Abstract
The gut microbiome plays a significant role in health and disease, and there is mounting evidence indicating that the microbial composition is regulated in part by host genetics. Heritability estimates for microbial abundance in mice and humans range from (0.05–0.45), indicating that 5–45% of inter-individual variation can be explained by genetics. Through twin studies, genetic association studies, systems genetics, and genome-wide association studies (GWAS), hundreds of specific host genetic loci have been shown to associate with the abundance of discrete gut microbes. Using genetically engineered knock-out mice, at least 30 specific genes have now been validated as having specific effects on the microbiome. The relationships among of host genetics, microbiome composition, and abundance, and disease is now beginning to be unraveled through experiments designed to test causality. The genetic control of disease and its relationship to the microbiome can manifest in multiple ways. First, a genetic variant may directly cause the disease phenotype, resulting in an altered microbiome as a consequence of the disease phenotype. Second, a genetic variant may alter gene expression in the host, which in turn alters the microbiome, producing the disease phenotype. Finally, the genetic variant may alter the microbiome directly, which can result in the disease phenotype. In order to understand the processes that underlie the onset and progression of certain diseases, future research must take into account the relationship among host genetics, microbiome, and disease phenotype, and the resources needed to study these relationships.
Highlights
Candidate genes and genome-wide association studies (GWAS) have yielded significant insight into the genetic variations influencing health and disease
Since the largest pool of microbes exists in the distal gastrointestinal tract, dysbiosis of the gut microbiome is most readily associated with region-specific gastrointestinal diseases such as Crohn’s disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colorectal cancer, and celiac disease (reviewed in (Gorkiewicz and Moschen 2018))
We found that treatment of these mice with antibiotics resulted in the restoration of sleep behaviors, suggesting that the genetic variant altered the microbiome, which was responsible for the phenotype (Fig. 1, Pathway III)
Summary
Candidate genes and genome-wide association studies (GWAS) have yielded significant insight into the genetic variations influencing health and disease. Genetic association studies have identified several specific relationships between host genetics and microbiome composition (Table 1). A recent GWAS study utilizing numerous populations and microbiome sequencing methods identified 20 loci and reproduced the LCT association with Bifidobacterium (Kurilshikov et al 2021).
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