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

Intestinal Permeability and Spondyloarthritis

Disruption of the intestinal epithelium has profound implications for the loss of mucosal tolerance. Further to the epithelium's role in providing physical and chemical barriers between microbe and host, the provision of mucus and other metabolites (e.g. fucose) to support the colonization of commensals is well described. Although a number of studies support increased intestinal permeability in SpA patients,[58] mirroring IBD populations,[59] this is not a universal observation.[60] Nonetheless, it is conceivable that transient or subclinical mucosal lesions may significantly disrupt local barrier integrity without overt systemic changes in intestinal permeability. The 'chicken-egg' dichotomy of inflammation and barrier function remains unresolved. Either local inflammation drives damage to the epithelium itself or dysbiotic changes that do not favor epithelial fitness (e.g. the loss of SCFA-producing bacteria), or a disrupted epithelium promotes a breakdown of mucosal homeostasis with resulting inflammation and dysbiosis (Fig. 1). Therefore, events in SpA leading to increased intestinal permeability may be spatiotemporally linked. Currently, HLA-B27 transgenic rats that develop subclinical and overt IBD provide a robust model to dissect some of these details. These transgenic animals exhibit background strain-dependent disease activity and severity, with Fischer (F344) animals exhibiting the most severe disease and Lewis animals less severely affected (manuscript in preparation). In contrast, HLA-B27 transgenic rats with the Dark Agouti background remain disease free, providing an opportunity to determine genetic and environmental factors that control gut inflammation.

Figure 1.

Host genetics, environmental triggers, or inflammation may all trigger changes to the intestinal microbiota (dysbiosis). Importantly, changes to the intestinal microbiota itself may cause or contribute to inflammation. Host genetics may either create niches that promote dysbiosis, or directly alter immune responses to the 'normal' microbiota. These altered immune responses may manifest in hyperactive innate and adaptive immune responses that promote inflammation. Due to intimate epithelial-microbiota interactions, dysbiosis may also disrupt barrier function and intestinal homeostasis leading to inflammation, a process itself that may impair barrier integrity. Environmental triggers of dysbiosis are incompletely understood, but include diet and antibiotic use.

Studies in HLA-B27 rats indicate intestinal inflammation and impaired barrier function occur concurrently.[61] Thus, development of barrier dysfunction, dysbiosis, and inflammation may be tightly linked both temporally and spatially. HLA-B27 expression is known to cause an unfolded protein response in APC triggered by protein accumulation and misfolding.[62] Although not detectable in ileal biopsies,[63] it is possible that individuals with HLA-B27 have a stress response in a subset of inflammatory cells. This could lead to either a disruption of the epithelial barrier, a local inflammatory response, or both culminating in the loss of barrier function and the loss of oral tolerance. It is conceivable that increased translocation of microbial products may prime the development of spondylitis-inducing immune cells that subsequently migrate to the periphery. Moreover, given that microbial products may induce peripheral inflammation themselves, for example, the curdlan/SKG model described above or endotoxin-induced uveitis, translocated microbial products may contribute to the inflammatory cascade at extraintestinal sites.[32,64]