Umbelliferone potentiates intestinal protective effect of Lactobacillus Acidophilus against methotrexate-induced intestinal injury: Biochemical and histological study

Abstract

Intestinal injury is a common adverse effect of methotrexate (MTX) therapy, limiting its clinical use. Despite oxidative stress and inflammation being the most embedded mechanism of injury, pharmacological agents that exhibit antioxidant and anti-inflammatory impacts could prevent such toxicities. This study aimed to assess the enteroprotective effect of lactobacillus acidophilus (LB) and/or umbelliferone (UMB) against MTX-induced intestinal injury. Histologically, pretreatment with LB, UMB, or their combinations preserve the intestinal histological structure and mucin content with superior effect in combination therapy. In addition, oral pretreatment with UMB, LB, or their combinations significantly restored oxidant/antioxidant status, as evidenced by the upregulation of Nrf2, SOD3, HO-1, GSH, and GST levels concurrent with a decline in MDA contents. Besides, they suppressed the inflammatory burden by inhibiting STAT3, MPO, TLR4, NF-κB, TNF-α, and IL-6 levels. Moreover, LB, UMB, or their combinations significantly upregulated Wnt and β-catenin expression. Notably, pretreatment with the combination therapy is superior to monotherapy in protecting rats' small intestines from MTX-induced enteritis. In conclusion, combined pretreatment with LB and UMB could be a novel therapeutic regimen for conditions of intestinal injury induced by MTX via restoring oxidant/antioxidant balance and suppressing inflammatory burden.