Colorectal Cancer Prevention via Modulation of Gut Microbiota: History
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Contributor:
Marco Dacrema
,
Arif Ali
,
Hammad Ullah
,
Ayesha Khan
,
Alessandro Di Minno
,
Jianbo Xiao
,
Alice Maria Costa Martins
,
Maria Daglia

Colorectal cancer (CRC) is the second most frequent cause of cancer-related mortality among all types of malignancies. Sedentary lifestyles, obesity, smoking, red and processed meat, low-fiber diets, inflammatory bowel disease, and gut dysbiosis are the most important risk factors associated with CRC pathogenesis. Alterations in gut microbiota are positively correlated with colorectal carcinogenesis, as these can dysregulate the immune response, alter the gut’s metabolic profile, modify the molecular processes in colonocytes, and initiate mutagenesis. Changes in the daily diet, and the addition of plant-based nutraceuticals, have the ability to modulate the composition and functionality of the gut microbiota, maintaining gut homeostasis and regulating host immune and inflammatory responses.

  • dietary spices
  • gut microbiota
  • colorectal cancer

1. Introduction

Colorectal cancer (CRC) is the most prevalent form of carcinoma, and represents a leading component of the global health burden. Advancements in treatment methods, colonoscopy, and avoidance of risk factors, such as smoking and red meat consumption, have contributed to a decline in CRC cases over the last three decades in the United States [1][2]. However, similar declines have only been observed in developed countries [3]. Despite innovative strategies of treatment and diagnosis, CRC remains the third most common cancer and the second leading cause of mortality across the globe. In the year 2018 alone, 1.8 million new CRC cases were recorded including 881,000 deaths [4]. CRC cases may rise to 2.5 million by the year 2035 [3]. The modifiable risk factors for CRC include obesity [5], cigarette smoking [6], heavy alcohol use [7], poor diet [8], and a sedentary lifestyle [9]. The genetic contribution towards CRC is in the range of 12–35% as demonstrated in twin and family studies [10][11]. While 60–65% of cases arise sporadically without any family history of CRC [12]. This sizeable sporadic contribution to the instigation of CRC shows the significance of environmental factors, which play a large role in causing CRC [13]. Among environmental factors, infectious agents are responsible for 15 percent of all cancers [14]. Colorectal carcinogenesis is a process involving years of development, possibly taking decades. In such scenarios, early life risk factors and lifestyle modification are pertinent contributors [15]. The current rise of CRC in the young adult population in the US is alarming [2], and this supports the concept that early life risk factors provide a major impact on CRC carcinogenesis [16].
The human microflora counts around thirty trillion bacteria without considering fungi and viruses. The microbiota is not only altered by the environment but also by the relationship between the host and the symbiotic organisms [17]. The total number of microbial cells is 10 times greater than that of human somatic cells [18][19][20][21][22] and these include over 1000 different species of bacteria populating our gut. Most of these belong to the Firmicutes and Bacteroides phyla and are linked to the protection of the host, as they can produce metabolites and bioproducts promoting a protective effect against different pathologies. The dietary compounds and vitamins produced by these bacteria are considered protective elements against the infiltration of gut pathogens and the development of pathologies [23][24][25]. The impairment of the microbiota could lead to dysbiosis, and several studies sustain this link between tumorigenesis and microbiome diversity, thanks to the combination of next-generation sequencing and computational analysis [26][27][28][29][30][31]. A well-regulated microbiome is essential for maintaining the homeostasis of the metabolism and immune response, in fact, several clinical studies underline how the immunotherapeutic response could be influenced by the gut microbiome, suggesting that treatments could be enhanced or depressed according to the gut microbiota status [31][32][33][34].
Another important role of the microbiome is the recognition of the conserved regions of Gram-negative pathogenic bacteria after the production of immunoglobin G antibodies [35][36]. However, the composition and the alteration of the microbiota are also related to different host life stages and diets [37][38][39][40][41]. It is calculated that 20% of all cancers are related to dysbiosis, and with this perspective, probiotics could be used as therapeutic agents to re-establish the normal microbial environment, enhancing the immune response to counteract tumor growth. Literature data have shown that gut microbiota may provide the missing link between dietary factors and CRC incidence [42]. Some dietary components, such as saturated fats, processed carbohydrates, red meat, and ultra-processed food can affect the gut microbiota and lead to inflammation [43], and inflammation is a known factor for 20–30% of CRC cases and is acknowledged as the principal driver of tumorigenesis [44][45][46].
While chemotherapy and radiotherapy are the key approaches employed for the treatment of patients with cancer, both are associated with serious adverse events that may outweigh their therapeutic benefits in certain cases. Drug resistance is another concern that is very common for anticancer therapies and may result in failure of the treatment [47]. Nature has provided a range of preventive and therapeutic agents with the potential to fight against the most devastating chronic disorders including cancer [48][49]. Edible plants containing phytochemicals are known to alter numerous molecular pathways that may impact anticancer effects (i.e., oxidative stress, inflammatory cascade, apoptosis, epigenetic regulation, p53 signaling pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) pathway, mitogen-activated protein kinases (MAPKs), proteasome pathway, insulin-like growth factor-I mediated signal transduction pathway, matrix metalloproteinases (MMPs), vascular endothelial growth factor, Hippo signaling pathway, phosphoinositide 3-kinase–protein kinase B–mammalian target of a rapamycin signaling pathway (PI3K/Akt/mTOR), cyclooxygenase-2, and the Janus kinase–signal transducer and activator of transcription signaling pathway) [50][51][52][53][54][55][56][57].
Some spices such as turmeric, black cumin, ginger, ginseng, garlic, saffron, and black pepper, are potential sources of cancer prevention owing to their natural bioactive compounds (curcumin, thymoquinone, piperine, and capsaicin) [58][59][60]. About 80% of the world population is currently relying on phytomedicine for their primary healthcare [61], in fact, these natural products are commonly considered a safer alternative for patients, if compared to systematic chemotherapeutic drugs although their scientific validity and efficacy are currently under analysis [62][63]. These spices and herbs have been used for thousands of years in small amounts thanks to their beneficial effects. In particular, curcuma, ginger, garlic, clove, chili pepper, saffron, and flaxseed seem to inhibit CRC growth thanks to their chemotherapeutic roles [58][64][65][66]. CRC development is sustained by cancer stem cells (CSC), which are self-renewal and pluripotent stem cells able to promote carcinogenesis and the formation of heterogeneous tumors [67]. Increasing evidence sustains the link between microbiota alterations and mature tumor formation. In particular, their metabolome [68] can promote pro or anti-carcinogenic actions. The preservation of the CSC is essential and mediated by several phytochemicals such as curcumin, quercetin, lycopene, cinnamic acid, resveratrol, sibilin, and epigallocatechin-3-gallate [EGCG] [69]. The main pathways involved in the regulation of the CSC phenotype are Hedgehog, Notch, and Wnt/β-catenin [70], which are modulated thanks to the colonic microbiota transformation of phytochemicals. At the same time, these substances can modify the microbiota population. Thus, the diet can change the colonic bacteria and vice versa in a triangular rapport where is involved CRC formation.

2. Gut Dysbiosis and Carcinogenesis

The maintenance of healthy gut microbiota during an individual’s lifespan, and any potential loss of diversity, is strictly connected with their diet. The progression of a disease could also involve the long-term depletion of specific groups of bacteria, which could be induced by lifestyle changes and other societal factors [37][38]. Healthy conditions are completely different from those of patients affected by dysbiosis. In the first case, the immune system can easily recognize pathogenic microbes, promoting their consequent elimination [71], most gut bacteria are non-pathogenic, and they offer an important defense role in inhibiting colonization by pathogens. The immune cells (i.e., dendritic cells, macrophages, and phagocytes) are involved in the gut microbiome and are essential for the recognition of pathogenic bacteria [72]. Healthy individuals could suffer either mild or severe issues if bacteria translocate across the epithelial mucosa. Kupffer cells may be involved, after the production of endotoxins and viable or dead bacteria. However, in the case of dysbiosis, the commensal bacteria may also spread into extra-intestinal sites and tissues. Obviously, this event can promote septic shocks, sepsis, organ failure, and death [73] over short-term periods. The dysregulation of the microbiota is associated with various pathologies, and this could be also induced using antibiotics which are known to reduce microbiotal diversity. The state of the art sustains that diabetes types 1 and 2, obesity, arthritis, Crohn’s disease, arthritis, and celiac disease are linked with the deregulation of the microbiotal metabolism and inflammation, which promotes the incidence of these pathologies [73][74][75][76][77][78].
Obviously, the microbiota is strongly involved in the absorption and metabolization of nutrients, thanks to the expression of a great number of genes, which are not expressed in our own organism. The impairment and the downregulation of these processes can promote inflammation, which may also lead to cancer in the longer-term [79][80]. The increased incidence and prevalence of cancer over recent decades are mainly due to a higher exposure to cancer-causing molecules, but also to high-fat diets, which promote dysbiosis and the inflammation process [76]. The microbial alteration could be one of the main factors, which contribute to carcinogenesis [81], in fact, different studies have supported the importance of the relationship between carcinogenesis and lifestyle. The inflammation process remains a driving force in the progression of cancer, promoting its development through the production of inflammatory cytokines [82], with microbial dysbiosis leading to increased concentrations of interleukin (IL)-1, 6, 10, and tumor necrosis factor alpha (TNF-α). The production of IL-10 is essential for the body’s elimination of cancer, in fact it is considered the most effective anti-inflammatory cytokine involved in tumorigenesis [83][84][85]. Wnt signaling is involved with NF-ĸB and MAPKs, which together can lead to an increase in oxidative stress and inhibition of apoptosis [86][87]. Animal and human studies have shown that bacteria such as Fusobacteria, Alistipes, Porphyromonadaceae, Coriobacteridae, Staphylococcaceae, Akkermansia species and Methanobacteriales are predominantly increased in CRC, while Lactobacillus, Bifidobacterium, Faecalibacterium species, Treponema, Roseburia, and Ruminococcus are known to reduce [88].
The production of toxins can also influence the tumorigenesis process, with Helicobacter pylori, Escherichia coli, and Shigella flexneri, for example, inducing double-strand DNA cuts causing apoptosis or alteration of the cell cycle [89]. Starting from E. coli, colibactin and cytolethal distengin toxins induce genomic instability, promoting breaks in the host’s DNA and tumorigenesis [87]. S. Flexneri instead produces cysteine proteases, such as virulence gene A and the inisitol phosphate phosphatase D, with the final response, in this case, being necrosis, with the development of cancer and cell death due to the degradation of the p53 gene and host damage [90]. Fusobacterium nucleatum disrupts the junction of β-catenin through the effector adhesin A (FadA); moreover, it is responsible for the production of virulence factor (Fap2) but in this case, it is through the mediation of blocks of natural killer cells (NK cells) through the binding of the NK inhibitory receptor [90][91][92]. Bacteroides fragilis produces a toxin responsible for DNA damage after the production of reactive oxygen species and hydrogen peroxide [93], the same is the case for Enterococcus fecalis, which is responsible for the production of extracellular superoxide, able to trigger mutations in host DNA [55]. Finally, Lactobacillus casei is responsible for the production of the ferrichrome siderophore, which activates c-Jun N-terminal kinase (JNK) signaling and consequent apoptosis [94].

3. Gut Microbial Alteration, Chemotherapy, and Cancer Prevention

Our gut contains trillions of microorganisms interacting with the host, and it is important to underline their essential role in bodily function. Digestion, secretion of metabolites, and the intervention of the immune system as cited above, are strictly related to the microbiota. Bacteria-free mouse models underline how dysbiosis is related to immunoglobulin A, lymphadenitis, and the absence of mucus [95][96]. Cancers very often become resistant to the drugs most used for their treatment [97][98], and unfortunately in 90% of cases, this phenomenon is responsible for the patient’s death [99][100][101]. Obviously, this problem requires attention and time to promote the development of new treatments, and the gut microbiota in particular may also influence the efficacy of antitumor therapies [102].
The negative impact of the absence of a microbiota is becoming clearer year after year, with different studies on mice treated with antibiotics underlining the efficacy of chemotherapy and immunotherapy [103]. Moreover, it is possible that the efficacy of chemotherapy treatments may be heightened under normal conditions, promoting the destruction of cancer through the intervention of T-lymphocytes and myeloid cells. The antibiotic treatments applied in certain mice studies [104] can impair the presence of bacteria and the production of cytokines, however further clinical studies are required to confirm these preliminary findings. The combination of metabolomics and metagenomics underlines the importance of the gut-brain axis [105], which regulates the composition of the gut flora through the production of neuro-hormones and hormones. The case of cyclophosphamide is particularly interesting, a chemotherapeutic drug able to promote the T-cell immune response in the presence of commensal microbiota, which translocates from the spleen to the lymph nodes promoting their anticancer effect [92][106]. It appears that Bifidobacterium can enhance dendritic cells, promoting the activation of T CD8-positive cells and enhancing the efficiency of anti-programmed death ligand (PDL-1) therapy [107]. The five-year survival rate was found to have increased by 80% for 1000 sarcoma patients treated with killed microorganism activate (Serratia and Streptococcus) [108]. The T lymphocytes associated with antigen 4 (CTLA-4) seem to have anticancer effects, promoting the production of CTLA-4 inhibitors. In the absence of CTLA-4, germ-free mice registered a positive response against cancer following an exposure to Bacteroides [109] underlying the anticancer effects of these molecules.
Only a few studies to date appear to sustain the relationship between cancer prevention and the microbiota. The production of short-chain fatty acids (SCFAs) by microbiota (i.e., Propionibacteria such as P. freudenreichii) [110][111][112] has an anti-cancer effect [113], inhibiting the deacetylases of cancer cells. Indeed, a lower concentration of butyrate is registered in cancer patients. The production of SCFAs stimulates the production of IL-18, promoting the healing process in mucosal tissues [114]. Probiotic administration also exhibits interesting effects, as it seems to trigger the immune response with an antitumor effect. Gram-negative bacteria activate TLR4 and T-cells, with Salmonella enterica, for example, appearing to be very effective against cervical cancer [115]. Finally, L. casei stimulates apoptosis in cancer cells thanks to ferricrome production, through the activation of the JNK signaling pathway [87].

This entry is adapted from the peer-reviewed paper 10.3390/cancers14225682

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