Gut Microbes as the Major Drivers of Rheumatoid Arthritis: Our Microbes Are Our Fortune!

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease with an unknown etiology. While certain genes provide strong susceptibility factors, the role of environmental factors is becoming increasingly recognized. Among genetic factors, human leukocyte antigen (HLA) genes, encoded within the major histocompatibility complex (MHC), have been linked to predisposition to RA, while among environmental factors, smoking, infections and diet are the major contributors. Genetic and environmental factors impact microbial composition in the host. Based on the dysbiosis observed in the gut and lung microbiome, a mucosal origin of RA has been suggested. However, proving whether genes or microbes provide a stronger risk factor has been difficult. Studies from RA patients and various mouse models, specifically humanized mice expressing HLA class II genes, have been instrumental in defining the role of environmental factors such as smoking and endogenous small intestinal microbes in modulating arthritis severity. The consensus based on most studies support an interaction between host genetic and environmental factors in the onset and severity of disease. However, until now, no microbial markers for disease prognosis or treatment efficacy have been available. Here, the role of gut microbes as markers of disease severity, and the potential for using endogenous commensals for modulating immune responses to suppress inflammation in the context of genetic factors, are discussed.

Keywords: environment; genetics; host–microbiome interactions; human leukocyte antigens; rheumatoid arthritis; transgenic mice.

Figure 1

Mucosal origin of preclinical autoreactivity and the role of microbes in the pathogenesis of rheumatoid arthritis (RA). Intestinal microbial diversity is shaped by genetic factors encoded within the major histocompatibility complex (MHC-II) and environmental factors including lifestyle (smoking, diet, exercising), infections and geographic location, among others. Besides these factors, epigenetics, sex hormones, and an aging immune system also contribute to microbial composition, thereby establishing a unique microbiome for each individual. Intestinal microbial composition is based on the requirement and function of the region generating spatial microbial diversity. Individuals with RA-susceptible genes may harbor opportunistic pathogens which, under certain circumstances, cause the dysbiosis and expansion of those endogenous pathogens accompanied with reduced diversity. This can alter the metabolic profile with an increase in certain metabolites and a decrease in short chain fatty acids (SCFA) required for a healthy gut. Microbial/metabolic dysbiosis impacts the immune cell profile, causing inflammatory milieu in the gut, thereby increasing gut permeability. If the endogenous pathogen has molecular memory with a self-peptide, it can break tolerance and generate preclinical autoreactivity. Activated immune cells and luminal products can extravasate and cause systemic inflammation. In the joints, these activated cells can trigger the local immune system, causing inflammation and epitope spreading, resulting in a transition from asymptomatic to symptomatic arthritis and pathology. Knowledge of the endogenous pathogen can help define biomarkers of disease onset and progression. In healthy individuals, symbiosis between the immune system and gut microbes producing SCFAs helps with epithelial cell repair and the generation of T regulatory cells, keeping pathogens and inflammation in check. Besides the gut microbiome, other mucosal surfaces such as the oral cavity and lungs may also be involved suggesting a mucosal origin of preclinical asymptomatic autoreactivity. Treatments and diets can alter the gut microbiome and partially restore the microbiome, thus suppressing inflammation. The use of endogenous commensals with probiotic-like properties, such as Prevotella histicola, can generate eubiosis and help maintain T regulatory cells in the gut, which can reverse the inflammatory response and help with reducing symptoms associated with arthritis. Endogenous commensals that imitate the effect of biologics can further aid in reducing the dose of immunosuppressive drugs used for treating patients, thus helping to reduce side effects.