Tonsillar Microbiome‐Derived Lantibiotics Induce Structural Changes of IL‐6 and IL‐21 Receptors and Modulate Host Immunity

Abstract

Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin-21 (IL-21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL-6 and IL-21 receptors, thereby inhibiting the bindings of IL-6 and IL-21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides-mediated immunomodulation.

Multidimensional profile of gut microbiota in a large cohort of stratified rheumatoid arthritis

“…In addition, S. salivarius was higher in patients with lower disease activity in our follow-up cohort, suggesting a be cinal roles of S. salivarius in RA development. Recently, we have noticed de ciency of S. salivarius in RA tonsils 22 . Its production of salivaricins in the RA tonsils also declined, which is important to modulate immune responses and the production of autoantibodies in RA 22 .…”

“…Recently, we have noticed de ciency of S. salivarius in RA tonsils 22 . Its production of salivaricins in the RA tonsils also declined, which is important to modulate immune responses and the production of autoantibodies in RA 22 . S. salivarius is a safe and well-tolerated probiotic, and previous studies have shed light on the positive multifactorial implications of S. salivarius on host health.…”

pH and ROS Dual‐Sensitive Nanocarriers for the Targeted Co‐Delivery and On‐Demand Sequential Release of Tofacitinib and Glucosamine for Synergistic Rheumatoid Arthritis Treatment

“…A CIA model of DBA/1J mice was established as previously described. [ 34 ] Briefly, 100 µg of bovine collagen type II (CII) and 100 µL (4 mg L −1 ) of complete Freund's adjuvant (Chondrex, USA) that underwent complete emulsification were intracutaneously injected into the mouse tail base on day 0. On day 21, a boosting immunization was performed with 100 µg of CII in mice.…”

Intra-genus dysbiosis of Streptococcus in tonsillar microbiota is associated with host immune features in rheumatoid arthritis

“…Streptococcus taxa comprised 25.4% (17/67) of the RA-associated species, followed by Neisseria (13,19.4%) and Bacteroides (8, 11.9%) (Fig. 3C, Supplemental Fig.…”

“…Given the frequent migration of lymphocytes between the tonsils and the circulation, it is believed that changes of human-microbiota mutualism at tonsils can trigger autoimmune disorders such as RA, but little is known about the underlying mechanisms through which the tonsillar microbiota contributes to host autoimmunity. Previously, we have uncovered that the tonsillar microbiome-derived lantibiotic peptides salivaricins could directly bind to and inhibit IL-6 and IL-21 receptors and bene cially modulate host immunity in RA 19 . In the present study, we pro led the tonsillar microbiota, and identi ed a dysbiosis of tonsillar microbiota in RA patients, especially the imbalance in genus Streptococcus, which play important roles in modulation of host autoimmunity and provide mechanistic understanding for future intervention and treatments.…”