Epidemiology and risk of colorectal cancer in patients with a history of Helicobacter pylori infection: a population-based study

Introduction

The prevalence of colon cancer is rising in the developing countries and it is the third leading type of cancer in the world [1]. In the United States (US), it is the second most common cause of cancer-related death [2]. Numerous modifiable risk factors have been associated with the disease, including alcohol consumption, obesity, smoking history, and a diet rich in processed and red meat [3]. A history of inflammatory bowel disease, a family history of colorectal cancer (CRC), and age are non-modifiable risk factors that have also been associated with colon cancer. Some evidence of an association of CRC with pathogenic bacterial infection, including Fusobacterium nucleatum, Escherichia coli, Bacteroides gragilis, and Salmonella enterica, have been described in the literature [4].

Helicobacter pylori (H. pylori) is the most common bacterial infection worldwide and the strongest known risk factor for gastric cancer [5]. There is sparse evidence in the literature for the association of CRC with H. pylori infection [1,6-9]. Only one population-based study illustrated the increased risk of colorectal adenoma in patients with H. pylori-related gastritis [10]. Therefore, we aimed to assess whether the risk of CRC is greater in patients with a history of H. pylori infection.

Materials and methods

Results

Descriptive epidemiology

A total of 80,749,290 individuals were screened and of these 47,714,750 were selected after application of the inclusion and exclusion criteria. The baseline characteristics of our cohort are displayed in Table 1. The 20-year-period prevalence rate of CRC in the US population from 1999 to September 2022 was 370 per 100,000 individuals (0.37%). When the prevalence of CRC was compared among different ethnic and age groups, it was found to increase with age in all ethnic groups. Interestingly, Hispanic and Asian patients had a peak in CRC prevalence earlier in life (30- to 40-year group age category), as illustrated in Fig. 1.

Table 1 Baseline characteristics of patients with colorectal cancer (CRC) and controls

Figure 1 Prevalence of colorectal cancer (CRC) among different age and ethnic groups

Caucasian (70.31%) and Asian race (2.98%), T2DM (17.04%), hyperlipidemia (30.61%), obesity (21.23%), a positive serological test for H. pylori infection (0.34%), IBS (3.40%), smoking (16.32%), and alcohol use (2.74%) were more common in patients with CRC compared to controls.

Risk and predictors of CRC using univariate regression analysis

The risk of being diagnosed with CRC was greater in smokers (odds ratio [OR] 3.65, 95% confidence interval [CI] 3.30-3.42), obese patients (OR 3.70, 95%CI 3.63-3.76), those with IBS (OR 3.19, 95%CI 3.07-3.32), or T2DM (OR 4.60, 95%CI 4.52-4.69), and patients who had a history of H. pylori infection (OR 3.92, 95%CI 3.52-4.36) (Table 2).

Table 2 Risk of developing CRC according to a univariate regression analysis model

Risk and predictors of CRC using a multivariate regression analysis

In order to adjust for confounding variables, a multivariate regression analysis was performed. The risk of CRC was greater in smokers (OR 2.52, 95%CI 2.47-2.57), obese patients (OR 2.26, 95%CI 2.22-2.30), those with IBS (OR 2.02, 95%CI 1.94-2.09), or T2DM (OR 2.89, 95%CI 2.84-2.95), and patients who had a history of H. pylori infection (OR 1.89, 95%CI 1.69-2.10) (Fig. 2).

Figure 2 Forest plot for risk of developing colorectal cancer

IBS, irritable bowel syndrome; T2DM, type 2 diabetes mellitus; H. pylori, Helicobacter pylori

Discussion

H. pylori plays an important role in the development of gastric cancer [16]. However, most of the people infected with the bacteria will not develop cancer. The risk of gastric cancer secondary to H. pylori is altered by the polymorphic nature of the bacterial population in the host, the host genotype, and environmental exposures [17]. A number of factors, including cytotoxin-associated antigen A (CagA) proteins, HP-NAP, oipA and dupA, play a role in the virulence of the bacteria and determine the pattern of the disease [18]. Infection with H. pylori leads to chronic inflammation of the stomach lining, predisposing infected individuals to gastric malignancy.

H. pylori infection has also been associated in some studies with the development of colorectal adenoma [7,10] and carcinoma [7,10,19,20]. One study showed significant numbers of H. pylori in tubular and tubulovillous adenoma [19]. The presence of H. pylori is associated with gastrin secretion [7]. There is some evidence demonstrating that it might play a role in the development of CRC [21,22]. In one study, hypergastrinemia has been associated with a statistically significantly greater risk of colorectal malignancy [23]. In fact, gastrin could contribute to CRC by inducing a higher proliferation of colonic mucosal cells [24]. Other studies suggested that gastrin antagonism inhibits the growth of CRC cells in vitro [25,26]. Another potential mechanism involves changes in the colonization of the gut by H. pylori infection, which could contribute to CRC [27]. However, the association of gastrin with the development of CRC is still controversial [24]. One study showed that there was no difference in the seroprevalence of H. pylori in patients with colon polyp or cancer compared to the control group [16]. Other cohorts demonstrated that neither hypergastrinemia nor a seroprevalence of H. pylori was associated with an elevated risk of recurrence of colon adenoma [28,29].

One abstract reported a study that used a nationwide inpatient sample database and found an increased risk of CRC in patients with H. pylori infection [30]. However, only univariate regression analysis was used. Therefore, we considered that conducting a multicenter national study to assess the risk of CRC in patients with a history of H. pylori infection would be of high clinical value if confounding variables were held constant. To the best of our knowledge, we are reporting the first and largest population-based cohort demonstrating an independent risk of CRC in patients with a history of H. pylori infection based on positive serological testing. It is important to note that our results only illustrate a positive correlation between a history of H. pylori infection and the development of CRC and do not establish any direct causality. Moreover, despite the fact that the risk of developing CRC in patients with IBS is still controversial in the current literature [31,32], it is important to note that our study demonstrated a significantly elevated OR of 3.19 (95%CI 3.07-3.32).

Our article also shows a different age distribution of the prevalence of CRC among different ethnic groups (Fig. 1): Asian and Hispanic populations had an earlier peak of CRC prevalence. One study found that Japanese Americans and African American women are at higher risk of CRC relative to whites [33]. Another population-based study found that the specific CRC incidence rates were higher in Blacks and lowest in Latinos [34]. Differences in CRC epidemiology among ethnic groups could be explained in part by genetics, environmental exposure and access to health care services [33,35]. In fact, further studies would be needed to evaluate the effect of socioeconomic status on the risk of developing CRC in patients who have an active or past history of H. pylori infection. Furthermore, it would be interesting to compare the risk of developing CRC in patients who have received treatment for H. pylori infection vs. those who did not.

Nevertheless, our study has several limitations. First, it was limited by the use of a large research database that could lead to overpowering and overestimation of the measured outcomes. However, the Explorys database has been validated in multiple fields, including gastroenterology [14,15]. Second, some variables were not accessible; therefore, we could not control for patients who had a history of radiation therapy or a history of CRC, or those who had been using aspirin. Third, the diagnosis of H. pylori infection is based on serological studies, which cannot differentiate between active and past infection. Therefore, care must be taken in interpreting the results of this study, as it is limited by the fact that the risk of CRC was higher in patients who had either an active or a past history of H. pylori infection. In other words, no temporal association between the development of CRC and the time of H. pylori infection can be inferred from this study.

In conclusion, we have reported the first and largest population-based study demonstrating an independent positive association between the risk of CRC and a history of H. pylori infection. An increasing amount of evidence for this association exists in the literature, but it has not yet been established on a large scale.