Page 63 - Read Online

Page 10 of 23 Poznyak et al. Microbiome Res Rep. 2026;5:3

provide a novel approach to treating inflammatory arthritis. For example, the retinoic acid analogue AM80
enhances the expression of the gut-homing molecule α4β7 integrin on T follicular helper (TFH) cells,
effectively redirecting these cells away from inflamed regions of the intestine and thereby reducing arthritis
severity in K/B × N mice [141-143] . Conversely, blocking β7 integrins resulted in increased arthritis severity in
these mice; however, this effect was only observed in the presence of segmented filamentous bacteria (SFB).
This interaction occurs because the blockade of β7 integrins, combined with SFB, promotes the expansion of
α4β7+ TFH and α4β7+ TH17 cells, which accumulate at sites of inflammation due to their inability to return
to the intestine, thereby worsening arthritis symptoms.

Given that alterations in intestinal barrier function are integral to the activation and migration of mucosal
immune cells, it is noteworthy that enhancing the intestinal barrier during the early stages of arthritis using
agents such as butyrate or a cannabinoid receptor 1 (CB1) agonist can slow disease progression [144,145] .
Additionally, the role of zonulin in increasing intestinal permeability and potentially promoting the spread of
inflammation to the joints is significant. Administration of larazotide acetate, a zonulin inhibitor, before the
onset of arthritis in CIA mice resulted in a 50% reduction in arthritis severity. These findings suggest that
targeting the molecular mechanisms governing intestinal immune cell migration - such as α4β7 integrin or
zonulin - could represent a promising therapeutic strategy for RA. However, challenges for clinical
application may include ensuring specificity to pathogenic immune cells, avoiding interference with normal
immune surveillance, variability in patient microbiota that may influence efficacy, and potential off-target
effects on other tissues . This treatment improved intestinal barrier function and prevented the migration
[146]
of activated intestinal cells to systemic organs and joints.

Moreover, the detection of CD11c+ CD103+ dendritic cells, normally present in the intestinal lamina
propria, within the spleens of CIA mice indicates that these cells migrate from the gut to the spleen [147-149] .
These experimental findings not only support the existence of a gut-joint axis in RA but also underscore its
significance in disease progression, revealing several potential therapeutic targets .
[150]

Fecal microbiota transplantation
FMT involves transferring the gut microbiome from a healthy donor to another patient, aiming to restore the
balance of the gut ecosystem. Since its recognition in 2013, FMT has been incorporated into professional
guidelines as a standard treatment for recurrent and persistent Clostridioides difficile (C. difficile)
infections [151-153] . Its application has expanded to include autoimmune diseases, driven by reports from
patients with recurrent C. difficile infections who experienced unexpected improvements in celiac disease
symptoms. Research using animal models of autoimmune disorders has demonstrated that FMT can
mitigate gut imbalances, improve the function of autoreactive CD4+ T cells, and alleviate the severity of
clinical symptoms. In human studies, FMT has been associated with a more balanced gut microbiota and
increased production of beneficial SCFAs in individuals with multiple sclerosis and psoriatic arthritis [154,155] .
However, effectiveness has not been consistent across all clinical trials. For instance, one study observed no
significant improvement in a patient with Sjögren syndrome following FMT, while another reported only
minimal enhancements in physical function for patients with psoriatic arthritis who underwent the
procedure [156,157] .

Recent research has investigated the protective effects of FMT in RA. A supplement containing tuna oil was
found to help restore gut microbiota balance and enhance the function of the intestinal epithelial barrier in
mice with CIA. The altered gut microbiota from tuna oil-treated mice was subsequently used for FMT in
control CIA mice. Further investigation into elastin peptides - derived from the breakdown of tuna elastin -
revealed that transferring gut flora from mice treated with these peptides had therapeutic benefits [158,159] . This
effect was characterized by reduced production of pro-inflammatory cytokines [IL-1β, Tumor necrosis factor