Association and mechanism of garlic consumption with gastrointestinal cancer risk: A systematic review and meta-analysis

Abstract

Gastrointestinal cancer is one of the most commonly diagnosed cancer type worldwide, with millions of cases per year. The aim of this review was to investigate the relationship between garlic intake and the risk reduction of gastrointestinal cancer. We performed saturated data mining on various public domain databases, including PubMed (https://pubmed.ncbi.nlm.nih.gov/), Embase (https://www.embase.com/landing?status=grey), and Cochrane Library (https://www.cochranelibrary.com/), with key terms including: 'garlic', 'allium', 'stomach', 'gastric', 'colon', 'neoplasms', 'cancer' and 'tumor'. Furthermore, we identified additional references through expert manual curation. Finally, a meta-analysis was conducted to determine whether garlic intake reduces the risk of gastric and/or colorectal cancer. The association between garlic intake and reduction in the risk of gastric cancer [odds ratio (OR)=0.65, 95% confidence interval (CI)=0.49-0.87, P<0.001] were clear. Nine studies on garlic intake and colorectal cancer showed that garlic reduced cancer risk with a statistical significance (OR=0.75, 95% CI=0.65-0.87, P<0.001). We summarized that four main organic sulfides in garlic, diallyl disulfide (DADS), diallyl trisulfide (DATS), S-allylmercaptocysteine (SAMC) and allicin, may contribute to the regulation of tumor cell apoptosis, migration and the cell cycle. We identified the association between garlic intake and reduced risk of gastric and colorectal cancers and hypothesized that the active ingredients in garlic may act on multiple pathways to reduce the risk of gastrointestinal tumors according to published papers. Importantly, the potential tumor-preventing effect of these garlic ingredients warrants further investigation in regards to the specific mechanism of the underlying antitumor activities.

Keywords: garlic; gastric cancer; gastrointestinal cancer; meta-analysis.

Figure 1.

Flow diagram of the included studies. A total of 648 articles were initially searched, of which 226 articles were excluded as duplicate studies. Then we reviewed the titles and abstracts of each literature according to inclusion and exclusion criteria. We excluded additional articles, among which 323 were irrelevant to this study, 54 were meta-analyses and reviews, and 14 were non-English literature. After a careful review of the full texts in the remaining 31 articles, we finally included 20 articles after excluding 4 articles from the same study and 7 articles with insufficient data. OR, odds ratio; RR, relative risk.

Figure 2.

Associations between garlic intake and gastrointestinal cancer risk by garlic consumption. The (number/number) after each study in the figure indicates the (Cases/Controls). Vertical solid black line: invalid line; red dashed line: pooled effect size; horizontal black solid line: the width of the line represents the confidence interval (CI) of each study, the black diamond in the middle represents the OR of each study, and the gray square represents the weight of each study. Others: We have included some studies that differed from other classifications of garlic intake into this category. (A) Forest plots for the associations between garlic intake and gastric cancer risk by garlic consumption. The OR obtained by the pooled analysis was 0.65 (95% CI=0.49-0.87). (B) Forest plots for the associations between garlic intake and colorectal cancer risk by garlic consumption. The meta-analysis using the random-effects model showed a combined estimated OR of 0.75 (95% CI=0.65-0.87), suggesting that garlic intake could reduce the risk of colorectal cancer. OR, odds ratio; ES, effect size.

Figure 3.

Positive and negative association studies between garlic intake and gastric cancer. The (number/number) after each study in the figure indicates the (Cases/Controls), Vertical solid black line: invalid line; red dashed line: pooled effect size; horizontal black solid line: the width of the line represents the confidence interval (CI) of each study, the black diamond in the middle represents the OR of each study, and the gray square represents the weight of each study. Among the 11 included studies, 2 studies showed that garlic intake had no association with the incidence of gastric cancer (OR=1.36, 95% CI=0.93-1.99), including 12,6976 subjects, and 9 studies showed that garlic intake could reduce the incidence of gastric cancer (OR=0.54, 95% CI=0.41-0.70), including 9,944 subjects. OR, odds ratio; ES, effect size.

Figure 4.

Source of heterogeneity in the meta-analysis of garlic intake and gastrointestinal cancer risk. (A) The Galbraith test indicating the source of heterogeneity in the meta-analysis of garlic intake and gastric cancer risk. The studies of Gao et al (1999) and Kim et al (2018) were the main sources of heterogeneity. (B) The Galbraith test indicating the source of heterogeneity in the meta-analysis of garlic intake and colorectal cancer risk. The results indicate that 3 studies (Wu et al, Levi et al, and Wang et al) were the main sources of heterogeneity.

Figure 5.

Sensitivity analysis of garlic and gastrointestinal cancer. (A) Sensitivity analysis of garlic and gastric cancer. No significant differences were found among the studies. (B) Sensitivity analysis of garlic intake and colorectal cancer. The results of the sensitivity analysis showed that no articles exceeded the limits and there were no significant differences among the studies.

Figure 6.

Relationship between included studies and risk of gastrointestinal cancer by garlic intake. In all the included studies, the results of most studies indicated that garlic can reduce the risk of gastrointestinal cancers. OR, odds ratio.

Figure 7.

Potential publication bias assessed by Begg's test. Funnel plot indicating the publication bias in the studies included in the meta-analysis of the garlic intake and gastrointestinal cancers. There was no significant evidence of publication bias for gastric and colorectal cancers. (A) Begg's funnel plot for garlic intake and gastric cancer. (B) Begg's funnel plot for garlic intake and colorectal cancer.

Figure 8.

Potential molecular mechanisms of the anticancer effects of garlic. (A) DADS, DATS, SAMC and allicin can all promote the release of cytochrome c from mitochondria, thereby activating the caspase family proteins, such as caspase 3 and caspase 9, and inducing apoptosis; DADS, DATS and SAMC can activate the p53 pathway, resulting in decreased expression of Bcl-2 and increased expression of Bax. SAMC and DATS significantly activated the three pathways of MAPKs, including ERK, JNK and p38. In addition, the Wnt/β-catenin pathway plays a key role in the occurrence and development of tumors, DATS can significantly upregulate the level of GSK3β, thereby increasing the digestion of β-catenin, indicating that DATS can inhibit the Wnt/β-catenin pathway. DATS can also increase ROS production and activate the AMPK pathway. Allicin can reduce phosphorylated STAT3, thereby inhibiting the STAT3 pathway, and allicin can also activates Nrf2 and induces its translocation to the nucleus. Moreover, DADS can inhibit MMP-2 and MMP-9. (B) DADS and DATS can activate the P53/P21 pathway, and DADS can also inhibit the expression of cyclin B1, cdc2, and cdc25c proteins, leading to G2/M phase arrest of tumor cells. SAMC and DADS can affect the polymerization of tubulin and thus affect the function of the spindle, leading to mitotic arrest. Finally, allicin induces cell cycle arrest in the S phase. DADS, diallyl disulfide; DATS, diallyl trisulfide; SAMC, S-allylmercaptocysteine; GSK3β, glycogen synthase kinase 3 β; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; MMP, matrix metalloproteinase.