Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis

ARTICLE HIGHLIGHTS

Research background

Anti-tumor necrosis factor α (TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing.

Research motivation

The hypothesis behind this study is that anti-TNFα could induce a dysbiosis sustained by immunological changes: dysbiosis could represent one of the reasons for loss of response to anti-TNFα therapy or primary failure.

Research objectives

With this manuscript we aimed to evaluate, in colitic mice as well as healthy mice, intestinal immune system status and gut microbiota modulation induced by anti-TNFα therapy. A more comprehensive approach including gut microbiota modulation, if clarified, could be assessed by dedicated studies on active gut microbiota modulation during biologic therapy in inflammatory bowel disease (IBD).

Research methods

Healthy mice treated with anti-TNFα showed similar histological, microbial and immune features of untreated colitic mice, in particular a lymphomononuclear infiltrate both at 5^th and 12^th d at hematoxylin and eosin staining, an increase of type 1 helper T lymphocytes (Th1) and type 17 helper T lymphocytes (Th17) at day 12, and finally increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.

These findings are particularly relevant to understand the role that anti-TNFα modulation plays on gut microbiota (and vice-versa) also in humans: this finding could be of major interest in order to give more lights on mechanisms of loss of response to anti-TNFα, mechanisms of immunological shift with towards other pathways, like Th17 pathways, as well as novel potential therapeutic targets in IBD.

Research results

Gut microbiota contributes to immune system priming, development and activation. In course of IBD a decrease of Firmicutes (and, among these, the species Faecalibacterium prausnitzii) together with an increase in Proteobacteria has been demonstrated, associated to an increase of T lymphocyte differentiation toward Th1, Th17 subsets and a decrease of CD4⁺ regulatory T lymphocytes (Tregs). How these conditions are modified in course of medical treatment is not well clarified, particularly when a powerful modulator of the immune system, like anti-TNFα, is utilized.

Research conclusions

Our study confirmed data from the literature. The same features were confirmed in the experimental model of colitis presented in this paper. Furthermore, it was shown that higher representation of Bacteroides, Clostridiaceae and Faecalibacterium prausnitzii and lower representation of Enterococcaceae are associated to a healthy state while the opposite happens during colitis. Anti-TNFα is able to induce changing in gut microbiota toward a health state in course of active colitis, but a more dysbiotic effect when utilized in healthy controls. Healthy related-microbial assessment is associated to higher Treg cells count and lower Th1 and Th17 frequency, condition modified in course of active colitis or use of anti-TNFα in course of healthy condition.

The study conclusion demonstrates a clear relationship between microbial changes and immunological changes in healthy as well as in controls. However, whether these findings correlate to human disease needs to be assessed in a dedicated study as well the need of checking and correction of dysbiosis in patients exposed to anti-TNFα.

Research perspectives

This study strongly suggests a complete assessment of immune system and microbiota in course of powerful immunomodulatory therapy like anti-TNFα and opens new and important considerations. In order to personalize the therapeutic approach to an IBD patient, clinical studies assessing gut microbiota composition before starting an immunomodulatory therapy and in course of therapy are needed. Once an alteration has been demonstrated, the potential role of concomitant microbiota modulation could also be considered for newer and more personalized therapeutic approaches.