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Background: Parasitic helminths influence the composition of the gut microbiome. However, the microbiomes of individuals living in helminth-endemic regions are understudied. The Orang Asli, an indigenous population in Malaysia with high burdens of the helminth Trichuris trichiura, display microbiotas enriched in Clostridiales, an order of spore-forming obligate anaerobes with immunogenic properties. We previously isolated novel Clostridiales that were enriched in these individuals and found that a subset promoted the Trichuris life cycle. In this study, we aimed to further characterize the functional properties of these bacteria. Results: Clostridiales isolates were profiled for their ability to perform 57 enzymatic reactions and produce short-chain fatty acids (SCFAs) and hydrogen sulfide, revealing that these bacteria were capable of a range of activities associated with metabolism and host response. Consistent with this finding, monocolonization of mice with individual isolates identified bacteria that were potent inducers of regulatory T-cell (Treg) differentiation in the colon. Comparisons between variables revealed by these studies identified enzymatic properties correlated with Treg induction and Trichuris egg hatching. Conclusion: We identified Clostridiales species that are sufficient to induce high levels of Tregs. We also identified a set of metabolic activities linked with Treg differentiation and Trichuris egg hatching mediated by these newly isolated bacteria. Altogether, this study provides functional insights into the microbiotas of individuals residing in a helminth-endemic region. -EyM7p7tfAvrAjtAePB85J Video Abstract [ABSTRACT FROM AUTHOR]

Objective: The objective for this study was to evaluate the effects of short chain fatty acids (SCFAs) on arthritic bone remodeling. Methods: We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA‐supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum‐level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by transcriptional analysis. Results: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to robust osteoclast differentiation driven by an expansion of osteoclast progenitor cells (OCPs), accompanied by impaired osteoblast development. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow–derived OCPs from diseased mice expressed a higher level of SCFA receptors than those of control mice and that the progenitor cells in the bone marrow of SCFA‐treated mice presented a modified transcriptomic landscape, suggesting a direct impact of SCFAs on bone marrow progenitors in the context of osteoporosis. Conclusion: We demonstrated how gut microbiota‐derived SCFAs can regulate distal pathology (ie, osteoporosis) and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut–bone axis in these disorders. [ABSTRACT FROM AUTHOR]

T helper 17 (Th17) cells are important in adaptive immunity and are also implicated in inflammatory and autoimmune disorders. Th17 cell differentiation from naïve CD4+ T cells is tightly regulated in gene transcription through coordinated activities of the signal-responsive transcription factor STAT3 (signal transducer and activator of transcription 3), the pioneering factors IRF4/BATF, and the Th17-specific transcription factor RORγT, which support Th17 immune functions. Given that STAT3 acts as a master transcription factor in different cell types, whether STAT3 is regulated in a Th17-specific manner has remained a major unanswered question. In this study, we report that in mouse Th17 cells, Stat3 phosphorylation at serine 727, required for its transcriptional activity, is carried out by homeodomain-interacting protein kinase 2 (Hipk2), a nuclear kinase selectively up-regulated in Th17 cells, but not other Th subtypes that have distinct functions in immunity. Unexpectedly, we found that Hipk2 transcriptional expression is directed by Stat3 itself in Th17 cells and that, upon expression, Hipk2 in turn phosphorylates Stat3 at S727 that potentiates Stat3 activity for transcriptional activation of Th17 signature genes such as Il17a/f to ensure productive Th17 cell differentiation. We validated the in vivo function of Hipk2 for Th17 cell development in T cell-induced colitis in mice using Hipk2-knockout mice. Our study presents a previously unrecognized mechanism of self-directed cell type-specific regulation of the master transcription factor Stat3 through its own transcriptional target Hipk2 in Th17 cell differentiation, and suggests a therapeutic strategy for developing a targeted therapy for Th17-associated inflammatory disorders. [ABSTRACT FROM AUTHOR]

Spondyloarthritis (SpA) is a group of chronic, immune-mediated, inflammatory diseases affecting the bone, synovium, and enthesis. Microbiome, the community of microorganisms that has co-evolved with human hosts, plays a pivotal role in human health and disease. This invisible "essential organ" supplies the host with a myriad of chemicals and molecules. In turn, microbial metabolites can serve as messengers for microbes to communicate with each other and in the cross-talk with host cells. Gut dysbiosis in SpA is associated with altered microbial metabolites, and an accumulated body of research has contributed to the understanding that changes in intestinal microbiota can modulate disease pathogenesis. We review the novel findings from human and animal studies to provide an overview of the contribution of individual microbial metabolites and antigens to SpA. [ABSTRACT FROM AUTHOR]