Co-administration of ۱,۲۵-dihydroxyvitamin D۳ and infliximab improves colitis in mice by modulating Treg differentiation

Objective(s): The combination of TNF-α inhibitors and vitamin D in colitis remains to be elucidated. In the present study, we revealed the benefit of infliximab (IFX) and vitamin D in a mouse model of Ulcerative colitis (UC). Materials and Methods: A dextran sulfate sodium-induced colitis model was used. The therapeutic effect of the combination was evaluated by symptom and histopathology analysis. The synergistic mechanism was explored by detecting the regulatory effect of the combined therapy on Regulatory T cell (Treg) differentiation.Results: IFX and ۱,۲۵-dihydroxyvitamin D۳ (VitD۳) synergistically prevented the development of colitis by improving clinical signs, pathological and hematological manifestation, and inhibiting intestinal inflammation (decreasing TNF-α, IL-۱β, and IL-۶). Coadministration of IFX (۲.۵ mg/kg) with VitD۳ or IFX (۵.۰ mg/kg) with VitD۳ was more effective than administration of IFX (۲.۵ mg/kg, ۵.۰ mg/kg). There was no difference in therapeutic effect between IFX (۵.۰ mg/kg) and VitD۳+ IFX (۲.۵ mg/kg) groups or between the VitD۳+IFX (۵.۰ mg/kg) and VitD۳+ Azathioprine (AZA) groups. VitD۳ or combination therapy showed more powerful regulation of splenetic Treg differentiation and IL-۱۰ production than IFX alone. Moreover, VitD۳ alone or in combination induced higher levels of Foxp۳ and IL-۱۰ than IFX in colon tissue. In ulcerative colitis patients, serum VitD۳ levels positively correlated with Treg levels.Conclusion: VitD۳ and IFX synergistically inhibit colitis based on their powerful regulation of Treg differentiation. VitD۳ combined with IFX is an alternative therapy for patients who are intolerant to standard   doses of IFX or combination of IFX and AZA.

Keywords:

Colitis , Infliximab , Interleukin-۱۰ , Regulatory T cells , Vitamin D