane proteins, stress response, iron acquisition, and carbohydrate utilization/transport. Thus, host-derived production of small non-coding RNA may represent another mean by which the host regulate microbiota function. This exciting concept is supported by our preliminary data demonstrating gene knockdown in bacteria using mammalian extracellular vesicles (EVs) loaded with siRNA targeting prokaryotic genes. These findings suggest that bacteria differentially impact host- derived miRNA, which in turn could influence bacterial composition and gene expression. From these observations, we hypothesize that bacteria influence the production of miRNA, which in turn modified microbiota community function and consequently disease phenotype. We plan to test this hypothesis with the following two specific aims: Aim 1. Define the role of EV in bacteria-induced miRNA in Il10-/- mice. Aim 2. Define the impact of EV-mediated siRNA on microbial gene expression. This study will establish a proof of principal that enteric pathogens triggers selective EV-containing miRNA differently affecting microbiota. Our approach using microbial genomics, transcriptomic, genetic manipulation, and gnotobiotic technology represents a unique opportunity to address the interplay between host, microbiota activities, host response and inflammation. The findings generated from this project will provide a firm support for the existence of an interkingdom communication through small non-coding RNA and open new possibilities to exploit this discovery for microbial gene manipulation and therapeutic purpose.