Tanshinones from Salvia miltiorrhiza alleviate ulcerative colitis via reprogramming the gut microbiota-metabolite axis

Abstract

The anti-inflammatory properties of the traditional herb Salvia miltiorrhiza Bunge are well-established, yet its precise mechanism of action in ulcerative colitis (UC) remains unclear. Herein, we evaluate the therapeutic potential of four major tanshinones–tanshinone IIA (Tan IIA), miltirone, neocryptotanshinone, and dihydrotanshinone I–in a murine dextran sulfate sodium (DSS)-induced colitis model. Our results show that tanshinones effectively alleviate disease severity, suppress systemic and local inflammation, and restore intestinal barrier integrity. Integrated multi-omics analysis reveals that the therapeutic efficacy originates from a comprehensive reprogramming of the gut microbiota-metabolite axis. Specifically, tanshinones reverse colitis-associated dysbiosis and rectify metabolic disturbances in linoleic acid metabolism, bile acid biosynthesis, and amino acid utilization. Correlation network analysis identifies key functional modules linking beneficial microbes (e.g., Akkermansia) to anti-inflammatory lipid mediators and associating pathobionts (e.g., Desulfovibrio) with disrupted bile acid metabolism. Notably, supplementation with Akkermansia muciniphila synergizes with Tan IIA to amplify barrier restoration and metabolic normalization. Our findings establish that tanshinones ameliorate UC through microbiota-driven metabolic reprogramming, wherein the restructured microbial community actively shapes a therapeutic metabolic output. This work elucidates a metabolite-mediated mechanism of action and positions tanshinones as promising microbiome-targeting therapeutics for inflammatory bowel disease.

1. Introduction

Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disease (IBD) characterized by abdominal pain, bloody diarrhea, and weight loss [1,2]. While biological therapies targeting pro-inflammatory cytokines have revolutionized treatment, their variable efficacy and secondary failure highlight an urgent need for novel therapeutic strategies [3,4].

The pathogenesis of UC involves a complex interplay of genetic susceptibility, immune dysregulation, and environmental factors [5–7]. Among these, dysbiosis of the gut microbiota is recognized as a pivotal contributor [7,8]. Patients with UC exhibit a distinct loss of microbial diversity, an expansion of pro-inflammatory pathobionts (e.g., Proteobacteria and Enterobacteriaceae), and a reduction in beneficial commensals (e.g., Adlercreutzia) [9–12]. Importantly, gut dysbiosis in UC leads to a profound reprogramming of the gut metabolome, characterized by disrupted production of key metabolites such as short-chain fatty acids (SCFAs), bile acids (BAs), and tryptophan derivatives [8,12–14]. These metabolic alterations are not merely bystanders but active drivers of intestinal inflammation, barrier dysfunction, and immune imbalance [15]. Consequently, therapeutic strategies capable of restoring microbial ecological balance and metabolic homeostasis represent a promising avenue for UC intervention.

Salvia miltiorrhiza Bunge (Danshen), a renowned traditional herbal medicine, has recently demonstrated efficacy in ameliorating dextran sulfate sodium (DSS)-induced colitis in mice [16], an effect attributed to the anti-inflammatory properties of its lipophilic component tanshinones, including tanshinone IIA and cryptotanshinone [17–20]. However, despite these documented direct anti-inflammatory effects, it remains unknown whether tanshinones exert their therapeutic benefits by remodeling the gut microbiota and inducing beneficial metabolic reprogramming to counteract the pathological state in UC.