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Microbial -Enzymatic Mucin Metabolic Relay Suppresses Tumor Progression in Apcmin/+ mice

ABSTRACT:

Compelling evidence established the gut microbiota as a pivotal regulator of colorectal cancer (CRC) progression, although stage-specific mechanisms remain unclear. Our investigation in Apcmin/+ mice mapped tumor growth and microbial shifts across early, intermediate, and advanced stages. In Apcmin/+ mice, tumor growth exhibited an initial rapid phase followed by a gradual deceleration. Our study elucidated a niche complementarity model of gut microbiota in suppressing CRC progression: both critical gut bacteria (Akkermansia muciniphila, Muribaculaceae and other taxa) and their enzymes (hexosaminidase and SusD) exhibited the relay pattern in metabolizing intestinal mucin and producing N-acetylglucosamine (GlcNAc). Furthermore, rectal administration of GlcNAc suppressed Wnt/β-catenin signaling activation, might potentially contributing to the deceleration of tumor growth in the mid-to-late stages of cancer. This interplay between gut bacteria may reflect the significance of functional redundancy in maintaining the stability of microbial function.

INSTRUMENT(S): Liquid Chromatography MS - - - Gas Chromatography MS - positive

PROVIDER: MTBLS12754 | MetaboLights | 2025-07-20

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12754_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12754_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS12754.txt	Txt

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Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, Î±6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD. Transcriptome analysis of RNA from normal versus inflamed and carcinomatous rectal mucosa of Î±6 integrin deficient intestinal epithelium mice was performed. RNAs were prepared from 5 adenocarcinomas, which were macrodissected from the rectal prolapses and 4 flanking inflamed rectal mucosa of 53-80 week-old Î±6fl/fl Villin-Cre mice. RNAs from normal rectal mucosa were obtained by rectum scraping from 4 matched control animals. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChipÂ® Command ConsoleÂ® Software (AGCC) (version 2.0) and numerical value were generated using Affymetrix Expression Consoleâ¢ Software (version 1.1).

Project description:Changes in IgG glycosylation have been reported to be associated with colorectal cancer (CRC), but the alteration in specific subclass of IgG is unknown. Herein, we optimized five common IgG glycopeptides enrichment methods to acquire comprehensive profiling of IgG glycoproteomics in CRC. Notably, incomplete tryptic digestion of IgG occurred when using ordinary ratio of protease to protein, which significantly impacted the final statistical analysis of association between IgG glycosylation and CRC. We introduced a method based on two-step enzymatic digestion, enabling the complete digestion of IgG glycopeptides and further improving the detection intensity of the target glycopeptides. By this approach, total 47 IgG glycopeptides can be identified by nanoLC-ESI-MS/MS. Following rapid and automatic data processing through the self-developed program, we observed that IgG1_H3N4F1 and IgG1_H3N4 were substantially increased in CRC, while IgG1_H5N5F1, IgG1_H5N4F1S1and IgG2_H5N4F1 were markedly decreased. Strikingly, these four glycopeptides were continually significantly changed in early and late stages of CRC. Further evaluation of the diagnostic performance showed they all obtained a fair performance in discriminating the patients from the normal. In terms of the glycan features, it demonstrated that CRC progression associates with the increased agalactosylation, and the decreased digalactosylation and galactosylation per antenna on diantennay glycans of IgG1 and IgG2. Concurrently, the decreased sialylation of IgG1 was strongly correlated with CRC. Moreover, tumor-specific glycosylation analysis showed that the alterations of subclass-specific IgG glycosylation were more significant in colon cancer, and no obvious difference between colon and rectal cancer was found. More importantly, all these findings were validated in an independent cohort. This two-step enzymatic approach is crucial to explore the relationship between the disease progression and IgG glycosylation.

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Microbial -Enzymatic Mucin Metabolic Relay Suppresses Tumor Progression in Apcmin/+ mice

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