Systems pharmacology and transcriptomics reveal the mechanisms of Sanhuang decoction enema in the treatment of ulcerative colitis with additional Candida albicans infection

Zhijun Han,Xiaofen Tan,Guiming Yan,Changzhong Wang,Juan Sun,Tianming Wang,Kelong Ma

doi:10.1186/s13020-021-00487-2

Abstract

BackgroundUlcerative colitis (UC) is an important inflammatory phenotype in bowel disease (IBD), which is caused by multiple potential factors, including fungal dysbiosis. Candida albicans (C. albicans) was confirmed to be an important factor promoting the occurrence and development of UC. Sanhuang decoction (SHD) has been used for UC therapy in China for thousand of years, although its core active constituents and pharmacological mechanism remain undefined.MethodsIn this work, a murine model of UC with C. albicans colonization was established with dextran sodium sulfate (DSS) and C. albicans intragastric administration. The major bioactive constituents and potential mechanism of SHD against UC with fungal dysbiosis were comprehensively examined by combining systems pharmacology and in vivo transcriptomics.ResultsSHD attenuated C. albicans burden, reduced DAI, increased mucosal integrity and relived systemic inflammation in UC mice. Systems pharmacology analysis identified 9 core bioactive ingredients and 45 hub targets of SHD against UC. Transcriptomics analysis confirmed 370 differentially expressed genes (DEGs) after SHD treatment, which were mainly enriched in inflammatory and immune response related signaling pathways. Toll-like receptor and PI3K-Akt signaling pathway were screened out as the candidate targets involved in the action of SHD on fungal dysbiosis-associated UC, which were consistent with the findings in systems pharmacology. The expression of TLR4, IL-1β, NF-κB, PI3K and Akt proteins were stimulated by C. albicans, and partially reversed by SHD in UC mice.ConclusionThese findings suggested SHD could be a candidate for the treatment of fungal dysbiosis-associated UC via TLR4-NF-κB and PI3K-Akt signaling pathways.

Highlights

Ulcerative colitis (UC) is an important inflammatory phenotype in bowel disease (IBD), which is caused by multiple potential factors, including fungal dysbiosis
C. albicans overtly aggravated UC as indicated by more pronounced body weight loss, elevated disease activity index (DAI) and histological score, reduced colon length and more severe colonic epithelial mucosa damage compared with the dextran sodium sulfate (DSS) group (Fig. 1B–F, Additional file 1: Figure S2)
Compared with the Model group, body weight loss was reduced and DAI was decreased in the Sanhuang decoction (SHD) groups (Fig. 1B, C)

Summary

Introduction

Ulcerative colitis (UC) is an important inflammatory phenotype in bowel disease (IBD), which is caused by multiple potential factors, including fungal dysbiosis. Candida albicans (C. albicans) was confirmed to be an important factor promoting the occurrence and development of UC. Ulcerative colitis (UC) represents an important chronic inflammatory disease of the gastrointestinal (GI) tract featuring abdominal pain, diarrhea and rectal bleeding, with a significant impact on the quality of life [1]. The pathogenesis of UC is complex, and several factors including genetics, environmental stimuli, immune disorder and the gut microbiota are considered to be involved in the occurrence and development of UC. C. albicans (Ca), one of the most common opportunistic fungi in the human GI tract, is thought to be associated with UC development. C. albicans administration aggravates dextran sulfate sodium-induced colitis in the mouse model, with higher inflammatory cytokine secretion levels and severer mucosal damage [12, 13]

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