Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice

Abstract

Inflammatory bowel disease (IBD) is associated with acute and chronic inflammation of the gastrointestinal tract and has emerged to be a global disease. Spermidine, a natural polyamine, plays a critical role in maintaining cellular homeostasis. Herein, we investigated the impact and mechanism of spermidine on both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis in mice. We found that spermidine exerted protective effects against acute colitis, evidenced by reduced disease activity index (DAI) and colonic inflammation, increased colonic length, and upregulated tight junction proteins in these two colitis models. Importantly, spermidine exerted significant therapeutic and preventive effects against DSS-induced colitis. Pre- and post-treatment with spermidine reduced the expression of proinflammatory cytokines, phosphorylation of (nuclear factor-κB) NF-κB and (mitogen-activated protein kinase) MAPK, and the activation of F4/80 macrophages and T cells in the colon. Furthermore, spermidine upregulated M2 macrophage markers, whereas it downregulated M1 markers in the inflamed colons. In parallel, spermidine reduced M1 pro-inflammatory markers and enhanced M2 anti-inflammatory genes in RAW264.7 cells. These results revealed that spermidine-ameliorated colitis might be through the regulation of M1/M2 macrophage polarization. In addition, spermidine treatment also alleviated LPS/TNF-α-induced inflammation in Caco-2 cells. Taken together, spermidine prevented and reversed colonic inflammation in colitis mice and might be a promising candidate for IBD intervention.

Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn’s Disease and Rheumatoid Arthritis

“…In inflamed colons and a mouse macrophage cell line, there was upregulation of anti-inflammatory M2 macrophage markers and downregulation of pro-inflammatory M1 markers with spermidine treatment [28]. Additionally, LPS/TNFα-induced inflammation decreased with spermidine treatment in Caco-2 cells [28]. These findings provide strong evidence for the potential use of spermidine as a therapeutic agent for IBD due to its ability to ameliorate colonic inflammation in mice with acute colitis [28].…”

“…These effects were also found to be greater in cells with the PTPN2:rs1893217-G SNP compared to wild-type cells [27]. Another study investigated spermidine's ability and mechanism in treating acute colitis in mice [28]. In the colitis models, spermidine was found to reduce the disease activity index (DAI), reduce colonic inflammation, and increase colonic length [28].…”

“…Another study investigated spermidine's ability and mechanism in treating acute colitis in mice [28]. In the colitis models, spermidine was found to reduce the disease activity index (DAI), reduce colonic inflammation, and increase colonic length [28]. Furthermore, pro-inflammatory cytokine expression, NF-κB (nuclear factor-κB) and MAPK (mitogen-activated protein kinase) phosphorylation, and activation of macrophages and T-cells in the colon decreased with pre-and post-treatment of spermidine [28].…”

“…In the colitis models, spermidine was found to reduce the disease activity index (DAI), reduce colonic inflammation, and increase colonic length [28]. Furthermore, pro-inflammatory cytokine expression, NF-κB (nuclear factor-κB) and MAPK (mitogen-activated protein kinase) phosphorylation, and activation of macrophages and T-cells in the colon decreased with pre-and post-treatment of spermidine [28]. In inflamed colons and a mouse macrophage cell line, there was upregulation of anti-inflammatory M2 macrophage markers and downregulation of pro-inflammatory M1 markers with spermidine treatment [28].…”

“…Furthermore, pro-inflammatory cytokine expression, NF-κB (nuclear factor-κB) and MAPK (mitogen-activated protein kinase) phosphorylation, and activation of macrophages and T-cells in the colon decreased with pre-and post-treatment of spermidine [28]. In inflamed colons and a mouse macrophage cell line, there was upregulation of anti-inflammatory M2 macrophage markers and downregulation of pro-inflammatory M1 markers with spermidine treatment [28]. Additionally, LPS/TNFα-induced inflammation decreased with spermidine treatment in Caco-2 cells [28].…”