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Article

Gut Microbiota Remodeling Mediates the Therapeutic Effects of a Plant-Based Medicine on DSS-Induced Ulcerative Colitis in Mice via the Butyrate-SVCT1-Vitamin C Axis

by
Haoran Shen
1,
Xiaoyou Yu
1,
Zhiyu Wang
1,
Sitong Zhou
1,
Jiandong Jiang
1,2,
Huihui Guo
1,* and
Yanxing Han
1,*
1
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
2
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(5), 2245; https://doi.org/10.3390/ijms27052245
Submission received: 15 February 2026 / Revised: 25 February 2026 / Accepted: 26 February 2026 / Published: 27 February 2026
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development: 2nd Edition)
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Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a rising global incidence in recent years. Dengzhan shengmai (DZSM), a plant-based formulation clinically used in the management of cerebrovascular diseases, possesses documented anti-inflammatory and antioxidant properties; however, its effects on UC are unclear. In this study, we investigated the therapeutic potential and underlying mechanism of DZSM in a dextran sulfate sodium (DSS)-induced murine colitis model. Our results showed that DZSM significantly alleviated UC-related parameters. Mechanistically, DZSM remodeled gut microbiota dysbiosis, specifically enriching the abundance of short-chain fatty acid (SCFA)-producing bacteria and elevating colonic levels of SCFAs. Notably, butyrate upregulated the expression of the sodium-dependent vitamin C transporter 1 (SVCT1) in colonic epithelial cells, thereby enhancing cellular vitamin C (VitC) uptake. The accumulated VitC synergized with butyrate to exert potent antioxidant and anti-inflammatory effects, further reinforcing epithelial barrier function. Importantly, fecal microbiota transplantation (FMT) confirmed that the protective effects of DZSM on UC were achieved by modulating gut microbiota, at least partially. Collectively, our findings demonstrate for the first time that DZSM alleviates DSS-induced colitis in mice through a novel butyrate-SVCT1-VitC axis driven by gut microbiota remodeling, providing new mechanistic insights into the microbiota-dependent efficacy of plant-based medicine.

1. Introduction

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by continuous mucosal inflammation of the colon and rectum [1]. UC represents a significant global health burden, affecting approximately 5 million patients worldwide in 2023. Currently, newly industrialized countries such as China are witnessing a rapid increase in the incidence and prevalence of UC [2]. The typical symptoms of UC include bloody diarrhea, abdominal pain, fecal urgency, and tenesmus, which seriously decrease the patient’s quality of life [3]. Currently, only a limited number of drugs, including 5-aminosalicylates, corticosteroids, immunosuppressants, and biologics, are used to alleviate UC symptoms [4]. However, these therapies are often have limited efficacy, substantial side effects, high costs, or frequent development of drug resistance [5,6]. Most importantly, not even a single drug can completely heal UC [4]. Consequently, there remains a critical unmet need for the development of safer, more effective and affordable treatment strategies.
The pathogenesis of UC is multifactorial and complex, involving genetic susceptibility, environmental factors, dysregulated mucosal immunity, and, importantly, a profound disruption of the gut microbial ecosystem [7]. Numerous studies have reported the imbalance of intestinal microorganisms in UC, characterized by reduced microbial diversity, depletion of beneficial commensals, and enrichment of several pathobionts [8]. Dysbiosis of the gut microbiota is not merely a bystander effect but negatively influences the health of its host by impairing intestinal barrier function, promoting inappropriate mucosal immune activation, and altering the production of key microbial metabolites [9]. Among these metabolites, short-chain fatty acids (SCFAs), including mainly acetate, propionate, and butyrate, derived from the microbial fermentation of dietary fiber, play a pivotal role in maintaining colonic homeostasis [10]. Butyrate, in particular, serves as the primary energy source for colonocytes, strengthens the epithelial barrier, and exerts potent anti-inflammatory and immunomodulatory effects through mechanisms involving histone deacetylase (HDAC) inhibition and/or G-protein-coupled receptors signaling pathways [11]. A deficiency in colonic SCFAs, especially butyrate, is a hallmark of UC and is closely linked to disease severity [12,13,14]. Thus, Butyrate has emerged as a promising treatment target for UC.
Recent studies have shown that vitamin C (L-ascorbic acid, VitC) may have beneficial effects on UC and that a deficiency of VitC leads to the development of UC [15,16,17]. VitC, as a potent antioxidant and cofactor, plays a significant role in alleviating oxidative stress, inflammation, and promoting tissue repair [18,19,20]. The intestine is one of the key sites for the absorption and metabolism of VitC, with its uptake primarily relying on the sodium-dependent vitamin C transporter 1 (SVCT1) [21,22]. However, it remains unclear whether the levels of colonic VitC absorption were modulated by gut microbiota and metabolites.
Dengzhan shengmai (DZSM) is a standardized plant-based medicine in China comprising four herbal components: Erigeron breviscapus, Panax ginseng, Ophiopogon japonicus, and Schisandra chinensis. It was officially approved by the China National Medical Products Administration in 2007 and has been included in the China National Essential Drugs List for its established use in the management of cardiovascular and cerebrovascular diseases [23]. This clinical application is supported by documented anti-inflammatory, antioxidant, and immunomodulatory properties attributed to DZSM and its bioactive constituents, such as scutellarin and various ginsenosides [24,25]. Notably, several of the herbal ingredients in DZSM are not exclusive to traditional Chinese medicine (TCM) but are also utilized in other global medicinal systems, further attesting to their recognized efficacy and safety profile as botanical agents [26,27]. However, many of these ingredients exhibit relatively low oral bioavailability, leading to high intestinal concentrations after oral administration, where they can directly interact with the gut microbiota [28,29]. Our group and others previously showed that DZSM can ameliorate metabolic and neurological disorders by reshaping the gut microbiota and enhancing the production of beneficial metabolites, including SCFAs [27]. Therefore, we hypothesize that DZSM has the potential to treat UC via modulation of the gut microbiota and its metabolites.
Therefore, this study aimed to systematically investigate the therapeutic efficacy of DZSM against UC in a mouse model and to elucidate the underlying mechanisms involving the gut microbiota regulation. Utilizing a dextran sulfate sodium (DSS)-induced murine colitis model, we investigated the modulation of DZSM on gut microbiota composition and the metabolites using 16S rRNA gene sequencing, metabolomics, and fecal microbiota transplantation (FMT). Our findings indicated that DZSM ameliorated DSS-induced colitis in mice by remodeling the gut microbiota to enhance butyrate production, which consequently upregulated colonic epithelial SVCT1 expression and VitC uptake, thereby activating VitC-mediated antioxidant and anti-inflammatory pathways. This study unveils a novel microbiota–metabolite–host axis through which DZSM exerts therapeutic action, providing fresh mechanistic insights for the treatment of UC.

2. Results

2.1. The Chemical Profile of DZSM

The chemical profile of DZSM is shown in Figure 1. A total of 21 compounds, including 5 phenolic acids (chlorogenic acid, 3,5-dicaffeoylquinic acid, caffeic acid, 3,4-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid), 2 flavonoids (scutellarin and apigenin-7-o-glucronide), 8 saponins (ginsenoside Rb1, Rb2, Rg1, Rg2, Rd, Rh2 and ophiopogonin D), and 6 lignans (schizandrin A, B, C, schisantherin A, B, and schisandrol A), were identified and quantified using UHPLC–HRMS. The contents of these compounds are shown in Table 1.

2.2. DZSM Attenuated DSS-Induced UC in Mice

The therapeutic effect of DZSM was evaluated in a DSS-induced acute UC model (Figure 2A). The administration of DSS resulted in substantial weight loss, severe diarrhea, and gross rectal bleeding, leading to a high disease activity index (DAI), which had clinical signs similar to those of patients with UC, whereas treatment with DZSM, particularly at high doses (1 g·kg−1), markedly attenuated weight loss, improved stool consistency, and reduced DAI scores (Figure 2B–D), especially in the recovery period of UC mice. Colon length is an essential visual observation that reflects intestinal damage. Macroscopically, DSS-induced colon shortening was significantly reversed by DZSM treatment (Figure 2E,F). Histopathological analysis of colonic tissue, utilizing hematoxylin and eosin (H&E) staining, revealed that DZSM treatment preserved crypt architecture and reduced inflammatory infiltration and histological scores (Figure 2G,H). Furthermore, alcian blue-periodic acid–schiff (AB-PAS) staining showed that DZSM restored the number of mucin-producing goblet cells, which were depleted in the DSS group (Figure 2I). At the molecular level, DZSM intervention downregulated colonic mRNA expression of pro-inflammatory cytokines (Il1β, Il6, and Ccl2) while upregulating key tight junction genes (Zo1, Ocln, and Cldn4) (Figure 2J,K). Collectively, these data suggest that DZSM effectively alleviated UC symptoms, inflammation, and barrier disruption.

2.3. DZSM Reversed Gut Microbiota Dysbiosis and Enhanced SCFAs Production

We performed fecal 16S rRNA gene sequencing analysis to evaluate the effect of DZSM on the gut microbial diversity and composition in DSS-induced UC mice. Analysis of α-diversity in the gut microbiota showed that mice in the DSS group exhibited a considerable reduction in both bacterial richness (Chao index) and evenness (Shannon index) compared to the control (CON) group; however, DZSM supplementation partially restored disorders of bacterial α-diversity (Figure 3A). Principal component analysis (PCA) and principal coordinate analysis (PCoA) revealed that UC altered the overall structure of the gut microbiota. Interestingly, the groups receiving DZSM treatment clustered together and were distinctly separated not only from the DSS group but also from the CON group, suggesting that the alteration of gut microbiota by DZSM may follow a different pattern (Figure 3B).
The analysis of the microbial community composition revealed that, at the phylum level, DZSM significantly enhanced the abundance of Verrucomicrobiota (Figure 3C). At the family level, DSS administration markedly reduced the abundance of several key SCFA-producing families, including Muribaculaceae, Lachnospiraceae, Lactobacillaceae, and Bifidobacteriaceae. However, DZSM intervention effectively restored the levels of these bacterial families (Figure 3D). At the genus level, DZSM significantly enriched SCFA-producing bacteria such as Akkermansia, Dubosiella, Faecalibaculum, and Lactobacillus, and reduced the abundance of potentially pathogenic genera including Romboutsia and Turicibacter (Figure 3E). Linear discriminant analysis effect size (LEfSe) analysis was performed and revealed that Dubosiella, Faecalibaculum, Lachnospiraceae, and Lactobacillus, which were all important SCFA producers, were markedly enriched by DZSM (Figure 3F). These results indicated that DZSM effectively corrected gut microbiota dysbiosis associated with UC and specifically enriched bacterial taxa involved in SCFA production. To investigate the relationship between the modulation of gut microbiota and amelioration of UC during the DZSM treatment, we performed Spearman’s correlation analysis and found that these SCFA-producing bacteria enriched by DZSM, including Dubosiella, Faecalibaculum, Lachnospiraceae, and Lactobacillus, exhibited significant negative correlations with the severity of UC indicators (Figure 3G). Redundancy analysis (RDA) further revealed the significant associations of SCFA-producing bacteria with UC-related markers (Figure 3H).
Targeted quantification of SCFAs confirmed that DZSM treatment significantly elevated the levels of acetate, propionate, and butyrate in the cecal contents of treated mice (Figure 3I). Collectively, these results demonstrated that DZSM effectively reversed gut microbiota dysbiosis in UC and promoted the production of beneficial microbial metabolites, specifically SCFAs.

2.4. DZSM Modulated Intestinal Metabolism and Enhanced Colonic VitC Uptake

To gain further insight into the metabolic changes after DZSM treatment, untargeted metabolomics analysis of colon content was performed. The results of both PCA and partial least squares discriminant analysis (PLS-DA) demonstrated that DZSM treatment markedly altered the profiles of intestinal metabolites (Figure 4A). The differential metabolites were identified using the following criteria: fold change (FC) ≥ 1.5; variable importance in projection (VIP) ≥ 1.0; and p < 0.05.
Volcano plots revealed 256 differential metabolites between the CON and DSS groups (214 up-regulated and 42 down-regulated metabolites) (Figure 4B). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these metabolites revealed significant enrichment in multiple pathways, including amino acid metabolism pathways, such as alanine, aspartate, glutamate, tryptophan, and lysine degradation, as well as vitamin metabolism-related pathways such as ascorbate and aldarate metabolism, vitamin digestion and absorption, and pantothenate and CoA biosynthesis (Figure 4C). Similarly, there were 77 differential metabolites in the comparison between the HD and DSS groups, among which 35 metabolites were up-regulated and 42 metabolites were down-regulated (Figure 4B). The main enrichment pathways between the DS and DSS groups were the purine metabolism and pyrimidine metabolism pathways, suggesting that DZSM may promote nucleotide synthesis in intestinal epithelial cells, providing substrates for the repair of damaged mucosa and cell proliferation. The glutathione pathway, a key endogenous antioxidant system, was also enriched, implying that DZSM effectively enhanced the scavenging of free radicals and protected cells from oxidative damage. Importantly, the vitamin C (VitC) metabolism and absorption pathway was also significantly altered following DZSM intervention (Figure 4C). The integrated KEGG suggested that vitamin-related metabolic pathways, particularly the VitC metabolism pathway, were significantly influenced after following DSS administration and DZSM intervention.
The expression pattern of metabolites in each differential group and the p value of metabolites were visualized using VIP bar charts. The results indicated that VitC was the most significant among the differential metabolites, showing a significantly lower expression level in the DSS group, which was restored after DZSM treatment (Figure 4D). Spearman correlation analysis indicated that changes in metabolites, including VitC, were positively correlated with the abundance of DZSM-modulated genera such as Dubosiella, Faecalibaculum, and Lactobacillus (Figure 4E). Moreover, the levels of VitC in colonic tissues and plasma were measured using commercial kits. Studies have shown that DZSM treatment significantly increased colonic uptake and absorption of VitC (Figure 4F). VitC is primarily transported to intestinal epithelial cells by sodium-dependent vitamin C transporter 1 (SVCT1). Western blot analysis found that DZSM intervention effectively upregulated SVCT1 protein expression in colonic tissues (Figure 4G). These results suggest that DZSM specifically enhances the accumulation of VitC in DSS-impaired colonic epithelial cells by augmenting SVCT1-mediated transport capacity in the colon.

2.5. Bacterial Butyrate Mediated the Effects of DZSM on Colonic VitC Uptake and Gut Barrier Integrity

To clarify the mechanism of DZSM on VitC uptake, in vitro experiments were carried out using Caco-2 cells. The results showed that treatment with DZSM at various concentrations did not alter the expression of SVCT1 (Figure 5A). Given the elevated SCFAs observed in vivo, we examined the effects of individual SCFAs on SVCT1 expression and found that butyrate, but not acetate or propionate, significantly upregulated SVCT1 expression in a dose-dependent manner (Figure 5B,C), suggesting that bacterial butyrate may be responsible for the accumulation of colonic VitC.
Afterwards, we evaluated the protective effect of VitC on gut barrier injury and inflammation in lipopolysaccharide (LPS)-induced Caco-2 cells with or without butyrate. Our results showed that VitC intervention alone had no effect on SVCT1 expression, while the addition of butyrate significantly upregulated SVCT1 expression and the accumulation of VitC (Figure 5D,E). Consequently, the combination of butyrate and VitC intervention effectively mitigated LPS-induced colonic epithelial injury, which was evidenced by a significant attenuation of the decline in transepithelial electrical resistance (TEER), a restoration of tight junction gene expression (Zo1 and Ocln), and a suppression in the levels of pro-inflammatory cytokines (TNFα, Il1β, and Il6) (Figure 5F–H). As expected, the significant accumulation of VitC induced by butyrate markedly improved the total antioxidant capacity (T-AOC) in LPS-induced Caco-2 cells (Figure 5I). Collectively, these findings demonstrate that DZSM attenuates colonic epithelial barrier injury via the bacterial butyrate-SVCT1-VitC axis.

2.6. Effects of DZSM on Ameliorating UC Can Be Reproducible by FMT

To further confirm the importance of gut microbiota regulation on DZSM alleviating UC, we constructed a germ-free colitis mouse model by administering an antibiotic cocktail (AB) to mice prior to DSS treatment, and transplanted fecal bacteria from DZSM- or DSS-treated mice into the DSS-induced pseudogerm-free mice model (Figure 6A). Recipient mice receiving fecal microbiota from DZSM-treated donors (HD-FMT) exhibited milder symptoms of colitis compared to those receiving microbiota from DSS-treated donors (DSS-FMT), as shown by less weight loss, lower DAI, longer colon length, and improved histopathology (Figure 6B–H). The beneficial effects on inflammation, goblet cells, and tight junctions were also transferred in the HD-FMT group (Figure 6I–K).
Analysis of 16S rRNA gene sequencing confirmed that the microbial characteristics of donor mice were successfully colonized in recipient mice. At the genus level, the alteration of bacterial abundance such as Dubosiella, Faecalibaculum, and Akkermansia in the HD-FMT group closely resembled that of the HD donor group (Figure 6L). Furthermore, the HD-FMT group exhibited a marked increase in the abundance of SCFA-producing bacteria, including Dubosiella, Faecalibaculum, and Lactobacillus, which correlated negatively with key phenotypic indicators of colitis severity (Figure 6M,N).
Metabolite analysis also confirmed that HD-FMT recipient mice successfully recapitulated key metabolic features of their donors, displaying significantly elevated levels of colonic butyrate and VitC (Figure 6O,P), as well as upregulated SVCT1 protein expression levels (Figure 6Q). These results demonstrated that the therapeutic benefits of DZSM against colitis, along with the activation of the butyrate-SVCT1-VitC axis, are transmissible via FMT.

3. Discussion

The pathogenesis of UC arises from the complex interactions of genetic, environmental, and gut microbial factors, which collectively disrupt intestinal barrier function and drive immune-related inflammatory responses [30]. In recent decades, numerous pieces of evidence have suggested that imbalanced composition of gut microbiota with a decrease in purportedly beneficial bacteria and increase in deleterious bacteria is closely correlated with the onset of inflammatory bowel disease, including UC [31]. Therefore, numerous scientists have shifted their attention to bacteriotherapy for restoring gut microbiota homeostasis, such as probiotic supplement or medicine selection targeted on the regulation of gut microbiota. Since multiple ingredients of herbal medicines possess poor oral absorption due to either high molecular weight or poor permeability, they can be directly transported to the colon, where they interact with the gut microbiota. This novel study investigated the efficacy of DZSM, an approved TCM for the treatment of ischemic stroke-related neurological conditions, in alleviating DSS-induced UC in mice and elucidated its microbiota-dependent mechanism. The DZSM treatment effectively improved the pathological features of colitis in mice, including weight loss, colonic shortening, DAI, intestinal barrier injury, and so on. In terms of the underlying mechanism, we identified a novel butyrate-SVCT1-VitC axis: increased microbial-derived butyrate levels after DZSM administration upregulates the colonic VitC transporter, SVCT1, thereby enhancing local VitC accumulation and potentiating its protection on gut barrier integrity by enhancing tight junctions, inhibiting intestinal inflammation, and restoring redox homeostasis.
Modern analytical techniques have identified that the main chemical components of DZSM include flavonoid glycosides (scutellarin, apigenin-7-o-glucronide, caffeic acid, chlorogenic acid, and other caffeic acid derivatives), saponins (ginsenoside Rb1, Rc, Rd, Rg1, ophiopogonin D, and other saponins), and lignans (schisandrol A, schisantherin A, schisantherin B, schizandrin C, and other lignans). Furthermore, multiple ingredients of DZSM have been reported to attenuate intestinal inflammation in vivo and in vitro. Li et al. found that scutellarin alleviated UC by activating the colonic cAMP/PKA/NF-κB pathway [32]. Caffeic acid effectively inhibited intestinal inflammation by targeting cyclooxygenase 2 (COX-2) expression and advanced glycation end product formation [33]. Ginsenoside Rg1 ameliorated experimental colitis by regulating the balance of M1/M2 macrophage polarization, associated with the inhibition of Nogo-B/RhoA signaling [34]. These findings indicate the potential of DZSM in the management of UC. To the best of our knowledge, this study is the first to provide evidence showing that DZSM alleviates DSS-induced colitis. However, in our previous study, DZSM did not affect the intestinal barrier integrity and inflammation in Caco-2 cells [27], implying that there are other underlying mechanisms. Recent studies have demonstrated that DZSM components such as caffeic acid and ginsenosides can enrich SCFA-producing bacteria to mediate therapeutic benefits [35,36,37], suggesting the participation of microbiota on the efficacy of DZSM intervention.
A hallmark of UC is gut microbiota dysbiosis, characterized by reduced diversity and depletion of beneficial, SCFAs-producing bacteria, which compromises epithelial barrier integrity and disrupts immune homeostasis. In this study, we found that the effects of DZSM on ameliorating UC can be reproduced by FMT, providing direct causal evidence that the gut microbiota, at least partially, mediated DZSM’s protective effect in UC mice; moreover, our 16S rRNA sequencing data found that DZSM treatment effectively reversed these dysbiotic features. DZSM effectively improved the α and β diversity of the gut microbial in UC mice. At the genus level, DZSM significantly increased the abundance of SCFAs-producing commensal microbes including Akkermansia, Dubosiella, Faecalibaculum, and Lactobacillus [38,39,40], which were all negatively associated with UC-related markers. As probiotics, these SCFAs-producing bacteria can provide energy sources for enterocytes, protect intestinal mucosa integrity, regulate immunity, and reduce inflammation [41]. The deficiency of SCFAs is a key pathological feature in UC, and their restoration has become a promising therapeutic strategy [42]. Aligning with our previous work [27], the remodeling of microbial communities resulted in a substantial increase in colonic SCFAs levels. These findings highlight DZSM’s ability to increase bacterial SCFAs in different disease conditions, implying that DZSM may be used in the management of other SCFAs deficiency-related disorders.
Besides bacterial-SCFAs regulation, the alteration of other metabolic pathways was also analyzed in DZSM-treated UC mice using untargeted metabolomics. VitC metabolism and absorption was identified as the most significant metabolic pathway. In line with this, targeted measurement confirmed a marked increase in VitC levels in colonic tissues in DZSM-treated mice and HD-FMT mice. As one of the main antioxidants in biological systems, VitC plays a crucial role in scavenging reactive oxygen species and inhibiting inflammatory response [15,20,43]. In DSS-induced mice, VitC significantly reduced clinical signs, inflammatory cytokines, myeloperoxidase (MPO), and malonaldehyde (MDA) activities, and elevated the activities of antioxidant enzymes such as superoxide dismutase, catalase (CAT), and glutathione peroxidase (GPx) [44]. Furthermore, VitC has been demonstrated to help preserve intestinal barrier integrity by upregulating the expression of tight junction proteins [45]. This evidence indicates that intestinal VitC may have played an important role in DZSM alleviating UC.
The intestinal uptake of VitC depends on the transporter, SVCTs. The human SVCT family comprises three isoforms (SVCT1-3). Functionally, SVCT1 and SVCT2 are Na+-dependent VitC transporters with different functional properties that cooperatively maintain VitC homeostasis. SVCT1 is primarily expressed in epithelial tissues, such as the intestine and kidney, and plays a key role in maintaining the whole-body homeostasis of VitC. In contrast, the widely expressed SVCT2 distributes VitC to various tissues, including the brain, retina, placenta, spleen, and prostate. SVCT3 does not transport VitC, and its function is still unknown [21,46,47]. Our findings indicated that DZSM intervention significantly upregulated the expression of SVCT1 in UC mice, and the effects of DZSM on SVCT1 expression can also be delivered by FMT, thus implying that the gut microbiota altered by DZSM can adequately induce SVCT1 expression and VitC uptake. Subsequently, the underlying mechanisms of how DZSM elevates SVCT1 expression were investigated, and our in vitro experiments using Caco-2 cells revealed that bacterial-butyrate serves as a key mediator. More importantly, using an LPS-induced barrier injury model demonstrated that butyrate acts as a microbial trigger that upregulates the host’s SVCT1 expression, and the consequent increase in intracellular VitC synergizes with butyrate to amplify antioxidant and anti-inflammatory response, thereby alleviating intestinal barrier damage and breaking the vicious cycle of inflammation in UC.
This study has several limitations. First, the findings are predominantly based on an acute DSS-induced UC model. Further investigation is required to determine the efficacy of DZSM in chronic relapsing models. Second, we identified butyrate as the key upstream regulator of SVCT1 but the precise molecular circuitry remains to be fully elucidated. Butyrate, a HDAC inhibitor, might influence SVCT1 transcription by modulating the acetylation status of histones associated with its promoter. Alternatively, butyrate could indirectly regulate SVCT1 expression through the activation of G-protein-coupled receptors. Additional experiments including HDAC activity assays, promoter reporter assays, or siRNA knockdown of candidate transcription factors, should be conducted in future studies to elucidate the molecular mechanism. Third, in the FMT experimental design, the addition of a healthy control group (CON-FMT) will make the conclusion more convincing. Furthermore, exploring the efficacy of DZSM in other UC models (TNBS-induced or oxazolone-induced UC model) would enhance the generalizability of our findings. Finally, translational and clinical studies are imperative to validate the therapeutic efficacy of DZSM in patients with UC and mechanisms relevant to the butyrate–SVCT1–VitC axis.

4. Materials and Methods

4.1. Materials

DZSM spray-dried powder was supplied by Biovalley Pharmaceutical Co., Ltd. (Kunming, China). Sodium acetate (AA: A610481), sodium propionate (PA: A600882), sodium butyrate (BA: A510838), VitC (A100143), vancomycin (A414413), neomycin sulfate (A610366), metronidazole (A600633), and amphotericin B (A429759) were sourced from Sangon Biotech (Shanghai, China). Dextran sulfate sodium (S14048) was acquired from Beijing LABLEAD Trading Co., Ltd. (Beijing, China). Minimum essential medium (MEM), 0.25% trypsin-EDTA, penicillin-streptomycin (P/S) solution, non-essential amino acids (NEAA), and fetal bovine serum (FBS) were purchased from Gibco (Thermo Fisher Scientific, Waltham, MA, USA). ELISA kits for T-AOC (BTK053), and VitC (EUN00173) were sourced from Bioswamp Life Science Lab (Wuhan, China). RNA extraction kit (R0027) was obtained from Beyotime Biotechnology (Shanghai, China). Evo M-MLV Transcription Kit (AG11728) was acquired from Accurate Biotechnology Co., Ltd. (Changsha, China). SYBR Green qPCR Master Mix kit (CW2601H) was acquired from Jiangsu Cowin Biotech Co., Ltd. (Taizhou, China). Primary antibodies against SVCT1 (sc-376090) were purchased from Santa Cruz Biotechnology (Dallas, TX, USA), while antibodies against GAPDH (60004-1-Ig) were sourced from Proteintech (Wuhan, China). Horseradish peroxidase-conjugated goat anti-rabbit IgG (A0208) and goat anti-mouse IgG (A0216) antibodies (Beyotime Biotechnology, Shanghai, China) were used as secondary antibodies. Bicinchoninic acid (BCA) protein assay kit was purchased from Thermo Fisher Scientific (Waltham, MA, USA).

4.2. Chemical Profiles of DZSM

The chemical profiles of DZSM were determined using an Agilent 1290 Infinity II ultra-high-performance liquid chromatography system coupled with a 6550 iFunnel quadrupole time-of-flight mass spectrometer featuring a dual AJS electrospray ionization source (UHPLC–HRMS; Agilent Technologies, Santa Clara, CA, USA) as described in our previous study [27] with a slight modification. Briefly, chromatographic separation was achieved on a Shim-pack GIST C18 column (250 mm × 4.6 mm, 5 μm). The mobile phase consisted of water containing 0.1% formic acid (A) and acetonitrile (B). The gradient elution program was set as follows: 10% to 20% B over 10 min; 20% to 55% B over 30 min; 55% to 95% B over 45 min; 95% to 100% B over 60 min; followed by a 5 min re-equilibration to initial conditions. The analysis was conducted in both positive and negative ionization modes with a constant flow rate of 0.4 mL·min−1, an injection volume of 5 μL, and the column temperature maintained at 35 °C.

4.3. Cell Culture and Treatment

Caco-2 (RRID: CVCL_0025) cell lines were obtained from the Cell Resource Center, Peking Union Medical College (which is the headquarters of the National Infrastructure of Cell Line Resource, NSTI, Beijing, China) and determined to be free of mycoplasma contamination. All cell lines were authenticated by autosomal short tandem repeat profile determination within 3 years. Caco-2 cells were maintained in MEM supplemented with 20% heat-inactivated FBS, 1% NEAA and 1% P/S solution. All cells were incubated at 37 °C in an atmosphere of 5% CO2 and 90% relative humidity.
To investigate the uptake of VitC in intestinal epithelial cells, Caco-2 cells were incubated for 24 h with DZSM (125, 250, or 500 μg·mL−1), AA (100 μM), PA (100 μM), and BA (50, 100, 200 μM). To evaluate the protection of VitC on gut barrier injury and inflammation with or without butyrate intervention, Caco-2 cells were pre-cultured with 5 μg·mL−1 LPS to induce inflammatory barrier injury and treated with BA (100 μM) or/and VitC (100 μM) for 24 h, followed by determination of the expression levels of tight junction protein and inflammation marker gene by RT-qPCR.

4.4. Mice and Treatments

Healthy 6–8-week-old male C57BL/6 mice (20–22 g) were purchased from SPF Biotechnology Co., Ltd. (Beijing, China), and housed in a specific pathogen-free facility under a 12 h light/dark cycle with free access to food and water. All animal experiments were conducted in accordance with rules set by the Laboratories Institutional Animal Care and Use Committee (IACUC) of the Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China) (Approval number: IMM-S-25-0231).

4.4.1. UC Modeling and DZSM Treatment

After acclimatization for 1 week, all mice were randomly divided into four groups (n = 8 per group): the control group (CON), model group (DSS), DZSM low-dose group (LD, 0.5 g·kg−1·d−1), and DZSM high-dose group (HD, 1 g·kg−1·d−1). Except for the CON group, all the mice received 2% DSS in drinking water ad libitum for 6 days to establish the UC model, after which they were switched to normal water. From day 3 of DSS modeling, mice were gavaged with DZSM or equivalent volume of vehicle (0.25% sodium carboxymethyl cellulose solution) continuously for 9 days.

4.4.2. FMT

Recipient mice were pre-treated with an antibiotic mixture (vancomycin 50 mg·kg−1·d−1, neomycin 100 mg·kg−1·d−1, metronidazole 100 mg·kg−1·d−1, amphotericin B 1 mg·kg−1·d−1) by gavage for 3 days to generate pseudogerm-free conditions, followed by 2% DSS in drinking water for 6 days to induce UC. During the modeling period, fresh fecal pellets from donor mice of the DSS group and HD group were collected daily and processed into fecal bacterial suspensions, according to a previously established method [27] with a little modification. Briefly, for fecal collection, fresh formed fecal pellets were collected by gently massaging the abdomen or by stimulating defecation upon handling. However, when severe diarrhea developed due to DSS induction, the feces were collected by the following procedure: donor mice were briefly placed in sterile cages lined with autoclaved filter paper, and the loose stools adhering to the filter paper were collected. Then, the loose stools were immediately scraped from the filter paper using a sterile spatula or forceps and transferred into pre-cooled, sterile phosphate-buffered saline (PBS) for subsequent fecal bacterial suspension preparation. Then, the fresh collected feces (0.2 g) in the DSS and the DZSM groups was homogenized in sterile PBS, and centrifuged at low speed (100 rpm) for 1 min. The feces were then washed three times with PBS. All the supernatants involving bacteria were precipitated at 5000 rpm for 20 min. Then, the resulting bacterial precipitates were washed three times to remove the residual DZSM components or metabolites, and re-suspended in sterile PBS (2 mL). Recipient mice were gavaged with fecal bacterial suspensions (0.2 mL per mouse) once daily for 9 days and were designated as the DSS-FMT and HD-FMT groups, respectively (n = 8 per group).
During the experimental period, the body weight, stool consistency, and fecal occult blood were recorded daily. At the end of the experiment, all mice were executed by inhalation of isoflurane, followed by the rapid collection of blood, feces, cecal contents, and colonic tissues for subsequent analyses.

4.5. DAI Score

The DAI was scored by monitoring body weight loss, stool consistency, and fecal bleeding according to established criteria [48]: (1) weight loss (0, none; 1; 1~5%; 2, 5~10%; 3, 10~20%; 4, >20%); (2) diarrhea (0, normal feces; 1, loose but formed; 2, loose unformed; 3, very loose; 4, diarrhea); and (3) bleeding in stools (0, negative; 1, weakly positive; 2, positive; 3, markedly positive; 4, rectal bleeding).

4.6. Histological Staining

For histological examination, sections of approximately 1 cm from the middle to distal colon were fixed in 4% paraformaldehyde, dehydrated and embedded in paraffin. For H&E staining, the deparaffinized tissue sections were stained according to standard protocols and imaged under a light microscope. Colonic mucosa damage was scored in a blinded manner according to the following criteria [49]: (1) inflammatory cell infiltration: 0, none; 1, mild; 2, moderate; 3, severe; (2) tissue damage: 0, none; 1, mucosal layer; 2, mucosal and submucosal layers; 3, transmural; and (3) crypt damage: 0, none; 1, basal 1/3 destroyed; 2, basal 2/3 destroyed; 3, only surface epithelium intact; 4, both epithelium and basal layer destroyed. The total histopathological score for each mouse was the sum of the three subscores. Additionally, colonic sections were stained with AB-PAS to visualize goblet cells containing neutral and acidic mucins.

4.7. Biochemical Assays

The levels of VitC in colonic tissue, plasma, and Caco-2 cells, as well as the T-AOC in Caco-2 cells, were measured using corresponding detection kits in accordance with the manufacturer’s instructions (Bioswamp, Wuhan, China).

4.8. 16S rRNA Sequencing Analysis

16S rRNA gene sequencing on an Illumina Nextseq2000 platform was used to analyze gut bacterial composition as described in our previous study [27]. The raw sequences were subjected to quality control using the Fastp software (version 0.19.6) and assembled simultaneously using Flash software (version 1.2.11). The DADA2 plugin within the QIIME 2 pipeline was used for denoising the quality-controlled, assembled sequences, generating amplicon sequence variants (ASVs). Taxonomic classification of the resulting ASVs was performed using Bayesian classification algorithm. The entire bioinformatics analysis was performed on the Majorbio cloud platform (http://www.majorbio.com/, accessed on 1 September 2025).

4.9. Untargeted Metabolomics Profiling

Cecal content samples (100 mg) were mixed with an extraction solution [methanol:water = 4:1, (v:v)] containing 0.02 mg·mL−1 of an internal standard (L-2-chlorophenylalanine) using the following protocols: The mixture was vortexed for 30 s, subjected to low-temperature ultrasonication for 30 min (5 °C, 40 kHz), and then centrifuged at 13,000× g for 15 min. The supernatant was transferred to an injection vial with an insert for analysis.
Liquid chromatography-mass spectrometry (LC-MS/MS) analysis was conducted on a Thermo UHPLC-Q Exactive HF-X system equipped with an ACQUITY HSS T3 column (100 mm × 2.1 mm i.d., 1.8 μm; Waters, Milford, MA, USA). The mobile phases consisted of 0.1% formic acid in water: acetonitrile (95:5, v/v) (solvent A) and 0.1% formic acid in acetonitrile isopropanol:water (47.5:47.5, v/v) (solvent B). The flow rate was 0.4 mL/min and the column temperature was 40 °C. Mass spectrometric data were collected using a Thermo UHPLC-Q Exactive HF-X Mass Spectrometer (Thermo, Waltham, MA, USA) equipped with an electrospray ionization source operating in positive mode and negative mode. The data matrix obtained by searching the database was uploaded to the Majorbio cloud platform (https://cloud.majorbio.com, accessed on 5 November 2025) for data analysis.

4.10. Targeted Metabolomics Analysis of SCFAs

Cecal content samples were weighed (40 mg) and homogenized (1:10, w/v) with ice-cold normal saline buffer, then centrifuged at 4 °C for 10 min at 10,000 rpm. Afterwards, 50 μL of the supernatant was mixed with 450 μL of acetonitrile containing 0.1% concentrated hydrochloric acid, vortexed for 10 min, and centrifuged again at 10,000 rpm for 10 min at 4 °C. The supernatant was aspirated accurately into an injection vial for subsequent gas chromatography (GC-MS) analysis.
GC-MS analysis was performed in a GCMS-TQ8040NX system coupled to a highly polar nitroterephthalic acid-modified polyethylene glycol cross-linked stationary phase capillary column (Agilent DB-FFAP122-3232, 30 m × 0.25 mm, 0.25 μm). The inlet temperature was 240 °C, the ion source temperature was 230 °C, and the interface temperature was 240 °C. The temperature program was as follows: The initial column temperature was 50 °C, ramped to 90 °C at 25 °C·min−1 for 2.1 min, then to 120 °C at 5 °C·min−1 for 1 min, and finally to 200 °C at 25 °C·min−1 for 1 min. High-purity helium was used as the carrier gas in constant linear velocity mode. The split ratio was 5:1, and the injection volume was 1 μL. Acquisition was performed in the selected ion-monitoring mode, with a dwell time of 50 ms per ion. Data acquisition was performed using GC-MS Solution.

4.11. Transepithelial Electrical Resistance Assay

Transepithelial electrical resistance assay (TEER) was performed with an EVOM2 Epithelial Voltohmmeter (WPI, Worcester, MA, USA) to assess the impact of BA and/or VitC on cell membrane integrity. Caco-2 cells were seeded in 12-well transwell dishes at a density of 2 × 105 cells per well. The cells were allowed to grow to a tight monolayer, with the culture medium being refreshed once every 2 days. Subsequently, the medium in the apical chamber was replaced with a fresh medium containing 5 μg·mL−1 LPS, 100 μM BA, 100 μM VitC, or their combinations, with six replicates for each treatment. The TEER of each well was measured after 24 h of treatment. The TEER values were based on the following formula:
TEER (Ω.cm2) = [Measured value (Ω) − Background value (Ω) × A (cm2)], where the background is cell-free inserts and A is the area of the membrane [50].

4.12. RNA Extraction and Real-Time qPCR

Total RNA was extracted from colonic tissue or collected cells using an RNA extraction kit. RNA concentrations were measured using a DS-11 Spectrophotometer (Denovix, Wilmington, DE, USA), and 1 μg of purified RNA from each sample was reverse-transcribed into cDNA using the Evo M-MLV Transcription Kit. qPCR was performed on a CFX Connect Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA) using Ultra SYBR Mix (Low ROX) (Jiangsu Cowin Biotech Co., Ltd., Taizhou, China). The results are presented as fold changes relative to GAPDH and were calculated using the 2−ΔΔCT method. The primers used for RT-qPCR are listed in Table S1.

4.13. Western Blotting

Total protein was extracted from the colonic tissue using radioimmunoprecipitation assay (RIPA) lysis buffer supplemented with protease and phosphatase inhibitors, and its concentration was measured using the BCA method. An appropriate amount of denatured total protein was separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred to a PVDF membrane via wet transfer for 120 min. After blocking with 5% skimmed milk in TBST, the membrane was incubated with primary antibodies at 4 °C overnight. After TBST washing, the membrane was incubated with horseradish peroxidase (HRP)-conjugated secondary antibodies at room temperature for 2 h. After washing three times in TBST, protein bands were visualized using an ECL chemiluminescence system (Millpore, Burlington, MA, USA).

4.14. Statistical Analysis

All statistical analysis was performed using GraphPad Prism version 8.0 software (GraphPad Software, San Diego, CA, USA) with data presented as mean ± standard deviation (SD). Statistical significance was defined as p < 0.05. Two-group comparisons employed unpaired two-tailed Student’s t-test, while multi-group analyses were performed with one-way ANOVA followed by a post hoc test for comparisons among three or more groups. Spearman’s correlation was used to test for relationships between disease markers, metabolites, and bacterial abundances. RDA was used to identify microbiome–phenotype associations.

5. Conclusions

In this study, it was demonstrated that the therapeutic effects of DZSM on DSS-induced colitis in mice are mediated through a gut microbiota-dependent mechanism. DZSM remodeled the dysbiotic gut microbiota, specifically enriching SCFA-producing bacteria and elevating colonic levels of butyrate. This microbial metabolite consequently increases the expression of the host VitC transporter SVCT1 in colonic epithelial cells, thereby enhancing local VitC accumulation. The accumulated VitC and butyrate then act in concert, synergistically restoring intestinal barrier integrity through combined antioxidant and anti-inflammatory actions. Our finding delineates a novel butyrate–SVCT1–vitamin C axis through which DZSM alleviates DSS-induced colitis in mice.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijms27052245/s1.

Author Contributions

Conceptualization, H.G., Y.H. and J.J.; Methodology, H.S., X.Y., Z.W. and S.Z.; Investigation, H.S., X.Y., Z.W. and S.Z.; Formal Analysis, H.S. and H.G.; Data Curation, H.S. and H.G.; Writing—Original Draft Preparation, H.S. and H.G.; Writing—Review and Editing, H.G. and Y.H.; Validation, All authors; Supervision, H.G. and Y.H.; Project Administration, H.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Fundamental Research Funds for Central Universities, Peking Union Medical College (No. 3332025150), the CAMS Innovation Fund for Medical Sciences [Nos. 2025-I2M-KJ-016, 2024-I2M-ZH-012), and the Beijing Nova Program from Beijing Municipal Science & Technology Commission (No. 20230484467).

Institutional Review Board Statement

The animal study protocol was approved by the Laboratories Institutional Animal Care and Use Committee (IACUC) of the Chinese Academy of Medical Sciences and Peking Union Medical College (protocol code: IMM-S-25-0231 and date of approval: 7 March 2025).

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AASodium acetate
AB-PASAlcian blue-periodic acid–Schiff
ANOVAAnalysis of variance
ASVsAmplicon sequence variants
BASodium butyrate
BCABicinchoninic acid
Ccl2C-C motif chemokine ligand 2
Cldn4Claudin-4
CONControl
DAIDisease activity index
DSSDextran sulfate sodium
DZSMDengzhan shengmai
FCFold change
FMTFecal microbiota transplantation
GC-MSGas chromatography-mass spectrometry
H&EHematoxylin and eosin
HDHigh-dose DZSM
HDACHistone deacetylase
IACUCInstitutional Animal Care and Use Committee
Il1βInterleukin-1β
Il6Interleukin-6
KEGGKyoto Encyclopedia of Genes and Genomes
LC-MSLiquid chromatography-tandem mass spectrometry
LDLow-dose DZSM
LEfSeLinear discriminant analysis effect size
LPSLipopolysaccharide
MDAMalondialdehyde
MEMMinimum essential medium
NEAANon-essential amino acids
NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells
OclnOccludin
PASodium propionate
PCAPrincipal component analysis
PCoAPrincipal coordinate analysis
PLS-DAPartial least squares discriminant analysis
RDARedundancy analysis
SCFAShort-chain fatty acid
SDStandard deviation
SVCT1Sodium-dependent vitamin C transporter 1
T-AOCTotal antioxidant capacity
TEERTransepithelial electrical resistance
TNF-αTumor necrosis factor α
UCUlcerative colitis
VIPVariable importance in projection
VitCVitamin C
Zo1Zonula occludens-1

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Figure 1. Chemical profile of DZSM by UHPLC-HRMS. The DZSM powder was accurately weighed (0.5 g), and extracted with an appropriate amount of 75% ethanol solution for 40 min at room temperature using ultrasonic method (100 W, 40 KHz). After filtering twice by 0.45 μm filter membrane, the filtrate was collected for HPLC-HRMS analysis. (A) The total ion chromatograms (TICs) of DZSM in negative mode. (B) The TICs of DZSM in negative mode. (C) The extracted ion chromatograms (EICs) of saponins in DZSM. (D) The EICs of flavonoids and phenolic acids in DZSM. (E) The EICs of lignans in DZSM. P1: ginsenoside Rb1, P2: ginsenoside Rb2, P3: ginsenoside Rg1, P4: ginsenoside Rg2, P5: ginsenoside Rd, P6: ginsenoside Rh2, P7: ophiopogonin D, P8: ophiopogonin D’, P9: 3-caffeoylquinic acid, P10: 3,5-dicaffeoylquinic acid, P11: caffeic acid, P12: apigenin-7-o-glucronide, P13: scutellarin, P14: 3,4-dicaffeoylquinic acid, P15: 4,5-dicaffeoylquinic acid, P16: schizandrin C, P17: schisantherin B, P18: schisandrol A, P19: schizandrin A, P20: schizandrin B, P21: schisantherin A.
Figure 1. Chemical profile of DZSM by UHPLC-HRMS. The DZSM powder was accurately weighed (0.5 g), and extracted with an appropriate amount of 75% ethanol solution for 40 min at room temperature using ultrasonic method (100 W, 40 KHz). After filtering twice by 0.45 μm filter membrane, the filtrate was collected for HPLC-HRMS analysis. (A) The total ion chromatograms (TICs) of DZSM in negative mode. (B) The TICs of DZSM in negative mode. (C) The extracted ion chromatograms (EICs) of saponins in DZSM. (D) The EICs of flavonoids and phenolic acids in DZSM. (E) The EICs of lignans in DZSM. P1: ginsenoside Rb1, P2: ginsenoside Rb2, P3: ginsenoside Rg1, P4: ginsenoside Rg2, P5: ginsenoside Rd, P6: ginsenoside Rh2, P7: ophiopogonin D, P8: ophiopogonin D’, P9: 3-caffeoylquinic acid, P10: 3,5-dicaffeoylquinic acid, P11: caffeic acid, P12: apigenin-7-o-glucronide, P13: scutellarin, P14: 3,4-dicaffeoylquinic acid, P15: 4,5-dicaffeoylquinic acid, P16: schizandrin C, P17: schisantherin B, P18: schisandrol A, P19: schizandrin A, P20: schizandrin B, P21: schisantherin A.
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Figure 2. DZSM attenuated dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. (A) Animal experimental design; (B) Changes in body weight of the mice; (C) Representative images of the anus and perianal feces; (D) disease activity index (DAI) scores; (E) Photomicrograph of colonic tissues; (F) Colon length measurement; (G) Representative hematoxylin and eosin (H&E) staining of colonic tissues; (H) Histological scores; (I) Representative alcian blue-periodic acid–schiff (AB-PAS) staining of colonic tissues; (J) The expression of colonic inflammation-related genes (IL-1β, IL-6, and Ccl2); (K) The expression of colonic tight junction genes (Zo-1, Ocln, and Cldn-4). Scale bar: 40 μm. Data are presented as means ± SD for 8 mice in each group. * p < 0.05, ** p < 0.01, *** p < 0.001, ns: No significant difference vs. DSS group, using ANOVA. control group (CON); model group (DSS); DZSM low-dose group (LD, 0.5 g·kg−1·d−1); DZSM high-dose group (HD, 1 g·kg−1·d−1).
Figure 2. DZSM attenuated dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. (A) Animal experimental design; (B) Changes in body weight of the mice; (C) Representative images of the anus and perianal feces; (D) disease activity index (DAI) scores; (E) Photomicrograph of colonic tissues; (F) Colon length measurement; (G) Representative hematoxylin and eosin (H&E) staining of colonic tissues; (H) Histological scores; (I) Representative alcian blue-periodic acid–schiff (AB-PAS) staining of colonic tissues; (J) The expression of colonic inflammation-related genes (IL-1β, IL-6, and Ccl2); (K) The expression of colonic tight junction genes (Zo-1, Ocln, and Cldn-4). Scale bar: 40 μm. Data are presented as means ± SD for 8 mice in each group. * p < 0.05, ** p < 0.01, *** p < 0.001, ns: No significant difference vs. DSS group, using ANOVA. control group (CON); model group (DSS); DZSM low-dose group (LD, 0.5 g·kg−1·d−1); DZSM high-dose group (HD, 1 g·kg−1·d−1).
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Figure 3. DZSM reversed gut microbiota dysbiosis and enhanced short chain fatty acids (SCFAs) production. (A) α-diversity index; (B) Microbiota community analysis based on principal component analysis (PCA) and principal coordinate analysis (PCoA) score plots; (C–E) Community abundance profiling of the gut microbiota at the phylum, family, and genus levels; (F) Linear discriminant analysis effect size (LEfSe) was evaluated from phylum to genus, and the linear discriminant analysis score was set at >3.0; (G) Heatmap of Spearman’s correlation analysis between the relative abundance of bacterial genera and UC-related indices; (H) Redundancy analysis (RDA) between the abundance of bacterial genera (ameliorated by DZSM) and the UC-related indices; (I) Concentrations of SCFAs in cecal content (n = 8). Data are presented as means ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001, ns: No significant difference.
Figure 3. DZSM reversed gut microbiota dysbiosis and enhanced short chain fatty acids (SCFAs) production. (A) α-diversity index; (B) Microbiota community analysis based on principal component analysis (PCA) and principal coordinate analysis (PCoA) score plots; (C–E) Community abundance profiling of the gut microbiota at the phylum, family, and genus levels; (F) Linear discriminant analysis effect size (LEfSe) was evaluated from phylum to genus, and the linear discriminant analysis score was set at >3.0; (G) Heatmap of Spearman’s correlation analysis between the relative abundance of bacterial genera and UC-related indices; (H) Redundancy analysis (RDA) between the abundance of bacterial genera (ameliorated by DZSM) and the UC-related indices; (I) Concentrations of SCFAs in cecal content (n = 8). Data are presented as means ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001, ns: No significant difference.
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Figure 4. DZSM modulated intestinal metabolism and enhanced colonic vitamin C (VitC) uptake. (A) The PCA and partial least squares discriminant analysis (PLS-DA) cluster diagrams of metabolites of cecal contents in different groups of mice; (B) Volcano plot visualizing differential metabolites from the CON group vs. the DSS group (left), HD vs. DSS group (right); (C) Kyoto Encyclopedia of Genes and Genomes (KEGG) bubble diagram of enrichment analysis in the CON vs. the DSS group (left), HD vs. DSS group (right); (D) Heatmap of differential metabolite expression levels and corresponding variable importance in projection (VIP) bar plot; (E) Heatmap of Spearman correlation between significantly altered metabolites and gut microbiota at the genus level; (F) VitC level in colonic tissues (left) and plasma (right) (n = 8); (G) Western blot analysis and quantification of vitamin C transporter 1 (SVCT1) protein expression in colon (n = 3). Date are presented as means ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4. DZSM modulated intestinal metabolism and enhanced colonic vitamin C (VitC) uptake. (A) The PCA and partial least squares discriminant analysis (PLS-DA) cluster diagrams of metabolites of cecal contents in different groups of mice; (B) Volcano plot visualizing differential metabolites from the CON group vs. the DSS group (left), HD vs. DSS group (right); (C) Kyoto Encyclopedia of Genes and Genomes (KEGG) bubble diagram of enrichment analysis in the CON vs. the DSS group (left), HD vs. DSS group (right); (D) Heatmap of differential metabolite expression levels and corresponding variable importance in projection (VIP) bar plot; (E) Heatmap of Spearman correlation between significantly altered metabolites and gut microbiota at the genus level; (F) VitC level in colonic tissues (left) and plasma (right) (n = 8); (G) Western blot analysis and quantification of vitamin C transporter 1 (SVCT1) protein expression in colon (n = 3). Date are presented as means ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001.
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Figure 5. Bacterial butyrate mediated the effects of DZSM on colonic VitC uptake and gut barrier integrity. (A) The mRNA expression of SVCT1 in Caco-2 cells with different concentrations of DZSM; (B) The mRNA expression of SVCT1 in Caco-2 cells with AA, PA or BA; (C) The mRNA expression of SVCT1 in Caco-2 cells with different concentrations of BA; (D) mRNA expression of SVCT1 in Caco-2 cells with BA, VitC, and their combination; (E) The level of VitC in Caco-2 cells; (F) Transepithelial electrical resistance (TEER) in Caco-2 cells; (G) The mRNA expression of tight junction genes (Zo-1 and Ocln) in Caco-2 cells; (H) The mRNA expression of inflammation-related genes (TNFα, IL-6, and IL-1β) in Caco-2 cell; (I) Total antioxidant capacity (T-AOC) in Caco-2 cells. n = 6. Data are presented as means ± SD, * p < 0.05, ** p < 0.01, *** p < 0.001, ns: No significant difference. AA, Acetate; PA, Propionate; BA, Butyrate; LPS: lipopolysaccharide.
Figure 5. Bacterial butyrate mediated the effects of DZSM on colonic VitC uptake and gut barrier integrity. (A) The mRNA expression of SVCT1 in Caco-2 cells with different concentrations of DZSM; (B) The mRNA expression of SVCT1 in Caco-2 cells with AA, PA or BA; (C) The mRNA expression of SVCT1 in Caco-2 cells with different concentrations of BA; (D) mRNA expression of SVCT1 in Caco-2 cells with BA, VitC, and their combination; (E) The level of VitC in Caco-2 cells; (F) Transepithelial electrical resistance (TEER) in Caco-2 cells; (G) The mRNA expression of tight junction genes (Zo-1 and Ocln) in Caco-2 cells; (H) The mRNA expression of inflammation-related genes (TNFα, IL-6, and IL-1β) in Caco-2 cell; (I) Total antioxidant capacity (T-AOC) in Caco-2 cells. n = 6. Data are presented as means ± SD, * p < 0.05, ** p < 0.01, *** p < 0.001, ns: No significant difference. AA, Acetate; PA, Propionate; BA, Butyrate; LPS: lipopolysaccharide.
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Figure 6. Effects of DZSM on ameliorating colitis can be reproducible by fecal microbiota transplantation (FMT). (A) Animal experimental design; (B) Changes in body weight of the mice; (C) Representative images of the anus and perianal feces; (D) DAI scores; (E) Macroscopic images of colonic tissue samples; (F): Colon length measurement; (G) Representative H&E stained photomicrographs of colonic tissues; (H) Histological scores; (I) mRNA expression of the inflammation-related genes (IL-1β, IL-6, and Ccl2) in colonic tissue of the recipient mice; (J) AB-PAS stained image of colonic tissues; (K) mRNA expression of tight junction genes (Zo-1, Ocln, and Cldn-4) in colonic tissue of the recipient mice; (L) Community abundance profiling of the gut microbiota at the genus level; (M) Pearson correlation heatmap analysis between genuses and colitis-related indices; (N) RDA between the abundance of bacterial genuses and the colitis-related indices; (O) Butyrate level in cecal contents; (P) VitC level in colonic tissues; (Q) Western blot analysis and quantification of SVCT1 protein expression in colon A-P: n = 8, Q: n = 3. Data are presented as means ± SD, * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 6. Effects of DZSM on ameliorating colitis can be reproducible by fecal microbiota transplantation (FMT). (A) Animal experimental design; (B) Changes in body weight of the mice; (C) Representative images of the anus and perianal feces; (D) DAI scores; (E) Macroscopic images of colonic tissue samples; (F): Colon length measurement; (G) Representative H&E stained photomicrographs of colonic tissues; (H) Histological scores; (I) mRNA expression of the inflammation-related genes (IL-1β, IL-6, and Ccl2) in colonic tissue of the recipient mice; (J) AB-PAS stained image of colonic tissues; (K) mRNA expression of tight junction genes (Zo-1, Ocln, and Cldn-4) in colonic tissue of the recipient mice; (L) Community abundance profiling of the gut microbiota at the genus level; (M) Pearson correlation heatmap analysis between genuses and colitis-related indices; (N) RDA between the abundance of bacterial genuses and the colitis-related indices; (O) Butyrate level in cecal contents; (P) VitC level in colonic tissues; (Q) Western blot analysis and quantification of SVCT1 protein expression in colon A-P: n = 8, Q: n = 3. Data are presented as means ± SD, * p < 0.05, ** p < 0.01, *** p < 0.001.
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Table 1. Contents of ingredients in dengzhan shengmai (DZSM) powders (n = 5).
Table 1. Contents of ingredients in dengzhan shengmai (DZSM) powders (n = 5).
No.IngredientsMWContents (mg/g)StylePlant Origins
P1ginsenoside Rb11109.04.075SaponinsPanax ginseng
P2ginsenoside Rb21079.35.207Saponins
P3ginsenoside Rg1801.08.357Saponins
P4ginsenoside Rg2770.03.039Saponins
P5ginsenoside Rd947.01.883Saponins
P6ginsenoside Rh2622.96.432Saponins
P7ophiopogonin D855.00.072SaponinsOphiopogon japonicus
P8ophiopogonin D’855.00.066Saponins
P93-caffeoylquinic acid354.323.13Phenolic acidsErigeron breviscapus
P103,5-dicaffeoylquinic acid516.54.126Phenolic acids
P11caffeic acid180.212.66Phenolic acids
P12apigenin-7-o-glucronide446.024.24Flavonoids
P13scutellarin462.0100.03Flavonoids
P143,4-dicaffeoylquinic acid516.555.52Phenolic acids
P154,5-dicaffeoylquinic acid516.564.34Phenolic acids
P16schizandrin C384.41.154LignansSchisandra chinensis
P17schisantherin B514.51.926Lignans
P18schisandrol A432.01.511Lignans
P19schizandrin A416.53.533Lignans
P20schizandrin B400.02.340Lignans
P21schisantherin A538.03.332Lignans
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Shen, H.; Yu, X.; Wang, Z.; Zhou, S.; Jiang, J.; Guo, H.; Han, Y. Gut Microbiota Remodeling Mediates the Therapeutic Effects of a Plant-Based Medicine on DSS-Induced Ulcerative Colitis in Mice via the Butyrate-SVCT1-Vitamin C Axis. Int. J. Mol. Sci. 2026, 27, 2245. https://doi.org/10.3390/ijms27052245

AMA Style

Shen H, Yu X, Wang Z, Zhou S, Jiang J, Guo H, Han Y. Gut Microbiota Remodeling Mediates the Therapeutic Effects of a Plant-Based Medicine on DSS-Induced Ulcerative Colitis in Mice via the Butyrate-SVCT1-Vitamin C Axis. International Journal of Molecular Sciences. 2026; 27(5):2245. https://doi.org/10.3390/ijms27052245

Chicago/Turabian Style

Shen, Haoran, Xiaoyou Yu, Zhiyu Wang, Sitong Zhou, Jiandong Jiang, Huihui Guo, and Yanxing Han. 2026. "Gut Microbiota Remodeling Mediates the Therapeutic Effects of a Plant-Based Medicine on DSS-Induced Ulcerative Colitis in Mice via the Butyrate-SVCT1-Vitamin C Axis" International Journal of Molecular Sciences 27, no. 5: 2245. https://doi.org/10.3390/ijms27052245

APA Style

Shen, H., Yu, X., Wang, Z., Zhou, S., Jiang, J., Guo, H., & Han, Y. (2026). Gut Microbiota Remodeling Mediates the Therapeutic Effects of a Plant-Based Medicine on DSS-Induced Ulcerative Colitis in Mice via the Butyrate-SVCT1-Vitamin C Axis. International Journal of Molecular Sciences, 27(5), 2245. https://doi.org/10.3390/ijms27052245

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