SSAT - MODIFYING THE GUT MICROBIOTA WITH PREBIOTICS STRENGTHENS THE GUT BARRIER AND PREVENTS THE DISSEMINATION AND GROWTH OF COLORECTAL CANCER CELLS

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MODIFYING THE GUT MICROBIOTA WITH PREBIOTICS STRENGTHENS THE GUT BARRIER AND PREVENTS THE DISSEMINATION AND GROWTH OF COLORECTAL CANCER CELLS
Roy Hajjar^*^1,2, Ayodeji S. Ajayi^1,2, Manon Oliero^1,2, Gabriela Fragoso¹, Annie Calve¹, Thibault Cuisiniere^1,2, Claire McCartney^1,2, Ahmed Amine Alaoui^1,2, Nassima Taleb¹, Claire Gerkins^1,2, Carole Richard^2,1, Manuela M Santos^2,1
¹Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; ²Universite de Montreal, Montreal, QC, Canada

Background
Colorectal cancer (CRC) is a significant public health issue, with surgical resection as a cornerstone of treatment. However, surgery induces systemic stress, inflammation, and weakens the gut barrier, potentially promoting cancer cell dissemination and metastasis. The gut microbiome, a key determinant of gut barrier integrity, may be modulated to reinforce the barrier and prevent recurrence. Despite its importance, data on this phenomenon remain limited.

Methodology
This project encompasses several components. We first assessed whether anastomotic leak (AL) increases CRC recurrence over a 10-year period in patients undergoing colorectal resection. Our previous studies demonstrated that inulin, a prebiotic enhancing beneficial short-chain fatty acids like butyrate, improves anastomotic healing in mice. We further evaluated the anticancer effect of dietary inulin supplementation in mice undergoing colorectal surgery and its influence on the progression of liver or subcutaneous CRC metastases. Using mice "humanized" with microbiota from CRC patients with AL, we studied inulin�s effects on local and systemic inflammation, CRC dissemination, and metastasis growth in various in vitro and in vivo models.

Results
Human data revealed that patients with AL experienced heightened systemic and local inflammation, higher CRC recurrence, and reduced survival (N=495). In mice, dietary inulin reversed poor surgical healing caused by deleterious microbiota from AL patients and improved anastomotic repair. Inulin reinforced the gut barrier post-surgery, preventing bacterial lipopolysaccharides from entering circulation. Strengthening the gut barrier also hindered CRC cells dissemination and liver metastasis progression fueled by systemic inflammation. Even in mice without surgery, oral inulin slowed subcutaneous CRC growth. Mechanistically, inulin�s benefits were mediated by the activation of the PPAR-? pathway in the gut, which has anti-inflammatory and anticarcinogenic properties. We validated these findings using oral 5-aminosalicylate in mice, a PPAR-? activator, and the same benefits were observed (Figure 1).

Discussion & Conclusion
This study is the first to demonstrate that inulin may improve CRC outcomes by reinforcing the gut barrier and mitigating systemic pro-carcinogenic inflammation. It highlights that a weakened gut barrier caused by surgical stress worsens CRC outcomes unless addressed with barrier-promoting agents like inulin. As a novel fermentable oligosaccharide, inulin is widely accessible. Its clinical role in colorectal surgery has not been previously tested. In addition to our previous data where inulin improved anastomotic healing, these results suggest it may also enhance oncological outcomes. This work lays the foundation for early-phase clinical trials to improve recovery, prevent metastasis progression, and reduce CRC recurrence.

Figure 1. Volume of subcutaneous CRC tumors in mice supplemented with inulin and 5-ASA

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