Genetic hypogonadal mouse model reveals niche-specific influence of reproductive axis and sex on intestinal microbial communities

Abstract

Background The gut microbiome has been linked to many diseases with sex bias including autoimmune, metabolic, neurological, and reproductive disorders. While numerous studies report sex differences in fecal microbial communities, the role of the reproductive axis in this differentiation is unclear and it is unknown how sex differentiation affects microbial diversity in specific regions of the small and large intestine. Methods We used a genetic hypogonadal mouse model that does not produce sex steroids or go through puberty to investigate how sex and the reproductive axis impact bacterial diversity within the intestine. Using 16S rRNA gene sequencing, we analyzed alpha and beta diversity and taxonomic composition of fecal and intestinal communities from the lumen and mucosa of the duodenum, ileum, and cecum from adult female (n = 20) and male (n = 20) wild-type mice and female (n = 17) and male (n = 20) hypogonadal mice. Results Both sex and reproductive axis inactivation altered bacterial composition in an intestinal section and niche-specific manner. Hypogonadism was significantly associated with bacteria from the Bacteroidaceae,Eggerthellaceae,Muribaculaceae, and Rikenellaceae families, which have genes for bile acid metabolism and mucin degradation. Microbial balances between males and females and between hypogonadal and wild-type mice were also intestinal section-specific. In addition, we identified 3 bacterial genera (EscherichiaShigella, Lachnoclostridium, and Eggerthellaceaegenus) with higher abundance in wild-type female mice throughout the intestinal tract compared to both wild-type male and hypogonadal female mice, indicating that activation of the reproductive axis leads to female-specific differentiation of the gut microbiome. Our results also implicated factors independent of the reproductive axis (i.e., sex chromosomes) in shaping sex differences in intestinal communities. Additionally, our detailed profile of intestinal communities showed that fecal samples do not reflect bacterial diversity in the small intestine. Conclusions Our results indicate that sex differences in the gut microbiome are intestinal niche-specific and that sampling feces or the large intestine may miss significant sex effects in the small intestine. These results strongly support the need to consider both sex and reproductive status when studying the gut microbiome and while developing microbial-based therapies.

Genetic hypogonadal (Gnrh1hpg) mouse model uncovers influence of reproductive axis on maturation of the gut microbiome during puberty

“…Members of the Lachnospiraceae, on the other hand, were more abundant in wild-type mice at peripuberty and adulthood compared to mutant mice, a result supported by a balance analysis that showed one specific genus of Lachnospiraceae to be more abundant in wild-type mice than mutant mice. Our previous study also found higher abundances of Lachnospiraceae in the cecum lumen of wild-type mice compared to mutant mice [65]. Studies have shown that Lachnospiraceae degrade host mucins and produce short-chain fatty acids that can affect host inflammation [66,67].…”

“…Bacteria in this family are known to degrade complex carbohydrate, including host mucins, and they are also know to contain genes for bile acid transformation [64]. Previous work showed that Muribaculaceae species were especially abundant in mutant adult mice in microbial communities of the small and large intestine [65]. Members of the Lachnospiraceae, on the other hand, were more abundant in wild-type mice at peripuberty and adulthood compared to mutant mice, a result supported by a balance analysis that showed one specific genus of Lachnospiraceae to be more abundant in wild-type mice than mutant mice.…”

Metagenomic analysis reveals the impact of sampling methods on intestinal microbiota in donkeys and cows

“…Although previous studies have shown that the sampling methods can impact on the diversity of microbial 15 , the effects of sampling methods on the intestinal microbial community composition and functional had rarely investigated systematically. This lack of research hinders our understanding of the complex interactions between the gut microbiome and human health.…”