Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn’s disease in the Ryukyu Islands

Abstract

Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.

Upregulation of Intestinal Barrier Function in Mice with DSS-Induced Colitis by a Defined Bacterial Consortium Is Associated with Expansion of IL-17A Producing Gamma Delta T Cells

“…Genera of Mucispirillum , which are increased during inflammation, have been suggested to be mucus-dwelling commensals that can cause disease, so called-pathobionts, because under some conditions, the immune system mounts an IgG response against them (42). Significant association of Prevotella with CD has been demonstrated by Said et al (43), and their further studies supported the possibility that the increase of Prevotella contributes, at least partially, to the genetic susceptibility to CD (44). In addition, Helicobacter ganmani , which are some of the most prevalent bacterial contaminants of laboratory mice, were found associated with alterations in inflammatory cytokines in IL10-deficient mice (45).…”

Altered Bacterial-Fungal Interkingdom Networks in the Guts of Ankylosing Spondylitis Patients

“…A recent quantitative metagenomic study, based on deep shotgun sequencing using gut microbial DNA from 211 Chinese individuals, also showed that alterations of the gut microbiome were associated with the development of AS (15). Alterations in the gut microbial genera, such as lower abundance of Bacteroides (16), increase of Prevotella (17), and Lachnospiraceae subgroups, etc. (18) in IBD were highly in accordance with the patterns that were observed in AS patients.…”

Protective association of TNFSF15 polymorphisms with Crohn's disease and ulcerative colitis: A meta-analysis

“…Among them, the majority were excluded after the first screening based on abstracts or titles, mainly because for reasons of overlapped citations, not relevant to the TNFSF15 polymorphisms and IBD risk, reviews, conference abstracts, or not a related gene polymorphism. Eventually, a total of five case–control studies were selected,[ 16 17 18 19 20 ] including five studies for rs3810936 polymorphism (2251 cases and 2442 controls), four studies for rs7848647 polymorphism (1503 cases and 1816 controls), and four studies for rs6478108 polymorphism (1502 cases and 1817 controls) [ Figure 1 ]. The characteristics of these included studies and the genotype distribution and allele frequency of TNFSF15 polymorphisms in case- and control-studies are shown in Table 1 .…”