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Background <p>Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and commonly starts from a pre-cancerous stage. This study aimed to identify potential fecal bacterial candidates associated with progression of CRC from the adenoma-carcinoma sequence and to explore underlying mechanisms of carcinogenesis.</p> Methods <p>Publicly metagenomic datasets were analyzed using MaAsLin2 to identify bacterial species enriched in CRC patients compared to healthy controls. Additionally, we established a large cohort in mainland China, consisting of 686 subjects, including 285 CRC patients, 73 advanced adenoma patients (AA), 134 non-advanced adenoma patients (nAA), and 194 healthy controls (NC). Fecal samples from this cohort were analyzed by duplex quantitative polymerase chain reaction (qPCR) to validate the abundance of key bacterial candidate and its association with tumor node metastasis (TNM) stages. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of <i>Christensenella hongkongensis</i> (<i>C. hongkongensis</i>) alone and in combination with fecal immunochemical test (FIT) across different CRC stages. In vitro experiments and transcriptome sequencing were performed to explore the effects of <i>C. hongkongensis</i> and its mechanisms in CRC progression.</p> Results <p>MaAsLin2 analysis identified seven bacterial species were significantly more abundant in fecal samples of CRC patients than in healthy controls (<i>p</i> &lt; 0.05). Among them, <i>C. hongkongensis</i>, an obligately anaerobic, catalase-positive, motile, non-sporulating, gram-positive coccobacillus was distinguished by its lowest abundance in healthy controls and significant enrichment in CRC patients. Validation in our recruited cohort showed that the abundance of <i>C. hongkongensis</i> progressively increased from non-advanced adenomas to advanced adenomas and CRC. For classifying AA from nAA, <i>C. hongkongensis</i> yielded an area under the ROC curve (AUC) of 0.60 (95% CI 0.53–0.68), with 45.2% sensitivity and 85.8% specificity. A combined model integrating <i>C. hongkongensis</i> abundance and FIT further improved diagnostic performance, increasing AUCs from 0.77 to 0.81 for AA vs NC (<i>p</i> &lt; 0.05) and from 0.76 to 0.82 for AA vs nAA (<i>p</i> &lt; 0.001). Linear regression analysis revealed a significant positive association between <i>C. hongkongensis</i> and TNM stages in CRC. In vitro experiments showed that <i>C. hongkongensis</i> promoted CRC cell proliferation, inhibited apoptosis, and enhanced the growth of patient-derived CRC organoids. RNA-seq analysis identified activation of the Wnt/β-catenin signaling pathway, which was further validated by elevated protein levels of active β-catenin, reduced phosphorylation of GSK3β, and the upregulation of downstream targets <i>c-Jun</i> and <i>Cyclin-D1</i>.</p> Conclusions <p>Our findings suggest that <i>C. hongkongensis</i> promotes colorectal tumorigenesis <i>via</i> Wnt/β-catenin activation, and highlight its potential as a novel non-invasive bacterial marker for early detection and monitoring of CRC progression.</p> Graphical Abstract

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Discovery and characterization of Christensenella hongkongensis as a novel bacterium in the adenoma-carcinoma progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • Wenqing Zhang,
  • Qi Su,
  • Haiyun Shi,
  • Yang Sun,
  • Xiaobo Li,
  • Mengbin Li,
  • Hui Wang,
  • Jun Yu,
  • Nathalie Wong,
  • Francis Ka Leung Chan,
  • Jingwan Zhang,
  • Siew Chien Ng

摘要

Background

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and commonly starts from a pre-cancerous stage. This study aimed to identify potential fecal bacterial candidates associated with progression of CRC from the adenoma-carcinoma sequence and to explore underlying mechanisms of carcinogenesis.

Methods

Publicly metagenomic datasets were analyzed using MaAsLin2 to identify bacterial species enriched in CRC patients compared to healthy controls. Additionally, we established a large cohort in mainland China, consisting of 686 subjects, including 285 CRC patients, 73 advanced adenoma patients (AA), 134 non-advanced adenoma patients (nAA), and 194 healthy controls (NC). Fecal samples from this cohort were analyzed by duplex quantitative polymerase chain reaction (qPCR) to validate the abundance of key bacterial candidate and its association with tumor node metastasis (TNM) stages. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of Christensenella hongkongensis (C. hongkongensis) alone and in combination with fecal immunochemical test (FIT) across different CRC stages. In vitro experiments and transcriptome sequencing were performed to explore the effects of C. hongkongensis and its mechanisms in CRC progression.

Results

MaAsLin2 analysis identified seven bacterial species were significantly more abundant in fecal samples of CRC patients than in healthy controls (p < 0.05). Among them, C. hongkongensis, an obligately anaerobic, catalase-positive, motile, non-sporulating, gram-positive coccobacillus was distinguished by its lowest abundance in healthy controls and significant enrichment in CRC patients. Validation in our recruited cohort showed that the abundance of C. hongkongensis progressively increased from non-advanced adenomas to advanced adenomas and CRC. For classifying AA from nAA, C. hongkongensis yielded an area under the ROC curve (AUC) of 0.60 (95% CI 0.53–0.68), with 45.2% sensitivity and 85.8% specificity. A combined model integrating C. hongkongensis abundance and FIT further improved diagnostic performance, increasing AUCs from 0.77 to 0.81 for AA vs NC (p < 0.05) and from 0.76 to 0.82 for AA vs nAA (p < 0.001). Linear regression analysis revealed a significant positive association between C. hongkongensis and TNM stages in CRC. In vitro experiments showed that C. hongkongensis promoted CRC cell proliferation, inhibited apoptosis, and enhanced the growth of patient-derived CRC organoids. RNA-seq analysis identified activation of the Wnt/β-catenin signaling pathway, which was further validated by elevated protein levels of active β-catenin, reduced phosphorylation of GSK3β, and the upregulation of downstream targets c-Jun and Cyclin-D1.

Conclusions

Our findings suggest that C. hongkongensis promotes colorectal tumorigenesis via Wnt/β-catenin activation, and highlight its potential as a novel non-invasive bacterial marker for early detection and monitoring of CRC progression.

Graphical Abstract