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Carcinogens in Areca Nut: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 3 by Conner Chen.

A large body of literature found that habitual areca nut (AN) chewing was tightly associated with the occurrence and development of oral, esophageal, and pharyngeal cancers. In addition, many studies revealed that long-term AN usage increased the risk of hepatocellular carcinoma (HCC).

  • areca nut
  • polyphenol
  • arecoline
  • gut microbiota

1. Contradictory Role of Polyphenols in Cancers

Evidence is emerging on the toxicity of the dietary polyphenols extracted by areca nut [1]. Major polyphenols found in areca nut (AN) are tannins, catechins, flavonoids, safrole, and eugenol, among which, tannins, safrole, eugenol, and catechins have been proven to be carcinogens. Many experimental and preclinical studies proposed that polyphenol and tannin fractions of AN had a relevant role in BQ-induced cancer development and progression, mainly attributed to their immunomodulatory properties [2][3]. For example, reactive oxygen species (ROS) produced during the autoxidation of BN polyphenols in the saliva of chewing BQ is crucial in the initiation and promotion of oral cancer [4]. Also, incidences of esophageal cancer have been reported to be associated with consumption of tannins-rich foods such as BN, and carcinogenic activity of tannins might be related to components associated with tannins rather than tannins themselves, suggesting a potential role of gut microbiota in tannins carcinogenicity. Epidemiological studies found that a polyphenol-rich diet protected against cancer, as well as many short-term assays revealed that AN polyphenols and tannins were not mutagenic and, in fact, even had antimutagenic effects. Some literature reported that polyphenols favored the generation of ROS [5]. Contrasting this, AN polyphenols were reported to be able to form conjugates with carcinogens, to trap nitrite and ROS [6][7]. The prominent polyphenols in AN and their contradictory activities are summarized in Table 1. And reported major classes of polyphenols extracted from other plants are also showed in Table 2.
Table 1. Prominent polyphenols in AN and their activities.
Formulas Polyphenols Activity Gut Microbiota-Relevant Reference
Table 2. Other reported major classes of polyphenols extracted from plants and their activities.
Polyphenols Representative Plant Activity Gut Microbiota-Dependent Reference
Molecules 27 08171 i001 Catechin Antimicrobial, antioxidant, anti-cancer and carcinogenic activity Yes [8][9]
Resveratrol Reynoutria japonica Houtt. and Vitis Antimicrobial, antioxidant, and anti-inflammatory activity Yes [14]
Molecules 27 08171 i002 Flavonoids Anti-inflammatory, antioxidant and anti-cancer effects, anti-bacteria and anti-virus Yes
Quercetin Fagopyrum esculentum Moench. Anti-virus, anti-bacterial, anti-cancer, and cardiovascular-protective effect[10][11]
Yes [15] Molecules 27 08171 i003 Safrole Anti-cancer and antioxidant effects
CatechinYes Green tea[12]
Anti-cancer, anti-virus, anti-fungi, anti-bacterial, and cardiovascular-protective effect Yes [16] Molecules 27 08171 i004 Eugenol Anti-bacteria and antihypertensive effect Yes [13]
Puerarin
Pueraria lobata Anti-oxidant, anti-inflammatory, antihypertensive, and neuroprotective activity Yes [17]
Anthocyanidin Elderberries Anti-oxidant, anti-mutagenic, and anti-proliferative properties Yes [18]
Tannic acid Fruit Anti-oxidant and anti-bacterial effect Yes [19]
The underlying mechanism of these observed dual, and apparently contradictory, functions of AN polyphenols and tannins in the process of BQ-induced carcinogenesis remains to be explored.

2. Bidirectional Interaction between Polyphenols and Intestinal Microbes

Polyphenols have an extremely low oral bioavailability and are almost unchanged when reaching the colon, and most of them are intensively catabolized by gut microbiota to a wide variety of new chemical structures that are often more active and better absorbed than the original phenolic compound passing hardly into the systemic blood circulation [20][21][22], and in turn, polyphenols could modulate oral and gut microbiota composition in host homeostasis and diseases. Several human and animal studies reported that polyphenols can elevate butyrate-producing bacterial and probiotics such as Lactobacillus and Bifidobacterium, while inhibiting opportunistic pathogenic or proinflammatory microbes. For example, bound polyphenol from foxtail millet bran can inhibit colitis-associated carcinogenesis by remodeling gut microbiota in a mice model [23]. The two-way interplay between microbial communities and polyphenols in the intestine is important for the latter to exert anticancer effects and might be the underlying mechanism for their contradictory and dual effects. Emerging studies have reported that diet polyphenols exert anti-obesity [24][25][26][27], anti-inflammatory, and anti-oxidant effects via modulating gut microbiota. For instance, Ho, et al. found that Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity [28]. Mei, et al. revealed that areca nut (areca catechu L.) seed polyphenol could ameliorate osteoporosis via altering gut microbiota to increase lysozyme expression and controlled the inflammatory reaction in estrogen-deficient rats [29]. Studies have shown that AN could supplement polyphenols such as chlorogenic acid, (+)-catechin, (−)-epigallocatechin gallate, (−)-gallocatechin gallate, rutin, and theaflavin, which could greatly reduce high-fat diet-induced adverse effects, via easing food stagnation, eliminating indigestion, enhancing gastrointestinal motility, and regulating the activity of related enzymes [30][31]. Meanwhile, studies have revealed that AN could increase the risk of obesity and hyperglycemia. Gut microbes have the potential to explain these two opposite effects induced by AN. Despite few studies having explored the role of gut microbes in the carcinogenicity of polyphenols, there have been several studies linking gut microbes to cancer development and treatment [32][33][34][35]. For example, intestinal fusobacterium nucleatum promotes colorectal cancer development and facilitates tumor metastasis and chemoresistance to 5-fluorouracil via its immunosuppressive effects [36][37][38]. Also, gut microbiota regulates the activity, efficacy, and toxicity of chemotherapy agents, such as gemcitabine [39], cyclophosphamide [40][41], irinotecan [42][43][44], and cisplatin [45][46][47]. Further research is required to clarify whether areca nut chewing changes the composition and function of intestinal microbes or whether intestinal microbes metabolize areca nut into carcinogens.
In recent years, there has been increasing evidence that the aryl hydrocarbon receptor (AhR) plays a major role in tumorigenesis and makes the AhR an interesting pharmacological target in cancer treatment [48][49][50][51]. Polyphenols, especially flavonoids, major constituents of AN, are the largest class of natural AhR ligands that are available for humans and animals [52][53]. Mounting evidence demonstrated that flavonoids, exhibiting AhR agonist and/or antagonist activity, are widely used for the regulation of the intestinal immune system and tumor treatment [54][55][56][57][58]. Dietary flavonoids are absorbed in the intestine, and the intestinal microbiota, which is deeply involved in the metabolism of them, originated from foods [59], and in turn, acting as AhR ligands, are able to regulate intestinal microbiota composition and intestinal immunity [60]. For example, tryptophan, a reported AhR ligand, could be metabolized by the certain bacterial strain, Lactobacillus bulgaricus OLL11816, to AhR-activating indoles that have shown AhR-activating potential [61][62]. However, whether flavonoids are dietary, generated by the host, or through bacterial metabolism has not been exactly established and requires further investigation.
In conclusion, few studies have reported the gut microbiome profiles in AN chewers, but some studies have shown oral microbiota composition alteration might mirror oral cancer progression in AN chewers [63][64]. However, whether microbial changes are involved in areca nut-induced oral carcinogenesis is only speculative. Further research is required to discern the clinical significance of an altered oral microbiota and the mechanisms of oral cancer development in areca nut chewers. Additional studies are necessary to clarify the precise metabolic intermediates of AN by gut microbiota or the single agent responsible for AN toxicity.

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