Dataset Information

Oral administration of low-molecular-weight heparin ameliorates colitis by enhancing the gut mucus barrier via microbial tryptophan metabolites

ABSTRACT:

Background and Purpose: Previous studies have reported that oral low molecular weight heparin (LMWH) ameliorated colitis by undefined mechanisms in ulcerative colitis (UC) patients. Our study explored the mechanisms of LMWH on colitis from the perspective of gut microbiota and its metabolites.

Experimental Approach: Dextran sulfate sodium (DSS; 2.5%) was used to induce colitis in mouse model, and LMWH was administered by either oral gavage, intracolonic delivery or subcutaneous injection to compare their therapeutic effects. Pseudogerm-free mice was established by using antibiotic cocktail, and faecal microbial transplantation (FMT) was performed to verify the role of microbiota in LMWH actions. Alcian blue staining, fluorescence in situ hybridization of EUB338 and immunohistochemical staining were performed to evaluate the integrity of gut mucus barrier. Amplicon sequencing, transcriptome sequencing and untargeted metabolome studies were used to explore LMWH mechanisms. The ameliorating effect of indole-3-propionic acid (IPA) was verified in vitro and in vivo.

Key Results: Oral, but not subcutaneous, administration of LMWH alleviated colitis and enhanced the gut mucus barrier. Pseudo-germ-free mice and FMT assays confirmed that therapeutic effects of oral LMWH were dependent on gut microbiota. Oral LMWH increased Firmicutes abundance and decreased Escherichia/Shigella abundance, subsequently increasing microbial tryptophan metabolites, especially IPA. The protective effects of oral LMWH were reproduced by IPA supplementation, with mucus barrier enhancing through regulating the Wnt/β-catenin pathway.

Conclusion and Implications: The results provide new insights into the signalling mechanisms associated with the therapeutic potential of LMWH in colitis, and highlight the application of IPA for UC treatment.

INSTRUMENT(S): Liquid Chromatography MS - positive

PROVIDER: MTBLS5770 | MetaboLights | 2025-10-12

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS5770_LC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS5770_LC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS5770.txt	Txt

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Oral administration of low-molecular-weight heparin ameliorates colitis by enhancing the gut mucus barrier via microbial tryptophan metabolites.

Zheng Dekai D Chen Shuze S Feng Hanxiao H Zhang Shaoheng S Zhang Cangui C Wang Ying Y Tan Weihao W Qing Qing Q Liu Le L Liu Xiuying X Wang Zhi Z Liang Liping L Sun Jian J Chen Ye Y

British journal of pharmacology 20250928 3

<h4>Background and purpose</h4>Previous studies have reported that oral low-molecular-weight heparin (LMWH) ameliorated colitis by undefined mechanisms in ulcerative colitis (UC) patients. Our study explored the mechanisms of LMWH on colitis from the perspective of gut microbiota and its metabolites.<h4>Experimental approach</h4>Dextran sulfate sodium (DSS; 2.5%) was used to induce colitis in mouse model, and LMWH was administered by either oral gavage, intracolonic delivery or subcutaneous inje ...[more]

PMID: 41016739

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Project description:<p><strong>BACKGROUND:</strong> Ulcerative colitis (UC) is a chronic recurrent inflammatory disease of the gastrointestinal tract. Recent studies demonstrate that the phenolic tannin paeonol (Pae) attenuates UC in mouse models by downregulating inflammatory factors; however, molecular mechanisms linking the gut microbiota and microbial metabolism with Pae remain elusive. </p><p><strong>METHODS:</strong> The UC mouse model was induced using 3% dextran sodium sulfate (DSS). Clinical symptoms were assessed, hematoxylin-eosin staining were used to analyze the effect of Pae on pathological changes to mouse colons, and ELISA was used to evaluate inflammatory factor expression in the serum. Transmission electron microscopy and immunohistochemistry were used to examine the structure of the colonic epithelial barrier and its tight junction proteins. Potential mechanisms of Pae were explored by 16S rRNA-based gut microbiota analysis, fecal metabolomics and construction of a multiscale, multifactorial network. </p><p><strong>RESULTS:</strong> Pae treatment significantly reduced the weight loss and disease activity index, colon shortening, tissue damage, and changes in TNF-α, IL-1β, IL-6, and IL-4 cytokine levels. Conversely, Pae restored the integrity of the intestinal epithelial barrier by increasing the expression of Occludin and ZO-1. Pae also partially reverted the DSS-induced disturbance in intestinal flora composition by increasing the proportion of probiotic bacteria and inhibiting UC-associated dysregulation of gut microbiota metabolites such as bile acids (BA) and short chain fatty acids. Network analysis demonstrated that Lactobacillus was associated with increased levels of unbound BAs, which in turn were strongly associated with inflammatory factor levels. The results suggest that Pae influences BA synthesis by regulating hepatic FXR-SHP/LRH-1 and ileum FXR-FGF15 signaling pathways to maintain intestinal integrity in UC mice. </p><p><strong>CONCLUSION:</strong> Pae can alleviate DSS-induced UC in mice by restoring dysregulated intestinal microbiota and BA metabolism, which improves intestinal barrier function and colonic inflammation, thus suggesting a new mechanism for Pae treatment of UC.</p>