Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy

Abstract

Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.

In vitro triple coculture with gut microbiota from spondyloarthritis patients is characterized by inter-individual differences in inflammatory responses

“…The discrepancy between our result and the previously published study may be attributed to the different sample types (fecal samples vs. ileal and colonic biopsies) and the limited number of donors we analysed. Interestingly, we noted that lower relative Dialister abundances were consistently observed with higher relative abundances of Phascolarctobacterium , possibly indicating that these propionate-producing genera are competing for the same functional niche in our samples 44 , 50 . Based on our data, however, no causal statements of these propionate-producing bacteria in relation to the SpA pathogenesis can be formulated.…”

“…Likewise, P3 had an initial dominant presence (0 h sample) of Bacteroides , a genus with species capable of mucin degradation (e.g. B. thetaiotaomicron , B. fragilis , B. vulgatus ) 44 , 47 , however, these bacteria were not detected at the 16 h endpoint, which means that no evidence can be provided to link initially present microbes with mucus degradation upon 16 h host-microbe coincubation. More data concerning the microbial changes during the 16 h coincubation and at the end of the 16 h host-microbe coincubations is required to determine which changes were driving mucus production.…”

“…Yet, mucus thickness tended to be consistently higher in triple cocultures exposed to healthy donors (significant in H1 and H2) compared to the blank controls (not exposed to bacteria). This microbiota-induced higher mucus production in healthy individuals is physiologically relevant and represents an important physical separation, limiting contact between microbes and the epithelial barrier in the gut 43 , 44 . While the P1 microbiota behaved similar to the healthy donors in displaying a tendency to promote mucus production, exposure to microbiota of P2 and P3 failed to stimulate mucus production.…”

Uveitis in spondyloarthropathies

“…These findings suggest a strong association between HLA-B27 and spondyloarthropathies. However, the mechanism(s) underlying this relationship are not fully understood [40,41]. Some commonly known theories include arthritogenic/uveitogenic peptide [23,26,42], molecular mimicry [43][44][45][46], misfolding of HLA-B27 [23,28,[47][48][49][50], and cell-surface HLA-B27 homodimer [25,41,42,[51][52][53][54][55][56][57][58].…”

Targeted Antimicrobial Agents as Potential Tools for Modulating the Gut Microbiome

“…Pathobionts often refer to symbiotic bacteria with pathogenic potential that contribute to the progression of a disease, but have not yet been recognized as pathogens (see review: Chow et al, 2011 ; Gill and Rosenbaum, 2020 ; Chandra et al, 2021 ). For example, Fusobacterium nucleatum , an oral symbiotic bacterium was demonstrated as a pro-carcinogenic bacterium in colorectal cancer (CRC; Brennan and Garrett, 2019 ; Yachida et al, 2019 ; Slade, 2021 ).…”