Background/Purpose: The intestinal microbiota plays a pivotal role in both host fitness and disease. Increasing evidence implicates microbial metabolites in the modulation of host immunity in both the gut and the periphery. In this study we used the HLA-B27 transgenic rat model of spondylarthropathy (SpA) to test the hypothesis that HLA-B27, a key SpA risk allele, impacts the host-microbiota metabolome and this may contribute to B27-associated spondylarthropathy.

Methods: We used ultra performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) to analyze the metabolic profiles of intestinal contents collected from Fischer HLA-B27/β2m rats and WT controls. Samples were collected at two time points, at 6 weeks of age and at 16 wks. These time points were chosen since they represent time points prior to and subsequent to the development of B27-associated inflammation. Intestinal dysbiosis in this study was analyzed using 16s rRNA sequencing and phyla/species-specific qRT-PCR primers.

                For functional studies, microbial metabolities (short chain fatty acids) were administered p.o. in drinking water. Animals were treated for 10 weeks, with treatment beginning at 6 wks. The development of HLA-B27-associated inflammatory sequelae was analyzed longitudinally and at necropsy. Inflammatory cytokine expression was determined in intestinal tissue by RNA extraction and qRT-PCR.

Results: UPLC-MS/MS analysis detected the presence of 582 host and microbial metabolites. Changes in metabolites related to energetics, inflammation, redox homeostasis and the microbiome were observed at both time points examined. Microbial metabolites of amino acids and of dietary components were strongly impacted by HLA-B27 expression. Medium chain fatty acids (MCFAs) and short chain fatty acids (SCFAs) were globally dysregulated in HLA-B27+ animals. Moreover, 16s analysis of gut microbiota community structure revealed HLA-B27 expression was associated in a marked loss of SCFA-producing Clostridial spp. Strikingly, administration of SCFA propionate led to a significant attenuation of B27-dependent inflammation.

Conclusion: To our knowledge this is the first study to report that expression of SpA-susceptibility allele HLA-B27 profoundly impacts the host-microbiota metabolome. Of the many B27-dependent changes to both host and microbiota metabolic profiles, loss of medium and short chain fatty acids were amongst the most pronounced. SCFAs are a fermentation product of dietary fiber and HLA-B27 expression was associated with reduced colonization by multiple SCFA-producing bacteria. The successful attenuation of B27-dependent spondylarthropathy by targeting these microbial metabolites highlights the translational potential of metabolomic profiling of the intestinal microbiota. These data strongly support further studies of the host-microbiota metabolome in SpA patient populations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-b27-expression-profoundly-shapes-the-host-microbiota-metabolome/