The Intestinal Microbiome in Spondyloarthritis

Tejpal Gill; Mark Asquith; James T. Rosenbaum; Robert A. Colbert


Curr Opin Rheumatol. 2015;27(4):319-325. 

In This Article

Animal Models of Spondyloarthritis

Gut commensals are important for educating our immune system, as animals raised in germ-free environments fail to develop lymphoid organs and have muted adaptive immunity.[23] Thus, it is not surprising to think that more subtle differences in microbial communities might influence (or be influenced by) autoimmune or autoinflammatory diseases. In HLA-B27 transgenic rats that develop SpA, inflammatory disease features including arthritis and colitis are absent when animals are derived into a germ-free environment.[3] Interestingly, reintroduction of normal flora enables the inflammatory disease to reestablish itself.[24] Although these early studies clearly established a role for the gut microbiome in SpA, more recent work has focused on defining the differences. HLA-B27 transgenic rats have a different cecal microbiome as compared with the wild-type (WT) (nontransgenic) rats.[25] How this affects immune modulation and disease severity is not clear. This study[25] found increases in Prevotellaceae and Rikenellaceae concomitant with development of inflammation in the intestine.

Recent murine experiments have demonstrated that overall microbial composition as well as individual species plays an important role in development of inflammatory arthritis. Intestinal segmented filamentous bacteria (SFB)[26] colonization of germ-free K/B x N mice was sufficient to drive arthritis development.[27] SFB colonization in the gut induced secondary and tertiary lymphoid tissues to generate IgA and Th17 T-cell responses.[28] Notably, SFB antigen presentation by intestinal dendritic cells (CD11c+) is crucial for the development of Th17 cells, evoking a highly SFB-specific Th17 response.[26] These observations provide mechanistic support for earlier research suggesting that mucosal T cells are modulated by gut bacterial components,[29] as well as outline the complex interplay between dendritic cells and innate lymphoid cells in regulating intestinal Th17-cell homeostasis. A common feature of SFB and other intestinal microbes that strongly potentiate Th17 responses such as Citrobacter rodentium is their intimate association/attachment to intestinal epithelial cells. This is consistent with the notion that mucosa-associated bacteria may be particularly relevant to IBD and/or SpA pathogenesis.

Another bacteria associated with SpA (reactive arthritis), Chlamydia trachomatis, has been associated with induction of interleukin 23 (IL-23) expression in infected target cells.[18] Polymorphisms in the IL-23 receptor (IL23R) have been associated with AS and IBD,[30] and the IL-23 interaction with IL23R promotes the expansion of Th17 cells, and is a direct stimulator of Th17 cytokine production.[31] In the BALB/c background mutant mice, designated as the SKG mice, SKG mouse, which is a model of SpA, T-cell receptor[32] signaling strength is impaired due to a mutation in ZAP-70. This results in the development and expansion of CD4+ Th17 T cells. When these mice are treated with microbe-associated molecular patterns such as curdlan, which is a strong inducer of IL-23, there is tremendous Th17 activation and a strong inflammatory response that produces a SpA-like phenotype. Although germ-free conditions ameliorate arthritis and ileitis, cohousing SKG mice with WT mice suppressed the ileitis but did not attenuate arthritis, suggesting that host microbiome interactions play a role in IL-23-dependent loss of mucosal function in SKG mice, triggering ileitis in response to curdlan.[33]

Animal models of IBD and SpA have also provided novel insight at antiinflammatory pathways elicited by the intestinal microbiota. The mucosal lining of the lumen has emerged as an important component of host–microbe interaction. Epithelial fucosylation helps promote commensal colonization, at the same time resisting pathogens in the mucosal lining.[34] Another emerging area is the action of short chain fatty acids (SCFAs), fermentation products of gut microbes whose production is enriched in mucus degrading bacteria.[35] One such SCFA, butyrate, regulates intestinal permeability.[36] Low doses of butyrate enhance barrier function, whereas high doses increase intestinal permeability, probably secondary to cell death.[37] Atarashi and coworkers[38,39] demonstrated that gnotobiotic mice colonized with Clostridium leptum and Clostridium coccoides have enhanced accumulation of Tregs in colonic lamina propria. They showed that Clostridium groups activate colonic intestinal epithelial cells to produce Transforming growth factor beta (TGF-b) TGF-β and other Treg-inducing molecules. Administration of diets that are rich in SCFA like butyrate to mice, or the administration of butyrate itself to naive CD4+ cells, can promote their differentiation to colonic Tregs.[40,41] The myriad reported antiinflammatory effects of SCFA also extend to imparting antiinflammatory effects on intestinal antigen presenting cells (APC).[42] Potential therapeutic effects warrant further scrutiny in SpA animal models or patient populations.[43]