Rheumatoid arthritis (RA) is considered a multifactorial condition where interaction between the genetic and environmental factors lead to immune dysregulation causing autoreactivity. While among the various genetic factors, HLA-DR4 and DQ8, have been reported to be the strongest risk factors, the role of various environmental factors has been unclear. Though events initiating autoreactivity remain unknown, a mucosal origin of RA has gained attention based on the recent observations with the gut dysbiosis in patients. However, causality of gut dysbiosis has been difficult to prove in humans. Mouse models, especially mice expressing RA-susceptible and -resistant HLA class II genes have helped unravel the complex interactions between genetic factors and gut microbiome. This review describes the interactions between HLA genes and gut dysbiosis in sex-biased preclinical autoreactivity and discusses the potential use of endogenous commensals as indicators of treatment efficacy as well as therapeutic tool to suppress pro-inflammatory response in rheumatoid arthritis.