Microbiome Study Provides New Clues to Common Pathology of Inflammatory Conditions

An alteration in gut microbiome diversity occurred in patients with three different inflammatory conditions, suggesting a common pathology, prospective rRNA sequencing of patients' stool samples showed.

Patients with axial spondyloarthritis (SpA), acute anterior uveitis (AAU), and Crohn's disease had a low concentration of Lachnospiraceae compared with a control group of patients with back pain and no inflammatory disorders. The most striking difference was a low abundance of Fusicatenibacter among nonsteroidal anti-inflammatory drug (NSAID) users in the control group versus the patients with the inflammatory conditions. The analysis also revealed disease-specific differences in microbiome diversity.

Substantial proportions of patients with AAU and Crohn's disease had concomitant diagnoses of SpA, supporting the concept of shared inflammatory pathology, reported Sofia K. Forslund, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, and coauthors in Arthritis & Rheumatology.

"Taken together, our results suggest there is much more to be uncovered about the immunomodulatory properties of certain bacteria in these epidemiologically related pathologies, especially at the molecular level, in order to eventually leverage the diagnostic and therapeutic potential of the microbiome," the authors stated. "Experimental work is needed to validate our findings, especially those which identified potential mediators of inflammation or disease activity."

The study added to the scientific discussion about the relationship among inflammatory conditions but went beyond many previous investigations by examining the gut microbiome for potential clues to the common pathology. The association between SpA and AAU is well established. Previous studies have shown that as many as a third of patients with SpA have concomitant AAU, making it the most common extra-musculoskeletal manifestation of SpA.

One recent study, also in Arthritis & Rheumatology, showed that a majority of 189 patients with AAU had concomitant SpA, which had not been diagnosed in 70% of the cases. The study also showed a previously documented linkage between uveitis, SpA, and HLA-B27 positivity. "Based on these findings, it can be recommended that all patients with AAU who report experiencing musculoskeletal symptoms should be referred to a rheumatologist for further evaluation," the researchers of that paper concluded.

Forslund and colleagues noted that SpA, AAU, and Crohn's disease have "a well-documented association, but the underlying pathophysiological mechanisms are not yet fully understood, despite decades of research." More than 30 years ago researchers hypothesized that reactive arthritis (sharing the genetic link to HLA-B27) could be triggered by gastrointestinal infection.

The gut microbiome offers a promising pathway to gain more insights into the shared and distinct pathophysiology of SpA, AAU, and Crohn's disease, the authors continued. Persistently dysbiotic microbiota composition reduces the resistance and resilience of the gut microbiome and can alter epithelial barrier integrity and increase intestinal permeability, leading to a "leaky gut" phenomenon that may drive inflammation associated with immune-mediated diseases.

To examine the gut microbiome for microbial disease signals, investigators performed rRNA sequencing on stool samples from 72 patients with Crohn's disease, 103 with AAU, and 102 with SpA, as well as a control group of 62 patients with back pain without any inflammatory disorder. Clinical data showed that 53.4% of patients with AAU had concomitant SpA (primarily axial), as did 16.7% of patients with Crohn's disease. Additionally, 15.3% of patients with Crohn's disease and 21.6% of patients with SpA had a history of AAU.

The rRNA sequencing showed that all four patient groups had similar microbiota, dominated by Firmicutes, followed by Bacteroidota, Actinobacteriota, and Proteobacteria. Investigators noted more inter-individual diversity at the genus level in all four cohorts. The control group, the AAU cohort, and the SpA cohort had more Prevotella-dominant individuals, whereas the patients with Crohn's disease had the highest proportion of Bacteroides-dominant individuals.

In an effort to identify potential mediators of concomitance among SpA, AAU, and Crohn's disease, investigators performed a differential abundance analysis. They found lower abundances of several Firmicutes across all disease groups, primarily amplicon sequence variants (ASVs) belonging to the Lachnospiraceae family.

The SpA group had higher abundances of Collinsella and several Lachnospiraceae ASVs. The Crohn's cohort was enriched in a Ruminococcus ASV and strongly depleted in a Blautia ASV. No ASVs or higher-level taxa had significant associations with the AAU phenotype.

"Although we did not observe a strong microbiota signal in our AAU-only patients, our results suggest that AAU patients with concomitant SpA ... are more similar to SpA-only patients than disease-negative controls," the authors stated. "Association studies seeking to link the HLA-B27+ microbiota to an existing clinical understanding of these diseases should prioritize inclusion of non-SpA HLA-B27+ groups for more precise powered comparisons."

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