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. 2025 Dec;17(1):2555446.
doi: 10.1080/19490976.2025.2555446. Epub 2025 Sep 5.

A new gut pathogenic bacteria and its metabolites promote colorectal cancer development and act as non-invasive early diagnostic biomarkers

Rui Zhang  1 , Mingxiao Li  1 , Hui Tan  1 , Jianyao Liu  1 , Lu Wang  2 , Wenling Dai  1 , Zhimin Fan  2 , Jihua Liu  1   3
Affiliations

A new gut pathogenic bacteria and its metabolites promote colorectal cancer development and act as non-invasive early diagnostic biomarkers

Rui Zhang et al. Gut Microbes. 2025 Dec.

Abstract

Gut microbiota dysbiosis is strongly linked to colorectal cancer (CRC), but reliable early diagnostic markers remain elusive. This study investigates the role of a novel Shigella flexneri strain in CRC pathogenesis. Metabolomic analysis of CRC patient feces identified elevated agmatine levels. A unique agmatine-producing strain (S. flexneri C.11) was isolated and validated in cell models and pseudo-sterile mice. Affinity fishing combined with HPLC-QTOF-MS characterized bacterial metabolites, while RNA sequencing elucidated mechanistic pathways. Repeated S. flexneri C.11 exposure-induced DNA damage and inflammatory-to-neoplastic transformation. Three genotoxic cyclodipeptides (CDP1-3) were identified, driving malignant transformation and accelerating colitis-associated tumorigenesis. Mechanistically, S. flexneri C.11 upregulated ERBB3, activating the PI3K-AKT pathway. Clinically, combined detection of S. flexneri C.11 and its metabolites differentiated CRC patients from healthy controls (AUC = 0.887), suggesting its potential as noninvasive diagnostic biomarkers for CRC. We identify S. flexneri C.11 as a pro-carcinogenic pathogen and propose ERBB3/PI3K - AKT signaling as a therapeutic target.

Keywords: Colorectal cancer; DNA damage; diagnostic marker; inflammatory bowel disease; intestinal bacteria; metabolite.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Metabolic alterations in CRC are found in serum and feces samples.
Figure 2.
Figure 2.
S. flexneri C.11 causes DNA damage in vitro, but not through agmatine.
Figure 3.
Figure 3.
S. flexneri C.11 induces intestinal inflammation and accelerates its transformation to cancer in mice.
Figure 4.
Figure 4.
Direct effects of S. flexneri C.11 genotoxic metabolites in vitro.
Figure 5.
Figure 5.
S. flexneri C.11 genotoxic metabolite CDPs facilitate the development of internal tumor in colitis mice.
Figure 6.
Figure 6.
S. flexneri C.11-induced tumorigenesis links to host gene expression alterations.
Figure 7.
Figure 7.
Clinical correlative validation of the S. flexneri C.11-ERBB3-DNA damage pathway in CRC.
Figure 8.
Figure 8.
ROC characterization of identified metabolite markers in feces to UC, CRC patients and HCs.
Figure 9.
Figure 9.
Mechanism and application of S. flexneri C.11 and its genotoxic in promoting CRC development in mice via DNA damage and activation of ERBB3/Nrg1/PI3K/AKT/mTOR signaling pathway.
See this image and copyright information in PMC

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