UCLA

The gut microbiome has received increasing attention as a potential modifier of disease susceptibility, but attempts to identify consistent disease-associated microbes have been met with limited success. Chapter 1 explores whether refocusing gut microbiome research away from fecal microbiomes and towards relevant intestinal regions may have more utility in defining microbes that drive disease pathology. Specifically, we find that small intestinal jejunal and ileal microbes have high predicted gut-brain and gut-metabolic functional capacity compared to microbes in the distal colon, and that these biogeographical distinctions are largely lost in mice colonized with human or mouse feces (a widely used technique in the field to establish causality). We additionally report that, while gut biogeographical patterns can be reproduced in broad strokes across facilities, ~50-60% of region-specific genera were limited to the individual facility, highlighting a central challenge in microbiome research.We next address whether disease-linked genetic risk loci can modify the gut microbiome, classifying such loci as microbiome quantitative trait loci (mb-QTL). While it is widely accepted that environmental factors affect gut microbiome composition, studies of identical twin cohorts and microbiome- genome wide association studies demonstrate that the gut microbiome is heritable to some extent. If the gut microbiome can be a vector in conveying both genetic and environmental insults to mediate disease, then this may account for the observed heterogeneity in disease incidence/susceptibility among risk loci carriers. In the 22q11.2 microdeletion mouse model of schizophrenia, we demonstrate that 22q11.2del/+ mice exhibit increased schizophrenia-like behavior compared to +/+ mice in addition to ileal but not colonic microbiome shifts (Chapter 2). In the latter half of this work, we evaluate the highly pleiotropic human A391T risk variant in the SLC39A8 gene as a potential mb-QTL in the context of two of its associated diseases - Crohn’s disease (increased risk) and Parkinson’s disease (reduced risk). We first report that SLC39A8 A393T (the murine equivalent of A391T) leads to small intestinal and colonic microbiome shifts along with inflammation in A393T mice, in a manner consistent with the effects of A393T on SLC39A8-encoded ZIP8 transport function (Chapters 3 and 4). Through transplantation of wild-type and SLC39A8 A393T microbes into antibiotic-treated wild-type mice, we show that A393T-linked microbes are sufficient to drive intestinal inflammation (Chapter 4). Lastly, through utilizing several mouse models of Parkinson’s disease (PD), we demonstrate that the microbiome- modifying A393T variant regulates susceptibility to synucleinopathy-induced PD (Chapter 5). The significance of these findings are as follows: (1) High gut-brain and gut-metabolic activity of the small intestinal microbiome warrant its consideration in experimental designs. (2) For phenotypes in which the outcomes are facility-specific, reporting gut microbiome composition alongside phenotypic outcomes is necessary and may in fact be physiologically relevant. (3) Risk loci may confer disease susceptibility through the gut microbiome. (4) Investigating microbiome-disease mechanisms of mb-QTL in preclinical studies enhances translational relevance while potentially alleviating reproducibility issues. (5) Clinically, future incorporation of microbiome information alongside genomic information could improve predictions of disease risk.