Elucidating potential molecular signatures through host-microbe interactions for reactive arthritis and inflammatory bowel disease using combinatorial approach

Abstract

Reactive Arthritis (ReA), a rare seronegative inflammatory arthritis, lacks exquisite classification under rheumatic autoimmunity. ReA is solely established using differential clinical diagnosis of the patient cohorts, where pathogenic triggers linked to enteric and urogenital microorganisms e.g. Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia have been reported. Inflammatory Bowel Disease (IBD), an idiopathic enteric disorder co-evolved and attuned to present gut microbiome dysbiosis, can be correlated to the genesis of enteropathic arthropathies like ReA. Gut microbes symbolically modulate immune system homeostasis and are elementary for varied disease patterns in autoimmune disorders. The gut-microbiota axis structured on the core host-microbe interactions execute an imperative role in discerning the etiopathogenesis of ReA and IBD. This study predicts the molecular signatures for ReA with co-evolved IBD through the enveloped host-microbe interactions and microbe-microbe ‘interspecies communication’, using synonymous gene expression data for selective microbes. We have utilized a combinatorial approach that have concomitant in-silico work-pipeline and experimental validation to corroborate the findings. In-silico analysis involving text mining, metabolic network reconstruction, simulation, filtering, host-microbe interaction, docking and molecular mimicry studies results in robust drug target/s and biomarker/s for co-evolved IBD and ReA. Cross validation of the target/s or biomarker/s was done by targeted gene expression analysis following a non-probabilistic convenience sampling. Studies were performed to substantiate the host-microbe disease network consisting of protein-marker-symptom/disease-pathway-drug associations resulting in possible identification of vital drug targets, biomarkers, pathways and inhibitors for IBD and ReA. Our study identified Na(+)/H(+) anti-porter (NHAA) and Kynureninase (KYNU) to be robust early and essential host-microbe interacting targets for IBD co-evolved ReA. Other vital host-microbe interacting genes, proteins, pathways and drugs include Adenosine Deaminase (ADA), Superoxide Dismutase 2 (SOD2), Catalase (CAT), Angiotensin I Converting Enzyme (ACE), carbon metabolism (folate biosynthesis) and methotrexate. These can serve as potential prognostic/theranostic biomarkers and signatures that can be extrapolated to stratify ReA and related autoimmunity patient cohorts for further pilot studies.

Lactobacillus rhamnosus GG for the prevention of reactive arthritis relapse in children

“…Дисбиоз нарушает тонкий баланс между кишечной микробиотой и хозяином, что может привести к заболеванию. Ось «кишечник -микробиота», структурированная на основе взаимодействий «хозяин -микроб», играет важную роль в этиопатогенезе РеА [28]. Результаты нашего исследования подтверждают, что дисбиоз кишечника является отличительной чертой РеА у детей.…”

Reactive Arthritis Update: Spotlight on New and Rare Infectious Agents Implicated as Pathogens

“…Multiple levels of interactions between the host and infecting pathogen are emerging as critical to disease induction. Recent in silico studies have indicated, for example, that the Na/H antiporter and kynureninase, among several other proteins, are important targets for such interaction; these and similar kinds of studies will provide critical guidance for researchers to design experimental systems for dissection of those detailed interactions, and for elucidation of pathogenesis mechanisms elicited by novel agents given in previous sections [79].…”

Quo vadis reactive arthritis?

“…In these cases, arthritis or other clinical attributes may be associated with some lipo-oligosaccharides from an infecting organism that interact with the patient's innate immune system [20]. It is clear from recent studies that the intestinal microbiome has wide-ranging effects on synovial and other pathogenic processes, and that experimental systems to dissect such long-distance interactions will be critical for the definition of unique pathogenic mechanisms [21][22][23].…”