Human leukocyte antigen (HLA) alleles are associated with a variety of autoimmune diseases. The composition of gut microbiome can be influenced by host immunity, which is partially regulated by HLA. In this review, first we provide evidence from animal and human studies on: if and how HLA-B27, HLA-DRB1 (shared epitope (SE)), and other HLA alleles alter the gut microbiome, then we analyzed the data for several hypotheses to explain the mechanism(s) of HLA alleles influences on gut microbiome, and finally, we discussed several potential clinical implications of HLA alleles and microbial data, such as bacterial biomarkers for diagnosis, treatment, and the screening of high-risk population.