Since the discovery of H. pylori as a cause of peptic ulcer disease in 1983, this bacterial infection continues to be a major public health issue worldwide. The prevalence of H. pylori infection varies by geographic area, age, ethnicity and socioeconomic status; in fact, the prevalence is higher in developing countries and in those in poor socioeconomic conditions [53]. Traditionally, Western and Eastern countries have different H. pylori infection rates in their general populations. The prevalence is highest in Africa (79.1%), Latin America and Asia (54.7%). On the other hand, the H. pylori infection rate is lowest in Northern America (37.1%) and Oceania (24.4%)[54,55].
H. pylori infection is the main cause of chronic gastritis and peptic ulcer disease and is the main carcinogen for gastric malignancy disease[56]. In the extragastric system, H. pylori infection has also been reported to be related to inflammatory bowel disease, colorectal neoplasms, and cardiovascular disease; to contribute to insulin resistance, associated metabolic syndrome, diabetes, autoimmune disease, and kidney disease; and to be associated with neurodegenerative disease, respiratory disease and hematologic disease [57,58]. In these studies, most scientists addressed the topic of H. pylori infection related to colorectal neoplasm formation[3,6,8,9,19, 21-42].
Now that it is known that H. pylori is an infectious disease, it can be cured with a course of antibiotics. In recent studies, H. pylori infection rate decreased due to public health improvement in developed countries and some developing countries. In many countries, the incidence of H. pylori infection has been decreasing in association with improved standards of living and levels of hygiene. However, as the prevalence rate of H. pylori infection remains high in most developing countries and is generally related to socioeconomic status, it remains one of the most important diseases in these areas[55]. Hong et al. published a meta-analysis of H. pylori infection and increased the risk of colorectal adenoma formation. In this study, he focused on Eastern or Western studies for subgroup analysis and found that the ORs of these two groups were similar[25]. This means that even the H. pylori infection prevalence was different in Eastern and Western countries, and this bacterial infection still increased colorectal adenoma formation. Although the detail mechanism of the relation between H. Pylori infection and colorectal adenoma formation was not clear. Butt J. stated H. pylori infection might contribute to colorectal carcinogenesis by direct or indirect effect. In direct effect, H. pylori might secrete toxins and present in the respective colorectal tissue. On the other hand, the indirect effect included several hypotheses. First, H. pylori infection could lead to changes in the colonization of the gut with other bacteria and then could induce colorectal carcinogenesis. Second, the gastrin level might increase after H. pylori infection and gastrin might act as mitogen. Third, H. pylori was found to be associated with metabolic diseases that associated with CRC risk. [59]
It also hints to a link between H. pylori infection and colorectal adenoma formation, which may be due to the third factor in this connection.
Unlike H. pylori infection disease, the prevalence of DM in the global world has persisted. The age-standardized DM prevalence increased from 4.3% in 1980 to 9.0% in 2014 in men and from 5.0% to 7.9% in women [60]. The rise in prevalence might be due to population growth and aging, as the number of adults with diabetes has increased nearly 4-fold over the past 35 years. The prevalence and number of adults with diabetes both increased and doubled in men and increased by 60% in women worldwide, shifting from an excess prevalence in women in 1980 to a higher male prevalence in 2014[61]. Persistent high blood sugar concentrations lead to damage to the blood vessels and peripheral nerves. This situation might result in an increased risk of cardiovascular diseases, such as heart attack and stroke, kidney disease, diabetic retinopathy and foot amputations [62]. DM is also considered an increased risk factor for colon adenoma and carcinoma [63]. These DM-related complications lead to higher costs for the health care system [64] as well as lower quality of life and reduced life expectancy [65].
A past study showed that DM prevalence was low in much of Asia and sub-Saharan Africa in the 1980s and 1990s [57,66]. However, several recent reports have demonstrated that the DM prevalence has increased in China, India, Turkey and Saudi Arabia [67-70]. Some high-income English-speaking countries, such as the USA and the UK, [71,72] also reported increased DM prevalence. On the other hand, DM prevalence did not increase in Western Europe, and some reports from Sweden, Germany and Switzerland showed similar results [73,74]. In accordance with a previous statement and based on geographical distribution, the prevalence of H. pylori infection and DM seems to be inversely related. In our study, when the background population DM prevalence was below 6%, H. pylori infection did not significantly increase the risk of colorectal adenoma formation (Group 1). This association became significant when the study population DM prevalence was over 6% (Group 2-4). The odds ratio of H. pylori infection-related colorectal formation was 2.16 (95% CI 1.61–2.91); it was the highest when the population DM prevalence was from 6~8% (Group 2). However, when the DM prevalence rate was elevated to 8~10% or more than 10% (Group 3, Group 4), the OR was mildly decreased to 1.40 (95% CI 1.24–1.57) and 1.52 (95% CI 1.46–1.57). H. pylori infection still significantly increased colorectal adenoma but was not distinct from Group 2 (DM prevalence between 6 and 8%). However, when DM prevalence increased, H. pylori infection might increase the risk of colorectal adenoma formation.
The cause of this condition may be related to the study period and location. Most studies in group 2 were carried out from 1996 to 2000, and group 3 studies were carried out from 2000 to 2010. The study’s location may also affect this result. Most of the Group 3 studies were from Korea, and Group 4 studies were from the USA. The Group 2 studies were more heterogeneous in location, including Japan, Taiwan, Turkey, Israel and Germany. The H. pylori infection rate of the study population was also collected and is shown in Table 1. There was no significant difference in the ORs of H. pylori infection-associated colorectal adenoma between the lower infection rate area (USA or Germany, 35.3% to 35.6%) and the middle infection rate area (Japan, Korea, China, Taiwan; approximately 51.7% to 55.8%). Further evaluation for the other reason that Group 2 studies revealed higher ORs in H. pylori infection- associated colorectal adenoma is necessary. In addition, our study might partially answer Plummer’s query “How to explain that some areas had a high prevalence of H. pylori infection but low CRC risk?” [10] According to our study, we could see that Brazil et al. had a higher H. pylori infection prevalence (71.2%) but a lower DM prevalence rate (5.8%). (Table 1) Buso’s study demonstrated that the H. pylori infection proportion did not significantly increase colorectal adenoma risk (OR: 1.98, 95% CI 0.82-3.15). [34] However, when the DM prevalence was higher (> 10%), even when the H. pylori infection rate was lower (35.6%), the OR of colorectal adenoma with H. pylori infection was significantly increased (Group 4: OR: 1.52, 95% CI 1.46-1.57). This means that the DM prevalence rate might be the key factor of increased colorectal adenoma risk with H. pylori infection.
Our previous study demonstrated the interaction of hyperglycemia and H. pylori infection in colon adenoma formation. We found that the OR for adenoma was 1.437 (95% CI 1.197–1.726) if H. pylori was present or 1.629 (95% CI 1.239–2.14) if HbA1c ≥ 6.5. When combining these two factors, the OR was elevated to 4.712 (95% CI 3.189– 6.963), suggesting that these two factors may have a synergistic effect in colorectal adenoma [19]. The likely reason for the synergistic effect may involve several processes. First, hyperglycemia status affected gastrointestinal morphology and function and resulted in gut barrier loss and changes in intestinal mucosa permeability. Second, high-fat and high-caloric diets also increase gut permeability, and this situation was more significant in DM patients [75]. Third, some intestinal microorganism-related products, such as lipopolysaccharides, would more efficiently pass through the gut barrier and stimulate the Toll-like receptors in the mucosa. This would trigger a serious inflammatory process, and finally, IL-17 and IL-6 will increase. IL-17 activates the signal transducer and activator of the transcription 3 pathway, promoting cell proliferation and survival and finally inducing tumorigenesis [76].
These animal models and individualized study results support this study finding that states that an elevated DM prevalence rate enhances the risk of colorectal adenoma in H. pylori-infected populations. Our study still had several limitations. First, in our subgroup analysis, we found that the Group 2 studies had more heterogeneity. The reason for this condition may be related to population studies with differences in study location, population, aging, and gender. Despite this heterogeneity, H. pylori infection also increased the risk of colorectal adenoma. Second, the asymmetry of the results of Egger’s test and funnel plots suggested the possibility of publication bias. However, because most of our included studies [3,6,8,9,19, 21-42] had statistically significant results, Egger’s test and funnel plots would show asymmetry. Third, the population DM prevalence rate might not completely represent our included studies participant’s diabetes condition. Only Lin et al. [24] and Hu et al. [19] included the DM prevalence rate in their studies. To the best of our knowledge, we tried to estimate the diabetes rate of each study as accurately as possible.