Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer
Authors: Niccolai E , Russo E , Baldi S , Ricci F , Nannini G , Pedone M , Stingo FC , Taddei A , Ringressi MN , Bechi P , Mengoni A , Fani R , Bacci G , Fagorzi C , Chiellini C , Prisco D , Ramazzotti M , Amedei A 
Published: April 2020

Background

Colorectal cancer (CRC) is a widespread disease that represents an example of chronic inflammation-associated tumor. In fact, the immune system, besides protecting the host from developing tumors, can support the CRC progression. In this scenario, the gut microbiota (GM) is essential to modulate immune responses and a dysbiotic condition can favor chronic/abnormal immune activation that support the tumor growth. GM can elicit the production of cytokines, influencing the immunostimulatory or immunosuppressive reactions, such as the tendency to mount Th1, Th17, Tregs or Th9 responses that play different roles towards colon cancer. Paradigmatic is the role of IL-9 that can both promote tumor progression in hematological malignancies and inhibit tumorigenesis in solid cancers. Therefore, to investigate the microbiota-immunity axis in CRC patients is crucial to well understand the cancer development with positive relapses in prevention and treatment.

Aim

The cellular and molecular characterization of the immune response and the evaluation of GM composition in healthy and tumor mucosa, focusing on the correlation between cytokines’ profile and GM signature.

Methods

We collected tumoral (CRC) and healthy (CRC-S) mucosa samples of 45 CRC patients. For each sample, we characterized the Tissue Infiltrating Lymphocytes (TIL)’s subset profile and the GM composition. In addition, in 14 CRC patients, we evaluated the CRC and CRC-S molecular inflammatory response (26 cytokines/chemokines) and we correlated this profile with GM composition using the Dirichlet Multinomial Regression.

Results

The analysis of T cells subsets distribution showed that CRC samples displayed higher percentages of Th17, Th2, Tregs, Tc17, Tc1/Tc17, and Tcreg, compared to CRC-S. Notably, also the number of Th9 was higher, even if not significantly, in CRC tissue compared to healthy one. In addition, we found that MIP-1α, IL-1β, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-γ, TNF-α, MCP-1, IL-1α, P-selectin and IL-9 were significantly increased in CRC compared to CRC-S. Moreover, the GM analysis revealed that CRC samples had significantly higher levels ofFusobacteria,Proteobacteria,Fusobacterium,Ruminococcus2(Lachnospiraceaefamily) andRuminococcus(Ruminococcaceaefamily) than CRC-S. Finally, we found that the abundance ofPrevotella sppin CRC samples was negatively correlated with IL-17A and positively with IL-9. In addition, the abundance ofBacteroidesandEscherichia/Shigellaspecies in CRC samples showed a negative association with IL-9 and IP-10 respectively.

Conclusions

Our data show a clear dissimilarity of inflammatory profile and GM composition between the tumor and the adjacent healthy tissue, displaying the generation of a peculiar CRC microenvironment. Interestingly, relating the tissue cytokine profile with the GM composition, we confirmed the presence of a bidirectional crosstalk between the immune response and the host’s commensal microorganisms; in detail, we documented for the first time thatPrevotella spp.andBacteroides spp.are correlated (positively and negatively, respectively) with the IL-9, whose role in CRC development is still debated.