Stachyose attenuates DSS-induced colitis and is associated with elevated colonic medium-chain fatty acids: an integrated multi-omics analysis

npj | science of food Article Published in partnership with Beijing Technology and Business University & International Union of Food Science and Technology https://doi.org/10.1038/s41538-025-00604-7 Stachyose attenuates DSS-induced colitis and is associated with elevated colonic medium-chain fatty acids: an integrated multi-omics analysis Check for updates 1,2,4 2,4 3 1 1 1 1 1234567890():,; 1234567890():,; Geunsoo Kim , Kaiwei Chen , Zhiyuan Xing , Xiaoyu Wu , Haoyan Zhang , Yu Fang , Zishuai Zhang , Ningning He2 , Shangyong Li2 & Fengjuan Zhang1 Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation, immune dysregulation, and gut microbiota dysbiosis. Using a dextran sulfate sodium (DSS) mouse model, we applied an integrated multi-omics approach comprising untargeted metabolomics, colonic transcriptomics, and 16S rRNA sequencing to evaluate the effects of the prebiotic stachyose (STA). STA supplementation alleviated colitis and coincided with marked increases in several medium-chain fatty acids (MCFAs), including azelaic acid and 3-hydroxyoctanoic acid. Transcriptomic profiling revealed modulation of fatty acid metabolism genes (e.g., Mfsd2a, Anxa1) and enrichment of pathways such as PPAR signaling and fatty acid degradation. Microbiota analyses showed enrichment of Ruminiclostridium_9, Roseburia, and Christensenellaceae, with partial restoration of microbial diversity and functions. Integrated correlations linked specific taxa, MCFAs, and host lipid-related genes. While associative and requiring mechanistic validation, these findings suggest colonic MCFAs as candidate mediators of the protective effects of STA in experimental colitis. Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic condition characterized by diffuse mucosal inflammation of the colon, leading to symptoms such as recurrent diarrhea, abdominal pain, rectal bleeding, and weight loss1,2, which collectively impair patients’ quality of life3. The etiology and pathogenesis of UC are complex and multifactorial, involving immune dysregulation4, genetic predisposition5, environmental factors6, dietary influences7, and significant dysbiosis of gut microbiota8. The incidence of UC is rising globally, particularly among young individuals, posing a significant public health challenge5. Mounting evidence indicates that gut microbiota dysbiosis contributes to UC development and progression9. For instance, Lactobacillus acidophilus and Clostridium butyricum mitigate colitis in mouse models by enhancing gut barrier function and reducing inflammation10, while the probiotic mixture VSL#3 similarly reduces colonic inflammation and strengthens epithelial barrier integrity in experimental models11. Additionally, recent research highlights the therapeutic potential of Akkermansia muciniphila in improving UC outcomes12. In contrast, a reduction in key gut bacteria, such as Roseburia hominis and Faecalibacterium prausnitzii, is associated with UC development, underscoring their role in maintaining gut health13. Collectively, these findings highlight the critical importance of restoring gut microbiota balance for effective UC management, laying a solid foundation for novel therapeutic strategies like STA. Stachyose (STA), a naturally occurring oligosaccharide abundant in legumes, has emerged as a candidate prebiotic14. STA resists digestion in the upper gastrointestinal tract and undergoes fermentation in the colon15–17, enriching beneficial taxa such as Bifidobacterium18 and Lactobacillus19. Our previous work demonstrated that STA supplementation alleviates DSSinduced colitis by modulating gut microbiota and enhancing butyrate–PPARγ signaling20. However, whether STA exerts broader metabolic effects beyond short-chain fatty acids (SCFAs) remains unclear. Recent evidence suggests that medium-chain fatty acids (MCFAs; typically C6–C12) play underappreciated roles in gut homeostasis. Unlike SCFAs, MCFAs are rapidly oxidized by colonocytes and also act as signaling 1 Department of Infectious Diseases, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. 2School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, China. 3Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, e-mail: ; ; Qingdao, China. 4These authors contributed equally: Geunsoo Kim, Kaiwei Chen. npj Science of Food | (2025)9:237 1 Article https://doi.org/10.1038/s41538-025-00604-7 Fig. 1 | STA supplementation is associated with improved clinical and histological outcomes in DSS-induced colitis. Schematic of experimental design. Male C57BL/6J mice (6 weeks old, n = 24) were acclimated for 1 week and then randomly assigned to three groups (n = 8 per group): NC (no treatment), DSS (2.5% DSS in drinking water during week 3), and STA (STA at 400 mg/kg/day orally for 3 weeks with DSS challenge during week 3) (A). Changes in body weight (B). DAI is evaluated daily based on weight loss, stool consistency, and fecal blood (C). Colon length at sacrifice (D). Representative colon sections and histological score of H&E staining (E, F). Concentrations of pro- and anti-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10) were measured in serum (G–J). In bar graphs, bar height represents the mean with error bars ± SD. In line graphs, each data point represents the mean with error bars ± SD. Statistical analysis was performed using one-way ANOVA with Tukey post hoc test. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. molecules involved in lipid metabolism and immune regulation21,22. For instance, azelaic acid and 3-hydroxyoctanoic acid have been implicated in anti-inflammatory pathways via PPAR activation or G-protein–coupled receptors23,24. These observations raise the possibility that diet–microbiota interactions could influence colonic MCFA pools and thereby modulate host responses during colitis. In this study, we employed an integrated multi-omics strategy, including untargeted metabolomics, transcriptomics, and 16S rRNA sequencing, to investigate how STA modulates the microbiota metabolite host axis in a DSS-induced UC mouse model. We report that STA alleviates colitis symptoms, enriches SCFAs-producing microbes, and markedly elevates colonic levels of several MCFAs. These metabolic shifts are accompanied by transcriptional activation of lipid metabolism and PPAR signaling pathways. Together, our findings extend the understanding of STA anticolitic mechanisms beyond SCFAs-mediated immune regulation and highlight MCFAs as potential mediators linking prebiotic fermentation to host metabolic protection. Results npj Science of Food | (2025)9:237 STA is associated with improvements in DSS-induced UC symptoms In our previous studies, we demonstrated that STA supplementation alleviated colitis features in mice20. In this study, we investigated the preventive and therapeutic effects of STA at a (...truncated)