Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels

Abstract

Background and aims A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs. Methods Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used. Results Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of MCT1 mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative. Conclusion Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis

“…Inhibition of calcineurin protected from epithelial damage and goblet cell loss and markedly reduced leukocyte infiltrations which stabilize mucosal erosions (27). This is in line with observations that point to a direct role of calcineurin in intestinal epithelial cell death (22,23), which is critical during DSS-induced colitis (28, 29). Our histological analyses point to a more consistent abrogation of mucosal damage, epithelial dysfunction and goblet cell loss in voclosporintreated mice.…”

“…We chose the dextran sodium sulfate-model of acute colitis, which shares many clinical features with acute severe ulcerative colitis, especially in regard to mucosal erosions, rectal bleeding and diarrhea development. Various studies have previously described protective effects of cyclosporine A in DSS-induced colitis (22,23,26). We observed that both voclosporin and cyclosporine A strongly abrogated severe colitis in this model.…”

Uptake and Advanced Therapy of Butyrate in Inflammatory Bowel Disease

“…The low amount of butyrate and other abnormalities of the microbiota are speculated to contribute to the refractory disease, even if drugs suppress inflammatory cytokines and immune cells. We reported that the efficacy of cyclosporine treatment in an animal colitis model deteriorated with antibiotic pretreatment but recovered with butyrate supplementation [60]. We showed that cyclosporine treatment upregulates the expression of membrane MCT1 in IECs without inducing transcriptional changes.…”

Bacterial Metabolites: A Link between Gut Microbiota and Dermatological Diseases

“…Interestingly, some of the drugs used in psoriasis management are potent agonists of these receptors; e.g., dimethyl fumarate exhibits a high affinity to the GPR109a receptor [ 63 , 64 ]. Cyclosporine, another antipsoriatic drug, may increase the intestinal uptake of certain SCFAs, especially butyrate [ 65 ].…”