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    • Disrupting the dialog between microbiota

    2022-06-05

    Disrupting the dialog between microbiota and the host, especially at the level of mucosal immunology, is expected to have profound effects on disease development. By using the AOM+DSS model of colitis-associated CRC, Singh et al. (2014) showed that development of inflammation and CRC are exacerbated in Grp109a mice compared to WT mice, a phenomenon associated with defective production of colonic IL-10 and cytoprotective IL-18 and heightened level of IL-17. The authors also observed a similar increased tumorigenesis when ApcMin/+ mice were crossed to Gpr109a mice, showing that the impact of Gpr109a on cancer is not restricted to a chronic wounding model (AOM+DSS). Interestingly, by using bone-marrow transfer studies, Singh et al. (2014) showed that the contribution of radio-resistant VX-689 sale to Gpr109a-mediated anticarcinogenic effect is greater than the one afforded by immune cells. The fact that IL-18 administration decreased tumorigenesis in Grp109a mice suggests that a complex network of immunoregulatory molecules (IL-10, Aldh1, IL-18) from various cellular sources (immune cells, epithelial cells?) participate in intestinal homeostasis (Figure 1). The importance of the microbiota in Gpr109a-mediated protective effect is clearly demonstrated in antibiotic-treated WT mice, which displayed enhanced AOM+DSS-induced tumorigenesis compared to untreated mice. Administration of niacin to antibiotic-treated mice was able to decrease tumor development, an effect not observed in Grp109a mice. Remarkably, the antibiotic experiment also indicates that the microbiota not only protects against tumorigenesis as seen in WT mice, but also promotes CRC in Grp109a mice. This deleterious effect was associated with expansion of bacteria belonging to the Prevotellaceae family and TM7 phylum, although the events leading to these microbial compositional changes were not established. To clearly link microbial-derived metabolites (byturate and niacin) with Gpr109a-mediated protective function, the authors fed ApcMin/+ mice with either a normal chow containing fiber or a fiber-free diet. As opposed to wide-spectrum antibiotic treatment, which eliminates virtually all bacteria, dietary fiber manipulation has a more targeted effect on the biota, essentially regulating the capacity of bacteria to generate SCFA. Remarkably, fiber-free diet enhanced tumorigenesis in ApcMin/+ mice, a phenomenon strongly attenuated by niacin supplementation. Grp109a mice failed to show a similar response to dietary fiber manipulation or niacin supplementation, providing strong evidence that the protective effect is mediated by this receptor. A recent report showed that butyrylated diet also promotes Treg cell development and prevented T-cell-adoptive-transfer-mediated chronic colitis (Furusawa et al., 2013), lending support to the key role of bacteria in promoting an homeostatic phenotype regardless of the initial insult (chemical or naive T cell transfer). The current study adds an important piece to the complex jigsaw puzzle formed by diet, microbiota, and immune cells interaction in the intestine and brings new understanding regarding the intricate communication network necessary for the maintenance of intestinal homeostasis. Although compelling and informative, the study also raised questions. It is striking to note that other SCFA receptors such as GPR41 and GPR43 are not able to compensate for the lack of Gpr109a, although butyrate binds both receptor types and elicits a Treg-cell-associated anti-inflammatory response (Smith et al., 2013). Comparing inflammation and CRC susceptibility between GPR43-deficient and Gpr109a−/− mice would help understand the potentially divergent role of these receptors in mediating intestinal homeostasis. Furthermore, the cell type (epithelial cells, immune cells) responding to SCFA exposure may also dictate the extent of the protective response. This is clearly demonstrated in immune-cell-derived GPR43 signaling, which mediates an anti-inflammatory response (Maslowski et al., 2009), whereas IEC-derived GPR43 signaling appears to promote an inflammatory phenotype in the DSS model of colitis (Kim et al., 2013). Noteworthy, a recent report showed that butyrate-mediated expansion of Treg cells is Gpr109a independent, suggesting a complex impact of this SCFA on immune cell behaviors (Arpaia et al., 2013). A careful genetic dissection of the cellular compartment (DCs, myeloid cells, epithelial cells) responsible for Gpr109a-mediated protective effect would be necessary to fully capture the essence of the cellular network responding to microbial cues in the intestine.