Cancer is a major cause of death and one of the most important global obstacles to improving life expectancy in the 21st century (1). Despite significant advances in cancer research, screening and treatment programs, gastrointestinal (GI) tumors have a high morbidity and mortality rate worldwide; according to the 2018 global cancer report, the mortality rate of colorectal cancer was 9.2%, that of gastric cancer was 8.2% and that of liver cancer was 8.2%, which account for the top 5 cancer mortality rates in the world (2). The high incidence of cancer in the digestive system, especially gastric, esophageal and colorectal cancer (CRC), is a major health burden in Asia, particularly in East Asia. Asia had the highest rate of CRC cases per 100,000 population (51.8%) and the highest mortality rate (52.4%) in 2018 (3). Additionally, >727,000 cases of gastric cancer were diagnosed in Asia in 2008, accounting for 11.9% of all confirmed cancer cases (4). Morbidity and mortality rates are also higher in East Asia than in other parts of the continent (4). China has the highest mortality rate of gastric cancer (30.1 per 100,000), followed by Japan (20.5 per 100,000) and South Korea (13.8 per 100,000) (4).

Since Bayer AG distributed acetylsalicylic acid as Aspirin™ in 1899, the drug has cornered the non-steroidal anti-inflammatory drug (NSAID) market, and with time, aspirin has become a generic name (5). Recently, aspirin has received increasing research attention. The effectiveness of low-dose aspirin (LDA) in preventing ischemic cardiovascular events has been confirmed (6–8). There is increasing evidence to support the role that aspirin may play in chemical protection, especially in patients without cardiovascular disease (CVD) (9–11). Using aspirin can reduce mortality rates and the incidence of GI tumors (12). However, aspirin can cause a range of GI side effects; aspirin taken in large doses has anti-inflammatory effects similar to those caused by non-selective NSAIDs in the GI tract (13). LDA is now widely used for cardiovascular prevention, but even at these very low doses it is still associated with upper and lower GI damage (14). In the upper GI tract, aspirin causes a series of adverse GI events, ranging from asymptomatic lesions to serious complications, such as peptic ulcer bleeding or even death (15). The link between aspirin and upper GI damage has been established, but the impact of aspirin on the lower GI tract remains unclear, although evidence has been mounting over the past few years (15,16).

The present review focuses on the advances made in understanding the benefits and the risks of long-term use of aspirin on the GI tract. To provide evidence for the rational use of aspirin in clinical practice, the appropriate dose of aspirin to protect the GI tract is analyzed and summarized.

The main benefit of aspirin in the GI tract is manifested in the chemoprophylaxis of GI adenoma and numerous types of cancer, such as CRC, gastric cancer and familial adenomatous polyposis (FAP). The main pros of aspirin, as will now be described, are also summarized in Table I. Additionally, the present review identified that the chemoprophylaxis dose of aspirin varied among studies. Therefore, the appropriate preventive doses of aspirin used in different studies are summarized in Table I.

The process by which normal cells turn into cancer cells is very complex and despite extensive study, the mechanisms by which aspirin may affect carcinogenesis remain unknown. However, in the early stages of cancer development, a common feature is that cells no longer respond to anti-proliferation and -differentiation signals, instead automatically producing signals to promote growth (54). The role of aspirin may be related to these processes.

One of the mechanisms involved in the anticancer activity of aspirin is commonly thought to be its ability to inhibit the activity of cyclooxygenase (COX) (55,56). COX-2 is strongly and rapidly induced in response to growth factors, cytokines, endotoxins and inflammation, and involves cell proliferation and the promotion of tumor development (57). As aspirin is a potent inhibitor of COX-2, it can reduce the production of prostaglandins and other inflammatory mediators (58). The deleterious effects of prostaglandins include promoting cell survival, stimulating cell proliferation and promoting angiogenesis, which can increase cancer metastasis (59,60).

However, the chemoprophylaxis of aspirin cannot be explained by inhibiting prostaglandin synthesis only, since some NSAIDs are still resistant to proliferation in cells that have no COX activity (61). COX-independent evidence has also been found in recent years, particularly in high-dose aspirin (31,62–65), which has been reported to induce apoptosis through the inhibition of activation of nuclear factor κB (NF-κB), the upregulation of tumor suppressor genes, such as TP53, CDKN1A and BAX, and the downregulation of antiapoptotic genes such as BCL-2 (55). Maintaining homeostasis requires apoptosis, or programmed cell death, to maintain a dynamic balance of the total number of cells in a tissue (66). Previous studies (67,68) reported reduced microsatellite instability and enhanced apoptosis in mismatch repair (MMR)-deficient cells exposed to aspirin, and suggested that aspirin may induce genetic selection for microsatellite stability in a subset of MMR-deficient cells. Aspirin may delete those aberrant stem cells most likely to progress rapidly to cancer (69). Recently, autophagy has been found to play a role in the chemoprevention of cancer by aspirin. It has been reported that LDA can induce autophagic death and inhibit the proliferation of various tumor cells, including HCC and CRC cells (70,71). Adenosine monophosphate-activated protein kinase (AMPK) can inhibit the growth and proliferation of tumor cells by affecting autophagy and inhibiting glycolysis. Recent studies have demonstrated that aspirin can promote the autophagy and apoptosis of tumor cells by activating AMPK (72,73). Aspirin can activate AMPK by the allosteric effect and by inhibiting the dephosphorylation of AMPKα at the Thr 172 site; AMPKα is an important activator of AMPK (74).

In addition, it has been reported that aspirin can stop or delay the growth and mutation of tumor cells instead of killing them directly. Aspirin can reduce the abnormal accumulation of genes in cancer tissues (75). Aspirin may also play a role in the DNA mismatch-repair system, Wnt signaling, NF-κB signaling and polyamine metabolism (76,77). Despite several recognized mechanisms of action for the anticancer effect of aspirin, the exact mechanism remains unknown.

The main cons of aspirin, as will now be described, are also summarized in Table II.

In general, the benefits of aspirin to the GI tract are mainly reflected in cancer prevention. Aspirin can reduce the incidence of gastric cancer, CRC, colorectal adenoma, live cancer and pancreatic cancer, and reduce the risk of Barrett's esophageal progression to esophageal adenocarcinoma. The protective effect of aspirin on CRC and colorectal adenomas is almost certain, especially in older adults at risk for CVD. In April 2016, the United States Preventive Services Task Force formally issued guidelines recommending LDA (75-100 mg/day) to prevent CVD and CRC in people aged 50–69 years with CVD risk but no elevated hemorrhage risk (11). However, the preventive effect for other GI cancer types is still controversial. The effect of aspirin on cancer prevention is mainly reflected after 4–5 years, even at low doses. However, a recent study (ASPREE trial) found that aspirin did not help reduce all-cause mortality (mainly cancer-related mortality, including GI cancer) (100). There are several possible reasons why the results of this study differ from those of previous studies: i) Most previous studies did not regard cancer as a predefined secondary endpoint, nor did they establish systematic approaches for the diagnosis and adjudication of cancer endpoints; and ii) the participants in the aforementioned study were mainly healthy individuals aged ≥70 years, with a median follow-up of 4.7 years, while previous studies mainly focused on people aged <70 and found that the effects of aspirin take 4–5 years to show. The other primary prevention trials of aspirin did not find similar results, suggesting that the deaths reported in the aforementioned study should be interpreted with caution.

Speculation remains as to the risk-benefit ratio of long-term aspirin use and the optimal dose required for effective chemoprevention while minimizing side effects. One of the most representative studies of the effects of different doses of aspirin on the risk of GI cancer is that conducted by Rothwell et al (35). The study found the same effect for 75–300 mg doses of aspirin with regard to the reduction of fatal CRC, with 75 mg daily being as effective as higher doses. The group also observed an absolute risk reduction in colorectal malignancy of ~1.5% after a 5-year period of treatment with at least 75 mg aspirin. However, very low doses of aspirin (e.g., 30 mg/day) are associated with a higher risk of fatal CRC compared with higher doses (34,35). The effective dose of aspirin in order to obtain the associated benefits of the drug in the GI tract varies between trials, although some studies have demonstrated that high-dose aspirin (>500 mg/day) may confer stronger protection than standard dose regimens (28,101). As summarized in Table I, numerous recent trials have challenged this notion, providing evidence for the use of LDA in cancer prevention. This phenomenon may be related to the different pharmacokinetics and pharmacodynamics of aspirin in different environments, and the physiological differences among patient populations (102,103).

The main harmful effects of aspirin on the digestive system are bleeding, ulcers, perforation, dyspepsia and discomfort, while hepatic dysfunction is rare (Table II). One study found that aspirin has low toxicity and leads to a lower incidence of bleeding in the upper GI tract, and that it mainly results in dyspepsia. This study demonstrated that the beneficial effects of aspirin on cancer outweigh the risk of aspirin-induced bleeding events (104). The main risk factors for bleeding in aspirin users are age and H. pylori infection (7,105). Age is a key factor when weighing the pros and cons of aspirin. Once an individual approaches 60 years old, there is a marked increase in the risk of aspirin-induced bleeding events, with a non-linear relationship between increased risk and subsequent age (106,107). Changing drug formulations would not alleviate the adverse effects of aspirin on upper GI mucosa, and neither buffer nor enteric-coated tablets can reduce the risk of massive upper GI bleeding (107,108). According to previous studies, long-term LDA use for >4–5 years still plays a role in the prevention of GI cancer in healthy people aged 55–65 years. Since aspirin takes 4–5 years to have an effect and there is an increased risk of GI side effects in people aged >60, the prophylactic use of aspirin alone in people aged >60 is not recommended. Numerous studies have demonstrated that proton pump inhibitors (PPI) significantly reduce the risk of GI adverse events in aspirin patients (14,89,109–111). H2-receptor antagonists can also inhibit the secretion of gastric acid to a certain extent, but their effect may not be as good as that of PPI preparation (112). This superiority was observed uniformly in the separate clinical circumstances in which these agents are used in peptic ulcer disease, namely the prevention, healing and treatment of acute upper GI bleeding (113). According to the report by the American College of Cardiology Foundation Task Force (Fig. 1) (107), PPI were recommended in association with low-dose aspirin for patients with prior history of ulcer diseases or complicated GI ulcer. For other patients who have more than one risk factor among the categories of corticosteroid use, dyspepsia or gastroesophageal reflux and age >60 years, PPI are recommended. As H. pylori is an important risk factor for ulcer and ulcer bleeding in patients on LDA, a systematic testing for and eradication of H. pylori is recommended before starting aspirin for patients with prior history of ulcer disease (107). The value of PPI combined with aspirin lies not only in its ability to decrease the incidence of adverse events in the upper GI, but also in its ability to decrease the risk of withdrawal of aspirin (114,115). This has been confirmed in both RCTs and observational studies (114,115).

Clinicians always face clinical dilemmas and need to balance the risks and benefits of treatment. The use of aspirin in preventing GI cancer (or adenoma) and the risk of GI damage is one of these situations. In conclusion, the continued prophylactic use of LDA (75–325 mg/day) for at least 4–5 years to prevent GI cancer in non-high-risk populations aged 55–65 years should be considered for several reasons: i) A large amount of evidence suggests that LDA may play a prophylactic role in GI cancer. In addition, LDA causes less damage to the GI tract compared with high-dose aspirin. ii) The negative effects of aspirin to the GI tract are mainly the damage to the upper GI tract. The efficacy of PPI in treating LDA-related gastroduodenal ulcers and bleeding in most populations has been well documented and recognized. iii) Although, there is no effective preventive measure for lower GI bleeding, the clinical significance of LDA-induced lower GI mucosal injury is still unclear. Most studies investigating lower GI bleeding events had small sample sizes with wide CIs. LDA is routinely used in the primary and secondary prophylaxis of CVD. With a globally aging population (116), the consumption of LDA seems likely to increase in the future. Effects of aspirin need to be seen from a risk-benefit perspective, and from all the aforementioned evidence, we believe that the benefits outweigh the risks. However, unanswered questions related to the exact mechanism of cancer-related effects, optimal dose, duration, treatment options, and the balance of risks and benefits among specific populations need to be further investigated. The present review will contribute to continued progress in this exciting area of research.