**6. Diet**

*Multidisciplinary Approach for Colorectal Cancer*

ral or lymphovascular invasion [17].

**4. What is a microbiome?**

microbial populations [23].

Stat3 signaling [25].

(immune).

Comparing to the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM classification system, the Immunoscore classification seems to be superior as prognostic tool. For all patients with CRC stages I/II/III, multivariate Cox analysis revealed that the immune criteria remained highly associated with prognosis [16]. Wirta et al. concluded that a lower Immunoscore was associated with increasing AJCC/UICC stage, as well as with increasing T stage, presence of lymph node, distant metastasis, and perineu-

One day the classification of cancer will have a new component, TNM-I

Additionally, Immunoscore can predict the response to treatment and could be a biomarker that helps clinicians to decide what patients must have chemotherapy. Morris et al. concluded that high TIL is predictive of response to chemotherapy with 5-fluorouracil [18], and Viaud et al. revealed that cyclophosphamide induces a TH17 and TH1 antitumor response, making the tumors resistant to this chemotherapy [19].

Human surfaces and cavities are populated by numerous microbial communities, like bacteria or fungi, which form a complex interactive network between themselves and the host. The gastrointestinal microbiota is estimated to contain over 1000 different phylotypes with a microbial gene catalog of 3.3 million genes [20], but it can be divided into four main categories: *Firmicutes*, *Bacteroides*, *Actinobacteria*, and *Proteobacteria* [21]. These agents play an indispensable role in human health, as they interact with the immune system, maintain epithelial homeostasis, metabolize indigestible polysaccharides, modulate the intestinal motility, regulate the luminal pH, and exclude potential pathogens from the human gut [22]. The disruption of intestinal microbial equilibrium has the capacity to alter the homeostatic network, thereby eliciting deleterious host responses as observed in inflammatory bowel disease and CRC. The dysbiosis refers to perturbations in

Wong et al. proved that intestinal microbiota has an important role in CRC carcinogenesis. Mice fed with stool from patients with CRC had a higher rate of high-grade dysplasia than the mice fed with stool from healthy controls, suggesting that human commensals may not be tumorigenic [24]. Bacteria may contribute to CRC in several ways: they can break the mucus layer and adhere to intestinal mucosa and deliver virulent proteins and molecules that will initiate oncogenic signaling in epithelial cells. As so, they can induce DNA damage leading to tumor initiation. On the other hand, bacteria can trigger procarcinogenic signaling and inflammatory microenvironment, such as IL-17 production or excessive Wnt or

Some studies have identified several bacteria that can promote carcinogenesis by different mechanisms: *Escherichia coli* can cause direct DNA damage such as crosslinks and double-strand breaks due to the colibactin toxin produced by it [26], *Fusobacterium nucleatum* can produce FadA adhesin to modulate E-cadherin/ beta-catenin signaling [27], *Peptostreptococcus anaerobius* can induce cell proliferation through toll-like receptor 2 and toll-like receptor 4 pathways [28], *Bacteroides fragilis* produces a toxin that activates Wnt and NF-kB pathways which induce a pro-inflammatory state [29], and *Streptococcus gallolyticus* induces tumor growth through enhancement of inflammatory signals including cyclooxygenase-2 [30]. Xu et al. compared normal tissue with adenomas and adenocarcinomas and concluded that the microorganisms are different between the three entities. In the

**70**

Some dietary compounds may reach the colon by several reasons: they could be too large to be absorbed in the small intestine, they could escape the deglycosylation and absorption in the small intestine, and they could not be accessible to the host due to the mixture of food. The dietary compounds that are absorbed in the small intestine could reach the colon by enterohepatic circulation [37]. Dietary bioactives can modify the carcinogenic process in several ways: by a direct or microbe-independent pathway and by an indirect or microbe-dependent pathway that include modifications in the substrates that alter the colonic microbiota or their metabolites [38]. The dietary fiber goes through the small intestine into the cecum and proximal colon where they are metabolized by the colonic microbiota and short-chain fatty acids are produced [39]. The most abundant short-chain fatty acids in the colon are acetate, propionate, and butyrate, and their concentrations typically decrease from the proximal to the distal colon [40]. The advantages from consuming fibers are the dilution of carcinogens and potential tumor promoters in the intestinal lumen [41] and the fast passage of the digesta through the colon which minimize the exposition to toxic products and increase the levels of short-chain fatty acids in the distal colon [42].

Butyrate is the preferred substrate of colonocytes [43]. This compost was incredibly studied due to its capacity to reduce oxidative stress, diminish inflammation and carcinogenesis, and support colonic barrier function [44].

The diet can shape the colonic microbiota and their function, and, on the other hand, the microbiota influences the health of the intestine. This way the host is protected from colon cancer and other inflammatory diseases.
