Metabolic dysfunction-associated steatotic liver disease mediates the relationship between Helicobacter pylori infection and colorectal adenoma risk

Abstract

BACKGROUND

There is a potential connection between Helicobacter pylori (H. pylori) infection, metabolic dysfunction-associated steatotic liver disease (MASLD) and colorectal adenoma.

AIM

To determine whether H. pylori infection and MASLD increase the probability of developing colorectal adenomas, and to analyze whether there is an interaction or mediation effect between these two risk factors.

METHODS

The study followed a retrospective cross-sectional design. Patients attending the Second Medical Center of Chinese PLA General Hospital for check-up between 2017 and 2021 were consecutively enrolled. We collected patients' basic information, laboratory test results, colonoscopy findings, H. pylori test results, and ultrasound data. Multivariate logistic regression analysis, interaction, and mediation effect tests were employed to assess the relationship between H. pylori infection, MASLD, and the risk of colorectal adenomas.

RESULTS

Of the 10066 participants, 29.40% had colorectal adenomas, 36.78% had H. pylori infection and 53.55% had MASLD. Adjusted multivariate analysis showed that both H. pylori [adjust odds ratio (aOR) = 1.3, 95%CI: 1.2-1.4, P < 0.001] and MASLD (aOR = 1.3, 95%CI: 1.2-1.5, P < 0.001) independently raised adenoma risk, with no interaction (P = 0.1836). MASLD might act as a mediator of the increased colorectal adenoma risk associated with H. pylori infection (mediation effect = 0.0009, 95%CI: 0.0002-0.0027, P = 0.0180).

CONCLUSION

H. pylori infection and MASLD independently elevate the risk of colorectal adenomas, with MASLD potentially mediating the relationship between H. pylori infection and the increased adenoma risk.

Key Words: Colorectal adenomas; Helicobacter pylori infection; Metabolic dysfunction-associated steatotic liver disease; Interaction; Mediation

Core Tip: This study identifies both Helicobacter pylori (H. pylori) infection and metabolic dysfunction-associated steatotic liver disease (MASLD) as independent risk factors for colorectal adenoma. No interaction was found between them, but MASLD mediated the infection-adenoma risk relationship. These results support enhanced screening for colorectal adenoma in individuals with H. pylori infection and MASLD.

INTRODUCTION

Colorectal cancer (CRC) is a leading global health concern and a significant cause of mortality, with approximately 900000 deaths every year[1]. It often develops from adenomas, and risk factors include male gender, older age, family history, unhealthy lifestyle, and diet. Emerging evidence implicates Helicobacter pylori (H. pylori) infection, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome in colorectal tumorigenesis[2-5].

H. pylori is a microaerophilic, gram-negative bacterium that primarily colonizes the stomach and infects more than half of the world's population. H. pylori infection is not only an independent risk factor for the development of gastric cancer but is also associated with many extragastric diseases[6]. It may increase the risk of colorectal adenomas[7-9], while some studies suggest that this association is influenced by age and smoking history[10]. The connection between H. pylori and colorectal adenomas remains a topic of scientific debate.

NAFLD was previously renamed metabolic-associated fatty liver disease, and has recently been renamed metabolic dysfunction-associated steatotic liver disease (MASLD)[11,12]. It is estimated to affect around 25% of the global populace[13]. A comprehensive meta-analysis indicates that MASLD may be considered an independent risk factor for the development of colorectal adenomas, presenting an odds ratio (OR) of 1.29 with a 95%CI ranging from 1.15 to 1.45[14]. Studies have shown that individuals testing positive for H. pylori infection are at an increased risk of developing MASLD compared to those who test negative[15-17], although this association has not been consistently supported by all research findings[18,19].

From the pathophysiological standpoint, H. pylori infection may result in the release of pro-inflammatory cytokines and stimulate the expression of numerous inflammatory markers[13]. It could alter the gut microbiota[20] and may be linked to insulin resistance[13]. These mechanisms share common pathways with the development of colorectal adenomas and MASLD[21-23]. Consequently, our study proposes potential links between H. pylori infection, MASLD, and colorectal adenomas[24], which have been investigated in a recent review, and indicated that insulin resistance and gut microbiome dysbiosis may be common pathways in the pathophysiology of NAFLD and colorectal neoplasm development. Therefore, the objective of this study was to further validate whether H. pylori infection and MASLD significantly elevate the risk of colorectal adenomas and to examine if there is an interaction or mediation effect between the two risk factors.

MATERIALS AND METHODS

Study design

This study was designed as a retrospective cross-sectional analysis. Patients who attended the Second Medical Center of Chinese PLA General Hospital for check-up between the years 2017 and 2021 were consecutively enrolled. This study complied with the principles outlined in the Declaration of Helsinki. It was reviewed and approved by the Ethics Committee of the PLA General Hospital (No. S2023-224-01). The ethics committee granted a waiver for the necessity of obtaining consent from participants.

Inclusion criteria: (1) Successful completion of a colonoscopy with or without colorectal tissue biopsy for histopathological examination; (2) Completion of a successful ¹³C-urea breath test; (3) Completion of a successful liver ultrasound examination; and (4) Completion of a physical examination and laboratory tests.

Exclusion criteria: (1) Viral hepatitis; (2) Alcoholic liver disease; (3) Autoimmune liver diseases; (4) Thyroid dysfunction; (5) Inflammatory bowel disease; (6) Incomplete clinical data; and (7) Non-adenomatous polyp.

The reporting of this study conforms to the STROBE guidelines. Following the general principles for estimating sample size in cross-sectional studies, which suggest that the sample size should be 10 times to 20 times the number of study variables, our study included 22 variables. Taking into account a 10% rate for ineffective samples, we ensured that our sample size was sufficient, with a minimum of 242-484 participants.

Data collection

The data collected from the records of the included patients included: (1) Basic characteristics: Age, sex, body mass index (BMI), systolic blood pressure, diastolic blood pressure, smoking history, and drinking history; (2) Laboratory assays: White blood cell count, hemoglobin, C-reactive protein (CRP), folic acid, homocysteine, brain natriuretic peptide precursor, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), creatinine, and 25-hydroxyvitamin D3; (3) Results of the colonoscopy and colorectal biopsies; (4) ¹³C-urea breath test results; and (5) Ultrasonography results. Blood was sampled from the antecubital vein after an overnight fast, with trained nurses conducting the physical parameter tests. All patient details have been de-identified to protect participant confidentiality in accordance with institutional and ethical guidelines.

Diagnostic criteria

Participants were categorized into two groups based on the findings from colonoscopy and colorectal biopsies: The adenoma group, and the non-polyp group. The colonoscopy was performed for screening purposes. After thorough bowel preparation, a CF-H260 colonoscopy (Olympus, Tokyo, Japan) was conducted on all eligible subjects. The procedures were carried out by skilled gastroenterologists adhering to a standard protocol. H. pylori infection was diagnosed by the ¹³C-urea breath test. The diagnosis of MASLD was established by ultrasonography indicating fatty liver, accompanied by one or more of the following conditions: (1) Overweight or obesity (BMI ≥ 23 kg/m²); (2) Diabetes (diabetic symptoms with random blood glucose ≥ 11.1 mmol/L, or FBG ≥ 7.0 mmol/L, or 2-hour post-glucose load blood glucose ≥ 11.1 mmol/L); and (3) At least two metabolic risk abnormalities. Metabolic risk abnormalities included: (1) Waist circumference ≥ 90 cm for men and ≥ 80 cm for women; (2) Blood pressure ≥ 130/85 mmHg or on specific medication; (3) Fasting plasma triglycerides ≥ 1.7 mmol/L or on specific medication; (4) Plasma HDL-C < 1.0 mmol/L for men and < 1.3 mmol/L for women or on specific medication; (5) Prediabetes (FBG 5.6-6.9 mmol/L, or 2-hour postprandial blood glucose 7.8-11.0 mmol/L, or HbA1c 5.7%-6.4%); (6) Homeostasis model assessment of insulin resistance score ≥ 2.5; and (7) Plasma CRP > 0.2 mg/dL. Ultrasonography was performed by at least two skilled sonographers blinded to the study's aim. The patient lay supine with the abdomen unshielded for examination of abdominal organs using an ultrasound probe. Criteria for diagnosing fatty liver on ultrasound included: Increased near-field echogenicity in the liver (“bright liver”) exceeding that of the kidneys; obscured intrahepatic ductal structures; and diminished far-field echoes within the liver. This diagnostic approach is largely consistent with the core criteria for MASLD established by the American Association for the Study of Liver Diseases and other international societies in 2023[12]. It is more stringent in defining metabolic disorders (meeting two or more of the metabolic abnormalities criteria proposed by the international expert consensus in 2020)[11].

Statistical analysis

Data analysis was conducted using the statistical software SPSS (version 26.0 for Windows). Prior to analysis, normality (via Kolmogorov-Smirnov test) and variance homogeneity tests were performed for measurement data to ensure the appropriateness of subsequent statistical methods. Measurement data that conformed to a normal distribution were represented as mean ± SD, and comparisons between two groups were made using the t-test; measurement data that did not conform to a normal distribution were represented median (Q1, Q3), and comparisons between two groups were made using the Mann-Whitney U test. Count data were expressed in terms of n (%), and intergroup comparisons were made using the χ² test or Fisher’s exact probability method (the latter for theoretical frequencies sample size).

Multivariate logistic regression analysis, interaction, and mediation effect tests were used to assess the relationship between H. pylori infection, MASLD, and the risk of colorectal adenoma occurrence. Based on the statistically significant differences between the two groups outlined in Table 1 and clinical rationality, confounding factors were selected, and factors implicated in the disease diagnostic criteria were removed to avoid over-adjustment and spurious associations. For multiple analyses including interaction and mediation effect tests, results were comprehensively judged by combining effect sizes (e.g., OR and 95%CI) with P-values to reduce type I error risk.

Table 1 Baseline characteristics, n (%)/mean ± SD.

	Non-polyp (n = 6930)	Adenoma (n = 3136)	P value
Helicobacter pylori infection			< 0.001
Yes	2408 (34.75)	1294 (41.26)
No	4522 (65.25)	1842 (58.74)
MASLD			< 0.001
Yes	3461 (49.94)	1929 (61.51)
No	3469 (50.06)	1207 (38.49)
Basic characteristics
Sex (male)			< 0.001
Male	4465 (64.43)	2552 (81.38)
Female	2465 (35.57)	584 (18.62)
Age (years)	49.31 ± 8.19	52.51 ± 7.38	< 0.001
BMI (kg/m2)	24.95 ± 3.31	25.84 ± 3.21	< 0.001
Systolic blood pressure (mmHg)	122.52 ± 139.14	125.09 ± 18.13	0.336
Diastolic blood pressure (mmHg)	80.70 ± 11.44	82.70 ± 11.79	< 0.001
Smoking history	1781 (25.70)	1214 (38.71)	< 0.001
Drinking history	3763 (54.30)	2056 (65.56)	< 0.001
Laboratory assays
White blood cell count (× 109/L)	5.82 ± 1.46	6.07 ± 1.48	< 0.001
Hemoglobin (g/L)	142.73 ± 15.85	146.96 ± 13.97	< 0.001
CRP (mg/dL)	0.14 ± 0.28	0.17 ± 0.36	< 0.001
Folic acid (ng/mL)	9.36 ± 4.27	8.90 ± 4.26	< 0.001
Homocysteine (μmol/L)	12.24 ± 9.31	13.24 ± 6.91	< 0.001
NT-proBNP (pg/mL)	34.64 ± 40.02	35.65 ± 52.70	0.299
TC (mmol/L)	4.72 ± 0.89	4.75 ± 0.91	0.152
Triglycerides (mmol/L)	1.76 ± 1.22	1.99 ± 1.39	< 0.001
LDL-C (mmol/L)	3.15 ± 0.84	3.18 ± 0.86	0.139
HDL-C (mmol/L)	1.26 ± 0.35	1.18 ± 0.32	< 0.001
FBG (mmol/L)	5.41 ± 1.21	5.63 ± 1.37	< 0.001
Creatinine (μmol/L)	67.63 ± 14.01	70.91 ± 14.03	< 0.001
25-hydroxyvitamin D3 (ng/mL)	19.72 ± 6.07	20.14 ± 6.12	0.002

MASLD: Metabolic dysfunction-associated steatotic liver disease; BMI: Body mass index; CRP: C-reactive protein; NT-proBNP: Brain natriuretic peptide precursor; TC: Total cholesterol; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; FBG: Fasting blood glucose.

All tests were two-tailed, and a P value less than 0.05 was considered statistically significant. Additionally, strict data quality control (including double data entry and outlier clinical verification) was performed to ensure data reliability and reduce false positive bias.

RESULTS

Baseline characteristics

Table 1 presents data from 10066 participants, of whom 3136 (29.40%) were diagnosed with colorectal adenomas. The prevalence of H. pylori infection was 36.78% (3702 of 10066), and MASLD was found in 53.55% (5390 of 10066). Among those with colorectal adenomas, the H. pylori infection rate was 41.26% (1294 of 3136), compared to 34.75% (2408 of 6930) in the non-adenoma group (P < 0.001). Similarly, the prevalence of MASLD was higher in the colorectal adenoma group at 61.51% (1929 of 3136), than in the non-adenoma group, which was 49.94% (3461 of 6930) (P < 0.001).

It is important to note that the colorectal adenoma group had a higher proportion of males, as well as higher averages in age, BMI, diastolic blood pressure, and rates of smoking and alcohol consumption, all with a statistically significant difference (all P < 0.001). Additionally, this group exhibited elevated average levels of white blood cell count, hemoglobin, CRP, homocysteine, triglycerides, FBG, creatinine, and 25-hydroxyvitamin D3 compared to the non-adenoma group. Conversely, the level of HDL-C was significantly lower in the colorectal adenoma group than in the non-adenoma group.

Association between H. pylori infection and colorectal adenoma

As shown in Table 2, the prevalence of adenomas in the H. pylori (+) group was significantly higher than that in the H. pylori (-) group [adjusted OR (aOR) 1 = 1.3, 95%CI: 1.2-1.5, P < 0.001; aOR2 = 1.3, 95%CI: 1.2-1.4, P < 0.001].

Table 2 Association between Helicobacter pylori infection and adenoma (multivariate logistic regression model).

Helicobacter pylori infection test	Adjusting for confounding factors 11		Adjusting for confounding factors 22
	OR (95%CI)	P value	OR (95%CI)	P value
-	1.0		1.0
+	1.3 (1.2-1.5)	< 0.001	1.3 (1.2-1.4)	< 0.001

¹Adjusting for confounding factors 1: Age, sex and body mass index.

²Adjusting for confounding factors 2: Age, sex, body mass index, systolic blood pressure, white blood cell count, hemoglobin, C-reactive protein, folic acid, homocysteine, total cholesterol, fasting blood glucose, creatinine, 25-hydroxyvitamin D3, smoking history, and drinking history.

OR: Odds ratio.

Association between MASLD and colorectal adenoma

The prevalence of adenomas was higher in the MASLD (+) group than in the MASLD (-) group (aOR1 = 1.3, 95%CI: 1.2-1.4, P < 0.001; aOR2 = 1.3, 95%CI: 1.2-1.5, P < 0.001) (Table 3).

Table 3 Association between metabolic dysfunction-associated steatotic liver disease and adenoma (multivariate logistic regression model).

MASLD	Adjusting for confounding factors 11		Adjusting for confounding factors 22
	OR (95%CI)	P value	OR (95%CI)	P value
-	1.0		1.0
+	1.3 (1.2-1.4)	< 0.001	1.3 (1.2-1.5)	< 0.001

¹Adjusting for confounding factors 1: Age and sex.

²Adjusting for confounding factors 2: Age, sex, white blood cell count, hemoglobin, folic acid, homocysteine, total cholesterol, creatinine, 25-hydroxyvitamin D3, smoking history, and drinking history.

MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio.

Participants were divided into four groups: H. pylori (-) MASLD (-), H. pylori (-) MASLD (+), H. pylori (+) MASLD (-), and H. pylori (+) MASLD (+), for multivariate logistic regression analysis of colorectal adenoma, as shown in Table 4. The H. pylori (+) MASLD (-) group had a higher risk of developing colorectal adenomas compared to the H. pylori (-) MASLD (-) group (aOR1 = 1.24, 95%CI: 1.11-1.39, P = 0.0002; aOR2 = 1.28, 95%CI: 1.12-1.45, P = 0.0002). Similarly, the H. pylori (-) MASLD (+) group also had a higher risk of colorectal adenomas than the H. pylori (-) MASLD (-) group (aOR1 = 1.28, 95%CI: 1.11-1.48, P = 0.0006; aOR2 = 1.18, 95%CI: 1.02-1.40, P = 0.0430). The risk of developing colorectal adenomas was significantly higher in the H. pylori (+) MASLD (+) group compared to the H. pylori (-) MASLD (-) group (aOR1 = 1.68, 95%CI: 1.47-1.91 P < 0.0001; aOR2 = 1.68, 95%CI: 1.45-1.93, P < 0.0001). Both H. pylori infection and MASLD were found to increase the risk of colorectal adenomas; however, no interaction between the two factors in promoting the development of colorectal adenomas was observed (adjusted P1 value = 0.2780; adjusted P2 value = 0.1836).

Table 4 Multivariate logistic regression model for colorectal adenoma and the interaction between Helicobacter pylori and metabolic dysfunction-associated steatotic liver disease.

	Adjusting for confounding factors 11		Adjusting for confounding factors 22
	OR (95%CI)	P value	OR (95%CI)	P value
H. pylori (-) MASLD (-)	1.0		1.0
H. pylori (+) MASLD (-)	1.24 (1.11-1.39)	0.0002	1.28 (1.12-1.45)	0.0002
H. pylori (-) MASLD (+)	1.28 (1.11-1.48)	0.0006	1.18 (1.02-1.40)	0.0430
H. pylori (+) MASLD (+)	1.68 (1.47-1.91)	< 0.0001	1.68 (1.45-1.93)	< 0.0001
Interaction between H. pylori infection and MASLD		0.2780		0.1836

¹Adjusting for confounding factors 1: Age and sex.

²Adjusting for confounding factors 2: Age, sex, white blood cell count, hemoglobin, folic acid, homocysteine, total cholesterol, creatinine, 25-hydroxyvitamin D3, smoking history, and drinking history.

H. pylori: Helicobacter pylori; MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio.

As shown in Table 5, the results of the mediation effect test indicate that the mediating effect of MASLD in the influence of H. pylori on the occurrence of colorectal adenomas was 0.0009 (95%CI: 0.0002-0.0027), with an effect contribution rate of 1.68% (95%CI: 0.37%-5.10%, P = 0.0180). This mediating effect was statistically significant.

Table 5 Mediation effect of metabolic dysfunction-associated steatotic liver disease in the influence of Helicobacter pylori on colorectal adenoma occurrence.

	OR (95%CI)	P value1
Total effect	0.0563 (0.0387-0.0763)	< 0.0001
Direct effect	0.0554 (0.0037-0.0753)	< 0.0001
Mediation effect	0.0009 (0.0002-0.0027)	0.0180
Mediation effect percentage	0.0168 (0.0037-0.0510)	0.0180

¹Adjusting for confounding factors 1: Age and sex.

MASLD: Metabolic dysfunction-associated steatotic liver disease; OR: Odds ratio.

DISCUSSION

The association between H. pylori infection, MASLD, and colorectal adenoma remains controversial, with high-quality reviews specifically discussing the relationship between the three[24]. The author points out that insulin resistance as a pro-inflammatory state and dysbiosis of the gut microbiota could represent common mechanisms between the development of MASLD and colorectal adenomas. Given the complex relationships and potential shared pathogenesis among the three, this study hypothesizes that MASLD might be a mediating factor in the increased risk of colorectal adenomas due to H. pylori infection. To verify this hypothesis, the present study divided a large Chinese population into colorectal adenoma and non-polyp groups, and examined the roles of H. pylori infection and MASLD in increasing the risk of colorectal adenoma development using multivariate regression models, interaction effects, and mediation effect validation.

This study further verified that H. pylori infection can increase the risk of colorectal adenoma. The potential mechanisms analyzed included: (1) Chronic H. pylori infection and colorectal tumors lead to a state of hypergastrinemia, where gastrin is a peptide hormone that acts as a mitogen, and some previous epidemiological studies have indicated an association between gastrin and CRC risk; (2) H. pylori infection causes inflammation, leading to increased production and activity of cyclooxygenase-2 and prostaglandin E2, which are biomarkers related to inflammation associated with CRC risk; and (3) H. pylori infection can cause an increase in the production of superoxide radicals and nitric oxide, and H. pylori itself has been recognized as a group 1A carcinogen for gastrointestinal cancers. A retrospective cohort study reported conclusions similar to those in this study, showing that the cumulative risk of CRC in the H. pylori infection cohort was significantly higher than in the non-H. pylori infection cohort [adjusted hazard ratio (HR) = 1.87; 95%CI: 1.37-2.57][5]. A retrospective cross-sectional study reported by the Physical Examination Center of Wenzhou Medical University in 2020 analyzed 6018 physical examinees, among whom 1012 (16.8%) were diagnosed with colorectal adenoma, including 143 cases (2.4%) with advanced adenomas[7]. The study found that H. pylori infection increased the risk of colorectal adenoma occurrence (OR = 1.220, 95%CI: 1.053-1.413, P = 0.008). İşsever et al[25] discovered a significant correlation between H. pylori infection and the prevalence of CRC, with H. pylori-positive patients having a 64% higher risk of developing CRC compared to H. pylori-negative patients. However, no significant statistical significance was found for advanced adenomas (OR = 1.303, 95%CI: 0.922-1.842, P = 0.134). In addition, the results by Kim et al[8] showed that the risk of developing advanced colorectal adenomas was higher in those infected with H. pylori compared to non-infected individuals (OR = 1.90, 95%CI: 1.05-3.56). Other researchers have found that H. pylori infection increases the risk of colorectal adenoma in patients < 50 years old (OR = 1.602; 95%CI: 1.194-2.150), but does not increase the risk in patients ≥ 50 years old (OR = 1.046; 95%CI: 0.863-1.268)[10].

In our study, MASLD was identified as an independent risk factor for the development of colorectal adenomas. This finding is consistent with the results of a meta-analysis that included 14 cohort studies, indicating that MASLD is associated with an increased risk of colorectal adenoma occurrence (OR = 1.23; 95%CI: 1.14-1.32; P < 0.001)[14]. Bioinformatics analysis suggests that ferroptosis and cuproptosis may be key processes linking MASLD and colorectal adenomas. Researchers have analyzed the following possible mechanisms: (1) MASLD can alter the systemic immune state, upregulating various pro-tumor cytokine levels, promoting the initiation and progression of colorectal adenomas; (2) MASLD can cause insulin resistance and increase circulating insulin levels, which has been recognized as a carcinogen for CRC. Moreover, elevated levels of blood glucose and insulin, obesity, and lack of physical activity are also associated with CRC; (3) The rise in fatty acids and carbohydrates in the blood caused by MASLD can stimulate the development of colorectal adenomas; and (4) In the progression of MASLD, a low inflammatory state induced by tumor necrosis factor (TNF)-α and interleukin (IL)-6 leads to intestinal microbiota dysbiosis, which may also promote the occurrence of colorectal adenomas. However, some studies suggest that MASLD only increases the risk of colorectal adenomas in men, while it does not have the same effect in women[4].

H. pylori infection has been identified as a contributing factor to the onset and progression of MASLD, with mechanisms involving various aspects such as metabolism, inflammation, gut microbiota, and hormones[13]. Some high-quality meta-analyses have indicated that individuals who are H. pylori positive have a higher risk of developing MASLD than those who are H. pylori negative, with OR values ranging from 1.19 to 1.38[15-17,26,27]. A prospective cohort study found that H. pylori-infected individuals had a higher risk of developing MASLD compared to non-infected individuals, with a HR of 1.21 and a 95%CI of 1.10-1.34[28]. There has been considerable discussion on the pathophysiological mechanisms, where researchers suggest that H. pylori infection is associated with insulin resistance and dyslipidemia. H. pylori-positive patients have been found to have higher levels of HbA1c and triglycerides than H. pylori-negative patients[13]. Animal experiments have confirmed that H. pylori infection can upregulate the expression of various inflammatory factors, including CRP, TNF, and multiple ILs. This inflammatory environment can activate stellate cells to produce fibrosis, accelerating liver steatosis and hepatic fibrosis[29,30]. Furthermore, H. pylori infection and its treatment can affect gut permeability, alter the diversity and abundance of gastrointestinal bacteria, leading to gut microbiota dysbiosis, and facilitate the entry of bacterial toxins into the liver, thereby inducing chronic liver inflammation[20,21].

From the data mentioned above, it seems that there is a close connection between the promoting effects of H. pylori infection on colorectal adenomas and MASLD, as well as the impact mechanism of MASLD on the occurrence of colorectal adenomas. Therefore, after confirming that both H. pylori infection and MASLD can increase the risk of colorectal adenomas, this study further verified our hypothesis by analyzing whether there was an interaction and mediation effect between these two factors. It should be acknowledged that the mediation analysis was based on the assumption of “Exposure: H. pylori positive → Mediating factor: MASLD → Outcome: Colon adenoma”. The identified 1.68% mediation effect, although small, provides initial evidence of the potential mediating role of MASLD in the relationship between H. pylori infection and colorectal adenoma. This finding can serve as a starting point for future longitudinal studies to further explore and validate the causal relationships between these factors. It also contributes to the existing body of knowledge by highlighting a possible new pathway in the complex mechanisms underlying colorectal adenoma development related to H. pylori infection. This insight underscores the importance of considering MASLD in the framework of colorectal adenoma prevention and management strategies, especially in populations with a higher prevalence of H. pylori infection.

Our study offers several innovative insights and advantages. Firstly, it challenges the existing paradigm by investigating the relationship between H. pylori infection, MASLD, and colorectal adenomas, a triad that has not been extensively explored in previous literature. By doing so, we provide a fresh perspective on the interplay between infectious agents, metabolic disorders, and gastrointestinal neoplasms. Secondly, our research benefits from a rigorous methodology, including a well-defined patient cohort and a thorough statistical analysis, which ensures the reliability of our findings. This robust approach enables us to draw more confident conclusions about the mediating role of MASLD in the association between H. pylori infection and the increased risk of colorectal adenomas. Moreover, the exclusion of patients with non-adenomatous polyps further refines our analysis by eliminating a potential confounding factor, thus adding clarity to the observed relationships. Finally, these discoveries have significant clinical implications, underscoring the importance of metabolic health assessment in the context of H. pylori infection and colorectal adenoma prevention. The identification of MASLD as a potential mediator opens new avenues for targeted prevention and intervention strategies, possibly leading to improved outcomes in colorectal adenoma management.

Despite the intriguing insights provided by our research, it is crucial to consider its limitations when interpreting the results. First, as a single-center study, it inherently possesses population biases. The data collected reflects a specific patient demographic and may not be generalizable to other populations. Therefore, the generalizability of the research results may be subject to certain limitations. Additionally, the retrospective nature of the study means that we are reliant on previously recorded data, which can be influenced by inaccuracies in documentation or patient recall. Furthermore, our study's cross-sectional observational design imposes constraints on drawing conclusions about temporal relationships and the directionality of the observed associations. We cannot infer clear cause and effect relationships. A long-term, prospective study better suited to disentangle the cause and effect relationships. Moreover, the sample size, although substantial, may not be sufficiently large enough to detect small to moderate effects, thereby potentially limiting the statistical power of our analysis. Notably, the absence of systematic subgroup analyses based on key clinical variables, such as age and gender, prevents a more granular understanding of the observed associations. Future prospective studies should incorporate such analyses to elucidate potential effect modifiers and underlying pathways. The identified 1.68% mediating effect is relatively small, indicating that the impact of MASLD in real-world clinical or public health scenarios requires further investigation. It should also be noted that it diagnosed MASLD using a combination of ultrasound and metabolic criteria. It is clinically practical and widely adopted, but its accuracy is inferior to that of liver biopsy or advanced imaging examinations such as MRI-PDFF. In light of these constraints, we emphasize the necessity for future prospective multicenter studies to validate and expand upon our findings. Such studies would provide a broader patient base and potentially enable a more precise understanding of the temporal relationships and mechanisms involved in the interplay between H. pylori infection, MASLD, and the occurrence of colorectal adenomas.

CONCLUSION

This study confirmed that both H. pylori infection and MASLD potentially increase the risk of developing colorectal adenomas. Notably, our comprehensive analysis did not identify an interaction between these two factors but highlighted a significant mediation effect of MASLD on the relationship between H. pylori infection and the risk of colorectal adenomas. In conclusion, both H. pylori infection and MASLD are independent risk factors for the occurrence of colorectal adenomas, and emphasis should be placed on the promotion and education of colonoscopy examinations for patients with H. pylori infection and MASLD.

ACKNOWLEDGEMENTS

We would like to thank the healthcare professionals of the Second Medical Center of Chinese PLA General Hospital for their professional assistance and care for all outpatients.