Substantial human and animal studies support the beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) on colonic inflammation and colorectal cancer (CRC). However, there are inconsistent results, which have shown that ω-3 PUFAs have no effect or even detrimental effects, making it difficult to effectively implement ω-3 PUFAs for disease prevention. A better understanding of the molecular mechanisms for the anti-inflammatory and anticancer effects of ω-3 PUFAs will help to clarify their potential health-promoting effects, provide a scientific base for cautions for their use, and establish dietary recommendations.
There are ~1.8 million new cases of and ~881,000 deaths from colorectal cancer (CRC) every year [1]. It is estimated that ~30% of cancers in developed countries are diet-related [2]. Therefore, it is important to develop effective diet-based prevention strategies to reduce CRC risks. Epidemiological and preclinical data support that ω-3 polyunsaturated fatty acids (PUFAs), such as plant-derived α-linolenic acid (ALA, 18:3ω-3) and marine fish-derived eicosapentaenoic acid (EPA, 20:5ω-3), docosapentaenoic acid (DPA, 22:5ω-3), and docosahexaenoic acid (DHA, 22:6ω-3), may reduce CRC risks, in part, through suppressing colonic inflammation. In contrast, ω-6 PUFAs, such as linoleic acid (LA, 18:2ω-6) and arachidonic acid (ARA, 20:4ω-6), are suggested to exaggerate the development of colonic inflammation and CRC [3][4][5][6][7][8]. This is important because the current Western diet has 30–50-times more ω-6 PUFAs than ω-3 PUFAs. The validation of the beneficial effects of ω-3 PUFAs on CRC will have a significant impact on public health. However, after decades of research, the anti-CRC efficacy of ω-3 PUFAs remains inconclusive, making it difficult to make dietary recommendations or guidelines of ω-3 PUFAs for CRC prevention [9]. The inconsistent results suggest that there could be more complex mechanisms, which may be subject to specific cellular and/or metabolic modulation, involved in the anticancer and anti-inflammatory effects of ω-3 PUFAs. Therefore, it is of critical importance to better understand the mechanisms behind the anticancer and anti-inflammatory activities of ω-3 PUFAs to optimize their use for CRC prevention.
A widely accepted molecular mechanism to explain the potential health-promoting effects of ω-3 PUFAs is that they can compete with ARA (a major ω-6 PUFA) for the enzymatic metabolism catalyzed by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, leading to reduced levels of ω-6-series metabolites (termed eicosanoids) that are predominately proinflammatory and protumorigenic, and/or increased levels of ω-3-series metabolites, which have less detrimental or even beneficial effects [10][11][12][13]. A recent study showed that there is a high degree of interindividual variability in metabolizing ω-3 PUFAs to generate lipid metabolites [14]. Thus, it is feasible that polymorphisms in the genes encoding the ω-3 PUFA-metabolizing enzymes could affect the metabolism of ω-3 PUFAs, impacting the generation of bioactive lipid metabolites in tissues and contributing to observed mixed results in ω-3 PUFA studies [15]. A better understanding of the interactions of ω-3 PUFAs with their metabolizing enzymes could lead to targeted human studies to better understand the metabolic individuality and nutrition effects of ω-3 PUFAs [15][16].
In this review, we summarize recent studies of ω-3 PUFAs on CRC and colonic inflammation (inflammatory bowel disease (IBD)) and discuss the potential roles of ω-3 PUFA-metabolizing enzymes, notably the CYP enzymes, in mediating the actions of ω-3 PUFAs.
Epidemiological and preclinical studies support the preventive effects of ω-3 PUFAs on CRC. In Table 1, we focus on the recent human studies on ω-3 PUFAs, as well as previous studies that have shown the beneficial effect of the ω-3 PUFAs and have been discussed by other review articles. A meta-analysis demonstrated a small but significant ~12% reduction of CRC risk between the highest and lowest ω-3 PUFA consumption groups [17][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. In the VITamins And Lifestyle (VITAL) cohort study, the individuals who routinely took fish oil supplements had lower risks of developing CRC compared with those who did not take supplements [18]. The European Prospective Investigation into Cancer and Nutrition (EPIC) study also showed that increased ω-3 PUFA consumption reduced CRC risks [19]. In a randomized, double-blind, placebo-controlled trial, EPA intake was associated with reduced polyp number and size in familial adenomatous polyposis (FAP) patients [20]. Increased intake of ω-3 PUFAs was also associated with improved disease-free survival in stage III CRC patients [21]. In a phase II double-blind, randomized, placebo-controlled trial, EPA intake increased overall survival in advanced CRC patients undergoing liver resection due to liver metastases (CRCLM) [22]. Together, these studies support the conclusion that ω-3 PUFAs reduce the risks of CRC.
Table 1. Recent epidemiological and clinical studies of ω-3 polyunsaturated fatty acid (PUFA) supplementation for the prevention/treatment of colorectal cancer (CRC).
Study |
Individuals |
N |
ω-3 PUFA treatment |
Dose |
Duration |
Control treatment |
Results |
Reference |
VITAL prospective cohort |
US adults |
68,109 |
Fish oil supplements |
N/A |
4+days/week for 3+years |
no use |
↓ CRC risk |
Kantor et al., 2014 [18] |
EPIC prospective cohort |
European adults |
521,324 |
Highest ω-3 PUFAs intake |
>470 mg/day |
Median 14.9 years |
lowest ω-3 PUFAs intake |
↓ CRC risk |
Aglago et al., 2020 [19] |
Randomized, double-blind, placebo-controlled trial |
FAP patients |
EPA-FFA (n = 28) |
EPA-FFA |
2 g/day |
6 months |
Placebo (n = 27) |
↓ polyp diameters |
West et al., 2010 [20] |
CALGB adjuvant chemotherapy trial |
stage III colon cancer patients |
1011 |
Highest marine ω-3 PUFAs intake |
0.33-0.57 g/day |
>8 years |
lowest marine ω-3 PUFAs intake |
↑ disease-free survival |
Blarigan et al., 2018 [21] |
Double-blind, randomised, placebo-controlled trial |
CRCLM patients |
EPA-FFA (n = 43) |
EPA-FFA |
2 g/day |
12–65 days |
Placebo (n = 45) |
↑ overall survival; no effect in disease burden and early CRC recurrence rates |
Cockbain et al., 2014 [22] |
HPFS and NHS cohort |
US adults |
123,529 |
Highest marine ω-3 PUFAs intake |
≥ 0.30 g/d (women) ≥ 0.41 g/d (men) |
24–26 years |
lowest marine ω-3 PUFAs intake |
No effect on overall CRC risk; ↑ distal colon cancer risk in men and women; ↓ rectal cancer risk in men |
Song et al., 2014 [23] |
Randomized, double-blind, placebo-controlled clinical trial |
colon cancer patients |
ω-3 PUFA (n = 21) |
ω-3 PUFA intravenous infusion |
0.2 g/ kg/day |
night before and morning after resection surgery |
Saline infusions (n = 23) |
↑ infectious complications |
Bakker et al., 2020 [24] |
Abbreviations: VITAL, VITamins And Lifestyle; EPIC, European Prospective Investigation into Cancer and Nutrition; EPA, eicosapentaenoic acid; FFA, free fatty acid; FAP, familial adenomatous polyposis; CALGB, Cancer and Leukemia Group B; CRCLM, colorectal cancer liver metastases; HPFS, Health Professionals Follow-Up Study; NHS, Nurses' Health Study.
Consistent with the human studies, recent animal studies also support the beneficial effects of ω-3 PUFAs on CRC (Table 2). Treatment with an ω-3 PUFA mixture or EPA reduced intestinal polyposis formation in a spontaneous intestinal cancer model (using ApcMin/+ mice) [25,26][25][26]. Dietary administration of EPA also decreased tumor incidence and multiplicity in a chemically induced colitis-associated colorectal cancer (CAC) model [27]. In addition, administration of fish oil suppressed the aberrant crypt foci number and adenoma incidence in 1,2-dimethylhydrazine (DMH) or azoxymethane (AOM)-induced CRC models in rats [28,29][28][29]. Besides dietary feeding studies using ω-3 PUFAs, previous studies also showed that fat-1 transgenic mice, which have higher tissue levels of ω-3 PUFAs, have reduced development of CRC in both Apc gene mutation-induced CRC model [30] and chemically induced CAC model [31,32][31][32].
In addition to the orthotropic CRC tumor models discussed above, ω-3 PUFAs have also been shown to inhibit CRC in xenograft and metastasis models. Our recent study showed that administration of an ω-3 PUFAs-enriched diet inhibited MC38 (murine colon adenocarcinoma cell) tumor growth in a murine xenograft model [33]. Consistent with our result, fish oil- or DHA-rich diets attenuated tumor burden and aggressivity in HCT-116 or SW620 (both are human colon cancer cells) xenograft tumor models in nude mice [34-36][34][35][36]. In a MC-26 colon cancer cell-induced CRC metastasis model, treatment of EPA suppressed liver metastases in BALB/c mice [37]. In a CC531 colon cancer cell-derived liver metastasis model in rats, administration of an ω-3 PUFAs-rich diet reduced hepatic tumor incidence and burden [38]. Moreover, ω-3 PUFAs could be used to enhance the actions and reduce the toxicity of anticancer drugs. The coadministration of oxaliplatin and DHA synergistically inhibited HCT-116 xenograft tumor growth in nude mice [35]. Overall, these results support the anti-CRC effects of ω-3 PUFAs.
Human and animal studies also support that the dietary intake of ω-3 PUFAs-rich foods, such as fish, flaxseed, and walnuts, reduces the risks of CRC. In the EPIC cohort study, the consumption of ω-3 PUFAs-rich fish was linked with lower risks of developing CRC [19]. Stage III CRC patients who regularly consumed dark fish (≥1 time per week) had increased disease-free survival rates and lower cancer recurrence/motility risks compared to those who did not [21]. Consistent with the human studies, the administration of a flaxseed-rich diet reduced aberrant crypt foci formation in both proximal and distal colon in an AOM-induced CRC model in rats [39]. The intake of a walnut-added diet also attenuated tumor growth in a HT29 cell-induced CRC xenograft model in mice [40]. ω-3 PUFAs could exhibit beneficial effects via regulating microbiota during CRC. The administration of EPA increased the abundance of Lactobacillus in a CAC cancer model in mice [27]. The intake of EPA and DHA mixture could also increase the levels of Bifidobacterium, Roseburia, and Lactobacillus in humans [41]. Though more studies are needed to determine the extent to which food components, besides the ω-3 PUFAs, contribute to the observed anti-CRC effects, these results further support the beneficial effects of ω-3 PUFAs on CRC.
Though many studies support the beneficial effects of ω-3 PUFAs on CRC, there are inconsistent results from animal and human studies. Some reports, in fact, have shown that ω-3 PUFAs had no effect [42,43][42][43] or even detrimental effects on the development of CRC [44,45][44][45] (Table 1–2). The Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS) cohort studies showed that ω-3 PUFA intake had no effect on overall CRC risks, and even increased distal colon cancer risk in certain individuals [23]. The supplementation of ω-3 PUFAs had no effect on the recurrence or survival rate in stage III colon cancer patients [46]. Moreover, in a randomized, double-blind, placebo-controlled clinical trial, compared with saline infusion, intravenous infusions of ω-3 PUFAs worsened the infectious complications in CRC patients undergoing colon resection [24]. Other postoperative complications were also reported in CRC patients who received ω-3 PUFAs after surgery [47]. Animal studies also showed that the treatment of fish oil exacerbated Helicobacter hepaticus-induced colitis and adenocarcinoma in SMAD3-deficient mice [45]. These inconsistent results make it difficult to effectively implement ω-3 PUFAs to reduce the risks of CRC.
Table 2. Preclinical studies of ω-3 PUFA supplementation for the prevention/treatment of CRC.
Model |
Species |
ω-3 PUFA treatment |
Dose |
Duration |
Control treatment |
Results |
Reference |
ApcMin/+ mouse |
C57BL/6 mouse |
Fish oil |
12% in diet |
10 weeks |
Standard diet with soybean oil |
↓ intestinal polyp growth |
Notarnicola et al., 2017 [25] |
ApcMin/+ mouse |
C57BL/6 mouse |
EPA-FFA |
2.5% or 5% in diet |
12 weeks |
AIN-93G diet with soybean oil |
↓ polyp number and load in both small intestine and colon. |
Fini et al., 2010 [26] |
ApcMin/+ mouse |
C57BL/6 mouse |
Endogenous ω-3 PUFA synthesis by transgene of fat-1 |
20 weeks |
ApcMin/+ mice on standard diet with safflower oil |
↓ intestinal polyposis |
Han et al., 2016 [30] |
|
AOM/DSS-induced CRC model |
C57BL/6 mouse |
Endogenous ω-3 PUFA synthesis by transgene of fat-1 |
16 weeks |
Wild‐type mice on standard diet |
↓ Tumor number |
Han et al., 2016 [31] |
|
AOM/DSS-induced CRC model |
C57BL/6 mouse |
Endogenous ω-3 PUFA synthesis by transgene of fat-1 |
11 weeks |
Wild‐type mice on AIN-93G diet with safflower oil |
↓ incidence and growth rate |
Nowak et al., 2007 [32] |
|
AOM/DSS-induced CRC model |
C57BL/6 mouse |
EPA-FFA |
1% in diet |
15 weeks |
AIN-93G diet with corn oil |
↓ tumor multiplicity, incidence and maximum tumor size |
Piazzi et al., 2014 [27] |
DMH-induced CRC model |
Wistar rat |
Fish oil |
18% in diet |
36 weeks |
AIN-93G diet with soybean oil |
↓ number of aberrant crypt foci; ↓ incidence of adenoma |
Moreira et al., 2009 [28] |
AOM-induced CRC model |
F344 rat |
Fish oil |
10% in diet |
26 weeks |
AIN-93G diet with mixed lipids |
↓ colon tumor incidence and multiplicity |
Reddy et al., 2005 [29] |
MC38 cell-based xenograft model |
C57BL/6 mouse |
DHASCO Algae oil |
8% in diet |
5 weeks |
AIN-93G diet with corn oil |
↓ tumor volume and weight |
Wang et al., 2016 [33] |
SW620 cell-based xenograft model |
Nude mouse |
Fish oil |
12% by calorie |
6 weeks |
Standard diet |
↓ tumor growth and less aggressive |
Bathen et al., 2008 [34] |
HCT116 cell-based xenograft model |
Nude mouse |
DHA |
10mg/kg |
every other day for 13 days |
Ethanol |
↓ tumor size |
Jeong et al., 2019 [35] |
HCT116 cell-based xenograft model |
Nude mouse |
DHA |
3% in diet |
14 days |
Standard diet with sunflower oil |
↓ tumor growth |
Fluckiger et al., 2016 [36] |
H. hepaticus-induced CRC model |
SMAD3 deficiency mouse |
Fish oil |
6% in diet |
12 weeks |
AIN-93G diet with corn oil |
↑ adenocarcinoma formation |
Woodworth et al., 2010 [45] |
Abbreviations: AIN, American Institute of Nutrition; AOM, azoxymethane; DSS, dextran sodium sulfate; DMH, 1,2-Dimethylhydrazine; i.p. intraperitoneal; SMAD3, mothers against decapentaplegic homolog 3.
IBD, which is characterized by chronic inflammation in intestinal tissues, severely impacts the quality of life of the patients. Symptoms include abdominal pain, vomiting, diarrhea, and rectal bleeding. The incidence and prevalence of IBD have risen dramatically in recent decades: In 2015, ~1.3% of US adults (3 million) were estimated to be diagnosed with IBD [48], representing a 50% increase from 1999 (2 million) [49]. To date, there is no cure for IBD, and the current anti-IBD treatments could lead to serious side effects, including infection, bone marrow dysfunction, and organ dysfunction [50]. Therefore, it is important to develop novel preventive strategies to reduce the risks of IBD.
Human and animal studies support the beneficial effects of ω-3 PUFAs on the development of IBD. The intake of fish oil reduced the abundance and activity of cytotoxic NK cells and improved the disease condition in IBD patients [51]. Fish oil also decreased disease activity index and reduced neutrophil infiltration in ulcerative colitis (UC, a subtype of IBD) patients [52,53][52][53]. In animal models, ω-3 PUFAs suppressed T cell-transplantation-induced colitis in severe combined immunodeficient (SCID) mice [54]. The treatment of a ω-3 PUFA (using linseed oil)-rich diet reduced the incidence of ovalbumin-induced allergic diarrhea in a food allergy mouse model [55]. The intake of ω-3 PUFAs, especially the EPA, reduced tissue damage and IBD-associated diarrhea, bloody stools, and weight loss in dextran sodium sulfate (DSS)-induced colitis models in mice and rats [56-58][56][57][58]. In ischemia-reperfusion (IR) rats, the intake of ω-3 PUFA-attenuated IR-induced mucosal injury in intestine [59]. In addition to the nutritional intervention of ω-3 PUFAs, fat-1 transgenic mice, which have higher tissue levels of ω-3 PUFAs, have been shown to exhibit reduced colonic inflammation in DSS- or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis [60,61]. ω-3 PUFAs mainly exhibit beneficial effects via regulating immune cell infiltration during IBD. The administration of ω-3 PUFAs reduced the colonic infiltration of neutrophils [53[53][58],58], macrophages [62][62], T cells [54], and NK cells [51] [51] in IBD mice and patients. Moreover, ω-3 PUFAs have been shown to decrease proinflammatory cytokines (TNF-α, IL-12, IL-1β, iNOS, and/or IL-6), enhance epithelial barrier function, upregulate antioxidative enzymes, and reduce lipid oxidation-derived compounds [54[54][57][58][59][60][61],57-61], and therefore inhibit the development of IBD in mice or rats.
There are also inconsistent reports, which have shown that ω-3 PUFAs have no effect or even adverse effects on IBD. In randomized, placebo-controlled trials, ω-3 PUFAs intake has had no effect in improving the recovery of colitis [63[63][64],64], and has even enhanced disease activity in UC patients [65]. Moreover, ω-3 PUFAs had no effect on either chemotherapy-induced enterocolitis in acute myeloid leukemia (AML) patients [66] or type 2 diabetes-induced duodenal inflammation in obesity patient [67]. In animal models, the treatment of fish oil has had little effect on DSS- or TNBS-induced colitis in rats [68[68][69],69], and has exacerbated the DSS-induced colitis in mice [70]. ω-3 PUFAs have also been shown to exaggerate chemotherapy (5-fluorouracil)-induced small intestine damage in rats [71].
Overall, the effects of ω-3 PUFAs on CRC and IBD are controversial, making it difficult to effectively use ω-3 PUFAs for disease prevention. There are several possible reasons for the mixed results in ω-3 PUFA studies.