Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages

Asuka Yasueda,Hisako Kayama,Tsunekazu Mizushima,Ken-Ichi Komatsu,Hidekazu Takahashi,Mamoru Uemura,Toshinori Ito,Junichi Nishimura,Shigeomi Shimizu,Yuichiro Doki,Takayuki Ogino,Kiyoshi Takeda,Koji Wakame,Chu Matsuda,Michiko Murohashi,Hidetoshi Eguchi,Toru Kitagawa,Norikatsu Miyoshi

doi:10.1038/s41598-020-65306-4

Abstract

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn’s disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.

Highlights

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease
Posttreatment with Sanguisorba officinalis L. (SO) led to promotion of tissue recovery in mice suffered from dextran sodium sulfate (DSS)-induced colitis. (Supplementary Fig. S3a)
Pretreatment with SO did not affect initiation of inflammation and tissue repair in the intestine (Supplementary Fig. S3b). These results demonstrate that co-administration of SO with DSS lead to inhibition of intestinal inflammation

Summary

Introduction

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix[4] upregulated the expression of marker genes of antiinflammatory Mφ including Arg[1], Cd206, and Relma These alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSSinduced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7dependent autophagy. IBD patients are on chronic medication, such as 5-aminosalicylates, corticosteroids, and biopharmaceuticals including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-12/23p40 antibodies[2] Therapeutic reagents, such as biological drugs and corticosteroids provide therapeutic benefit in the acute inflammation phase, and dramatically suppressed active inflammation. Anti-inflammatory cytokine IL-10 produced by Mφ and Foxp3+ regulatory T (Treg) cells negatively regulates expression of pro-inflammatory cytokines including Il23a, Il6, Il12b, Tnf in intestinal Mφ and DCs37–39

Methods

Results

Conclusion