A Role for Butyrate in Inducing T Cell Exhaustion and Increasing Susceptibility to Colorectal Cancer
Kristina Diana A. Zambo
Introduction: Colorectal cancer (CRC) is the 3rd most common cancer in the world. It is driven by genetic as well as environmental factors with different etiological mechanisms, such as inflammation and immune regulation. While the microbiome is known to be closely linked to the immune system, it’s mechanism in influencing susceptibility to colorectal cancer remains unclear. This research aims to shed light on how gut dysbiosis affects colon carcinogenesis for potential application to developing new therapeutic and preventative strategies.1 Methods: Inflammation-associated tumorigenesis was modeled in two groups of wild-type mouse colonies with distinct gut microbiomes to assess whether these differences were responsible for the differences in tumor phenotype. Lamina propria (LP) colon immune cell compositions were analyzed to better understand the mechanism by which the microbiome alters the immune response and tumor susceptibility.1 Further, to investigate the effects of the microbiome metabolite, butyrate, on tumor regression in conjunction with chemotherapy, extensive analysis of immune cell composition, genetic sequencing techniques, and functional assays were carried out in an Mc38 tumor-bearing mice.2 To monitor butyrate’s effects on epithelial barrier formation, human intestinal epithelial cells (IECs) were plated on transwell inserts and exposed to physiologically relevant concentrations of the metabolite, and further analysis was carried out by a combination of techniques such as immunoblotting, qPCR, and gene knockdown or overexpression.3 In addition, mouse models of intestinal cancer were treated with oral particle-based therapy containing recombinant murine IL-10, and tumor burden and gut permeability was analyzed.4 Finally, ATAC-seq was used to analyze stem-like CD8+ T cells from LCMV chronically infected mice and compared it with the epigenetic profile of more terminally differentiated and exhausted CD8 T cells.5 Results: Gut dysbiosis was found to increase susceptibility to CRC, and this was associated with lamina propria containing higher numbers of exhausted T cells as well as increased occludin expression in the gut epithelium.1 Among the various gut microbial metabolites, butyrate especially was shown to significantly upregulate homeostatic IFN-gamma production by CD8+ T cells via an ID2 dependent pathway.2 ID2 and IFN-gamma were identified as genes exhibiting higher accessibility and higher expression in an exhausted T cell population compared to a more stem-like, active T cell population.5 Butyrate has also been shown to increase levels of occludin in the gut epithelium by sensitizing gut epithelium to IL-10 by upregulating the expression of IL-10RA, and IL-10 is known to enhance tight junction protein expression.3,4 Discussion: The specific mechanism underlying host-microbiome interactions and its effects on colitis-associated tumorigenesis has yet to be defined. This research establishes how through butyrate, the gut microbiome can affect the baseline levels of CD8+ T cells and IFN gamma production in the gut lamina propria and induce early T cell exhaustion which correlates with differential tumor burden. Thus, it provides an important point of consideration especially for immunotherapy treatment. In other cancers like melanoma, butyrate has been associated with limiting immunotherapy effectiveness. Patients with melanoma who had higher baseline serum levels of butyrate demonstrated a worse response to the immunotherapy, Ipilimumab. Therefore, modulating gut dysbiosis by targeting butyrate or its downstream effectors can potentially be used to treat inflammation-associated colon cancer or improve patient response to specific immunotherapies.
- Yu AI, Zhao L, Eaton KA, et al. Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis. Cell Reports. 2020;31(1):107471. doi:10.1016/j.celrep.2020.03.035
- He Y, Fu L, Li Y, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metabolism. 2021;33(5):988-1000.e7. doi:10.1016/j.cmet.2021.03.002
- Zheng L, Kelly CJ, Battista KD, et al. Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor–Dependent Repression of Claudin-2. JI. 2017;199(8):2976-2984. doi:10.4049/jimmunol.1700105
- Bhutiani N, Li Q, Anderson CD, et al. Enhanced gut barrier integrity sensitizes colon cancer to immune therapy. OncoImmunology. 2018;7(11):e1498438. doi:10.1080/2162402X.2018.1498438
- Jadhav RR, Im SJ, Hu B, et al. Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc Natl Acad Sci USA. 2019;116(28):14113-14118. doi:10.1073/pnas.1903520116