
==== Front
Eur J Nutr
Eur J Nutr
European Journal of Nutrition
1436-6207
1436-6215
Springer Berlin Heidelberg Berlin/Heidelberg

38809325
3439
10.1007/s00394-024-03439-2
Original Contribution
Association between the consumption of ultra-processed foods and the incidence of peptic ulcer disease in the SUN project: a Spanish prospective cohort study
http://orcid.org/0000-0001-8063-8490
Leone Alessandro alessandro.leone1@unimi.it

12
De la Fuente-Arrillaga Carmen 345
Mas Mariano Valdés 6
Sayon-Orea Carmen 3457
Menichetti Francesca 1
Martínez-Gonzalez Miguel Angel 345
Bes-Rastrollo Maira 345
1 https://ror.org/00wjc7c48 grid.4708.b 0000 0004 1757 2822 International Center for the Assessment of Nutritional Status and The Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
2 https://ror.org/033qpss18 grid.418224.9 0000 0004 1757 9530 Clinical Nutrition Unit, Department of Endocrine and Metabolic Medicine, IRCCS Istituto Auxologico Italiano, Milan, 20100 Italy
3 https://ror.org/02rxc7m23 grid.5924.a 0000 0004 1937 0271 Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain
4 https://ror.org/00ca2c886 grid.413448.e 0000 0000 9314 1427 CIBERobn, Instituto de Salud Carlos III, Madrid, Spain
5 grid.508840.1 0000 0004 7662 6114 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
6 grid.411730.0 0000 0001 2191 685X Digestive Department, University of Navarra Clinic, Pamplona, Spain
7 Navarra Institute of Public Health, Pamplona, Spain
29 5 2024
29 5 2024
2024
63 6 23672378
1 2 2024
14 5 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose

Consumption of ultra-processed foods (UPF) has increased despite potential adverse health effects. Recent studies showed an association between UPF consumption and some gastrointestinal disorders. We evaluated the association between UPF consumption and peptic ulcer disease (PUD) in a large Spanish cohort.

Methods

We conducted a prospective analysis of 18,066 participants in the SUN cohort, followed every two years. UPF was assessed at baseline and 10 years after. Cases of PUD were identified among participants reporting a physician-made diagnosis of PUD during follow-ups. Cases were only partially validated against medical records. Cox regression was used to assess the association between baseline UPF consumption and PUD risk. Based on previous findings and biological plausibility, socio-demographic and lifestyle variables, BMI, energy intake, Helicobacter pylori infection, gastrointestinal disorders, aspirin and analgesic use, and alcohol and coffee consumption were included as confounders.We fitted GEE with repeated dietary measurements at baseline and after 10 years of follow-up. Vanderweele’s proposed E value was calculated to assess the sensitivity of observed associations to uncontrolled confounding.

Results

During a median follow-up of 12.2 years, we recorded 322 new PUD cases (1.56 cases/1000 person-years). Participants in the highest baseline tertile of UPF consumption had an increased PUD risk compared to participants in the lowest tertile (HR = 1.52, 95% CI: 1.15, 2.00, Ptrend=0.002). The E-values for the point estimate supported the observed association. The OR using repeated measurements of UPF intake was 1.39 (95% CI: 1.03, 1.87) when comparing extreme tertiles.

Conclusion

The consumption of UPF is associated with an increased PUD risk.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00394-024-03439-2.

Keywords

Ultra-processed food
Peptic ulcer disease
NOVA food classification system
Gastrointestinal disorders
Università degli Studi di MilanoOpen access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement.

issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Ultra-processed foods (UPF) are industrial formulations including, besides salt, sugar, oils, and fats, food-derived substances and additives, the aim of which is to make these products attractive, extremely palatable and convenient (ready-to-eat and with a long shelf life) [1]. Their consumption has increased dramatically in recent decades, so much so that nowadays they contribute 50% or more of daily calorie intake in some Western countries [2–4]. It has been reported that a diet rich in UPF is nutritionally unbalanced [5], and several prospective cohorts have repeatedly reported an association between UPF consumption and the risk of obesity [6–8], diabetes (both type 2 and gestational diabetes) [9, 10], cardiovascular diseases [11, 12], and other non-communicable diseases [13]. Moreover, recent prospective studies have showed an association between UPF consumption and some functional gastrointestinal disorders or diseases, such as irritable bowel syndrome, functional dyspepsia [14] and Crohn’s disease [15, 16]. However, the association between UPF consumption and peptic ulcer disease (PUD) has not been investigated.

PUD is characterized by an acid peptic lesion of the gastrointestinal mucosa, with depth to the submucosa. Ulcers are generally located in the stomach and proximal duodenum, but can sometimes affect the lower esophagus, distal duodenum or jejunum. The most common symptom of PUD is the burning epigastric pain occurring after meals. Gastrointestinal bleeding is the most common complication, with a mortality rate of 2.5–10%, mainly due to non-hemorrhagic causes such as multiorgan failure, pulmonary complications, and malignancy. Other PUD-related complications are perforation, with a mortality rate of 20%, and gastric outlet obstruction [17]. It has been estimated that 5–10% of individuals in the general population develop PUD during their lifetime. Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are the most common risk factors for PUD. However, the pathophysiology of ulcers not associated with H. pylori or NSAID ingestion is becoming more relevant as the incidence of H. pylori is dropping, particularly in the Western world [17].

Diet has been thought to play a role in the development of PUD, but the evidence is limited and controversial. Certain diet components, such as salt, refined carbohydrates, alcohol, fiber, vitamins and polyphenols have been suspected to be linked to the PUD risk [18–20]. Since UPF are characterized by a low content of protective nutrients, such as fiber, vitamins and polyphenols, and a high density of sugars and salt, a diet rich in these products could contribute to the development of PUD. To elucidate this issue, we conducted an analysis in the SUN cohort to appraise whether UPF consumption was associated with the incident risk of PUD.

Materials and methods

Study design and participants

The SUN project is a Spanish dynamic prospective cohort aimed on studying the relationship between dietary habits, lifestyle and health status. The recruitment began in 1999 and it still on going. Participants are former graduates of University of Navarra, health professionals and other graduates [21]. Participants were invited to participate by means of a letter (e-mail or regular mail) outlining the objective of the project, what their participation entailed, the information required over time, and the arrangements put in place to safeguard their privacy. Along with the invitation letter, participants received a questionnaire (online or paper) designed to collect basic information on sociodemographic and lifestyle variables, eating habits, and medical history. They were given the option to decline participation in the study simply by not submitting the completed questionnaire. Therefore, voluntary completion of the first questionnaire was considered as informed consent as it was approved by the Ethical Committee. Every two years, participants received a new questionnaire investigating the occurrence of new diseases. Ten years after entering the cohort, the questionnaire sent to participants also investigated dietary habits so that they could be updated. This does not imply termination of the study. In fact, participants continue to receive the health status update questionnaire every two years. Participants who were recruited in 1999 have more than 20 years of follow-up within the SUN database used for this study. The project conformed to the guidelines established in the Declaration of Helsinki, and the Human Research Ethical Committee at the University of Navarra approved all the study procedures (091/2008).

Up to December 2019, 22,894 participants completed the baseline questionnaire. To ensure two years in the cohort, 341 participants who responded the baseline questionnaire after March 2017 were excluded. We further excluded 1979 participants with no follow-up (retention rate 91%), 1012 participants with a history of PUD, 522 participants with unlikely energy intake (< 1st percentile and > 99th percentile), 304 participants with diabetes, 236 prevalent cases of cardiovascular disease, and 434 participants with a prior diagnosis of cancer. The final dataset included 18,066 participants who answered at least 1 follow-up questionnaire (Fig. 1).

Fig. 1 Flow chart showing the selection process of participants in the SUN project to be included in the present analysis

Exposure Assessment

We assessed dietary habits at baseline and again after 10 years using a validated semi-quantitative food frequency questionnaire consisting of 136-food items [22]. Each food item included a typical portion size. Participants were asked to report the frequency of consumption of each food item by selecting one of 9 frequency options reported in the questionnaire, ranged from never or almost never to more than 6 servings per day. We multiplied the frequency of consumption by the typical portion size to estimate the daily consumption of each food. Foods and beverages were then classified into one of the four categories of the NOVA classification [23]. The UPF group included processed meat, sausages, cookies and pastries, chocolate and candy, breakfast cereals, sweet or salty packaged snacks, margarine, instant soups, pre-prepared pies and pizza dishes, fruit yogurt, carbonated beverages, sweetened milk and fruit drinks, and alcoholic beverages produced by fermentation followed by distillation such as whiskey, gin and rum (a total of 34 items). To estimate the amount of UPF consumed daily, we summed the amount consumed (g/day) of each food item included in the UPF group. We then adjusted the consumption of UPF for the daily energy intake through the residuals method [24]. The use of daily grams of UPF instead of its caloric contribution made it possible to also consider foods that do not provide calories (e.g., calorie-free sweetened beverages). After that, we divided the sample into tertiles according to the total UPF consumption.

Outcome Assessment

Participants reporting a medical diagnosis of PUD in one of the follow-up questionnaires were defined as incident cases of PUD. To validate the self-reported diagnosis of PUD, a subgroup of 139 participants from the SUN cohort was randomly selected (51 reporting PUD and 88 not reporting PUD), and the information reported was compared against the medical history in the clinical records available at the university clinic. A gastroenterologist, blinded to the exposure, handled the comparison. From those who reported a diagnosis of PUD (n = 51), 30 (58.8%; 95% confidence interval [CI], 44.2-72.4% were confirmed through their medical history. From the rest (n = 21), 19 (90.5%, 95% CI: 69.6-98.8%) were diagnosed as gastritis (n = 14), esophagitis (n = 18) and/or epigastric pain (n = 1), and only 2 they did not have any diagnostic related to gastric disease. From the 88 who did not report a diagnosis of PUD, all (100%; 95% CI: 88.4-100%) were confirmed as non-cases of PUD.

Covariates

The baseline questionnaire collected information on sex, age, sociodemographic characteristics, weight and height, smoking, physical activity, and medical history. Self-reported weight and height were previously validated in a subgroup of our cohort [25]. Physical activity was assessed using the Spanish version of the 17-item Harvard Nurses’ Health Study physical activity questionnaire [26]. Leisure time activities were measured in metabolic activity equivalents (METs) per week by assigning habitual energy expenditure to each activity and multiplying by the time spent (in hours per week) on each activity. Total energy and nutrient intake were estimated from food consumption analyzed by the semi-quantitative FFQ using the most up-to-date version of the Food Composition Database for Spain.

Statistical analysis

Continuous variables are reported as median and interquartile range (IQR) because some descriptive variables did not have a Gaussian distribution. Discrete variables are reported as count and percent. A Cox regression model, stratified by smoking and physical activity, was conducted to evaluate the association between tertiles of UPF consumption and PUD risk. The hazard ratio (HR) was calculated using the lowest tertile as the reference category. To control for possible confounders, sex, age (decades), BMI (quartiles), calendar year of recruitment (1999–2001, 2002–2004, 2005–2007, 2008–2010, and from 2011 onwards), health career (yes/no), education (3–4, 5–6, 9 years), marital status (unmarried, married, other, missing), packs of cigarettes (0, 1–12 packs/year, 13–24 packs/year, > 24 packs/year, missing), energy intake (quartiles), known H. pylori infection (yes/no), gastroesophageal reflux (yes/no), hiatal hernia (yes/no), aspirin use (yes/no), NSAIDs use (yes/no), coffee consumption (no, 1–2 cups/day, > 2 cups/day), and alcohol intake from wine and beer (quartiles) were included in the model. Confounders were selected based on biological plausibility and previous causal knowledge on the topic as it is recommended by Hernan et al. [27]. Although we adjusted for a large number of confounding factors, we cannot rule out residual confounding. UPF consumption could also be closely related to other aspects of an unhealthy lifestyle. To assess this aspect, we calculated Vanderweele’s proposed E value [28]. This value represents the minimum strength of association on the risk ratio scale that an unmeasured confounder would need to have with both the UPF consumption and the PUD to fully explain away a specific exposure-outcome association, conditional on the measured covariates. The existence of a linear trend between exposure and outcome was assessed by assigning the median value of each tertile and treating the new variable as continuous. To confirm the result, we also ran the Cox regression model by including UPF consumption as a continuous variable (g/day). The linearity of exposure was assessed by the fractional polynomials method. We used repeated measures of dietary intake in order to consider possible changes in the consumption of UPF between baseline and after 10 years of follow-up. We used generalized estimation equations with family binomial and link logit to compute the odds ratio (OR). Only baseline exposure was considered for participants who developed PUD before the 10-year follow-up and those who did not develop PUD but had been in the cohort for less than 10 years. We also represented Nelson-Aalen survival curves, adjusted for potential confounding variables by means of inverse probability weighting methods, to describe the incidence of PUD over time across tertiles of UPF consumption. Sensitivity analyses was also carried out by rerunning the models under different scenarios: (1) changing energy limits, (2) including participants with prevalent diabetes, CVD and cancer, (3) excluding participants taking NSAIDs and aspirin, (4) excluding participants with prevalent gastrointestinal disorders, (5) excluding participants with obesity, (6) excluding participants with an alcohol intake > 25 g/day if woman and > 50 g/day if man, (7) additionally adjusting for sodium intake, (8) additionally adjusting for the adherence to the Mediterranean diet assessed by Trichopoulou score [29]. A p value < 0.05 was considered statistically significant. Statistical analysis was performed by means of STATA program, version 12.0 (StataCorp LP).

Results

A total of 18,066 participants (62.9% women) were included in the final dataset. The main characteristics of the participants are presented in Table 1. Median age at baseline was 35 years (IQR: 27; 45), and median daily consumption of UPF was 260 g/day (IQR: 187; 357), contributing to 28.9% of total energy intake (IQR: 21.0; 36.0). Table S1 shows the percentage contribution of UPF subgroups to the total UPF consumption.

Table 1 Baseline characteristics of participants according to UPF consumption (n=18,066)

	Tertiles of energy adjusted ultra-processed food consumption		
First
(≤212 g/day)
(n=6022)	Second
(212–318 g/day)
(n=6022)	Third
(>318 g/day)
(n=6022)	
N	%	N	%	N	%	P valueŦ	
Women	4004	66.5	3847	63.9	3506	58.2	<0.001	
Married	3591	59.6	2849	47.3	2323	38.6	<0.001	
Years of university							<0.001	
 3-4 years	2191	36.4	2017	33.5	1911	31.7		
 5-6 years	3231	53.7	3411	56.6	3542	58.8		
 9 years	600	10	594	9.9	569	9.4		
Health career	4138	68.7	3812	63.3	3646	60.5	<0.001	
Smoking status							<0.001	
 Current	1128	18.7	1324	22	1545	25.7		
 Former	1954	32.4	1640	27.2	1351	22.4		
Taking aspirin	220	3.7	182	3	208	3.5	0.147	
Taking NSAID	468	7.8	498	8.3	540	9	0.058	
Helicobacter pylori infection	26	0.4	40	0.7	28	0.5	0.159	
Hiatal Hernia	20	0.3	20	0.3	23	0.4	0.866	
Gastroesophageal reflux	13	0.2	5	0.1	5	0.1	0.062	
	Median	IQR	Median	IQR	Median	IQR	P value*	
Age (years)	41	31; 50	34	27; 44	31	26; 39	<0.001	
BMI (kg/m2)	22.9	20.8; 25.3	22.8	20.7; 25.3	22.9	20.8; 25.5	0.268	
Physical activity (METs/week)	17.6	6.7; 32.4	15.2	5.6; 28.9	15.0	4.3; 30.0	<0.001	
Energy (kcal/day)	2549	2122; 3071	2220	1802; 2718	2452	1996; 3025	<0.001	
Macronutrients intake (% energy)								
 Carbohydrate	44.5	39.4; 49.4	42.8	38.3; 47.2	43.4	38.9; 47.7	<0.001	
 Protein	17.9	16.0; 20.1	18.1	16.2; 20.2	17.2	15.4; 19.2	<0.001	
 Lipid	35.5	30.9; 39.9	37.0	33.2; 40.9	37.5	33.6; 41.1	<0.001	
  SFA	11.4	9.4; 13.4	12.6	10.8; 14.5	13.1	11.3; 15.0	<0.001	
  MUFA	15.3	12.9; 18.0	15.5	13.5; 17.7	15.4	13.6; 17.5	0.030	
  PUFA	4.7	3.9; 5.6	5.0	4.2; 6.1	5.3	4.3; 6.4	<0.001	
 Alcohol	0.8	0.2; 2.4	0.9	0.3; 2.5	0.9	0.2; 2.5	<0.001	
Alcohol consumption (g/day)	2.7	0.6; 8.8	2.8	1.0; 8.1	3.3	1.0; 9.1	<0.001	
Fiber (g/day)	32.8	25.5; 43.3	24.6	19.1; 31.8	23.7	17.9; 31.2	<0.001	
Micronutrients intake								
Sodium (mg/day)	2771	2097; 3660	2763	2059; 3766	3523	2503; 4952	<0.001	
Vit. A (μg/day)	2213	1408; 3253	1495	1065; 2370	1364	956; 2214	<0.001	
Vit. C (mg/day)	324	227; 444	238	169; 332	224	158; 318	<0.001	
Vit. E (μg/day)	7.1	5.3; 10.1	5.9	4.4; 8.2	6.3	4.7; 8.7	<0.001	
Food consumption (servings/day)								
Olive oil (g/day)	25.0	10.7; 29.5	12.3	8.7; 25.8	11.8	8.0; 25.2	<0.001	
Vegetables	2.6	1.8; 3.6	1.9	1.3; 2.8	1.8	1.2; 2.6	<0.001	
Fruit	2.8	1.7; 4.3	1.8	1.1; 2.8	1.6	0.9; 2.6	<0.001	
Red meat	0.5	0.3; 0.7	0.5	0.3; 0.7	0.5	0.3; 0.7	0.002	
Processed meat	1.7	1.2; 2.3	1.8	1.3; 2.3	2.0	1.5; 2.7	<0.001	
Sugar sweetened beverages	0.1	0.0; 0.1	0.1	0.1; 0.3	0.4	0.1; 0.9	<0.001	
High-fat dairy products	1.4	0.6; 2.6	1.3	0.7; 2.2	1.5	0.8; 2.4	<0.001	
Coffee consumption	1	0; 3	1	0; 3	1	0; 3	<0.001	
Ultraprocessed food (servings/day)	2.5	1.9; 3.2	3.7	3.2; 4.3	4.9	4.2; 6.0	<0.001	
Ultraprocessed food (g/day)	157.0	108.8; 186.9	259.8	235.4; 286.7	410.6	357.3; 506.5	<0.001	
Ultraprocessed food/energy (%)	20.3	14.9; 25.7	29.2	23.8; 34.8	36.5	30.0; 43.2	<0.001	
Abbreviations IQR, interquartile range; SFA, saturated fatty acids; MUFA, monounsaturated fatty acids, PUFA, polyunsaturated fatty acids; NSAID, nonsteroidal anti-inflammatory drugs

Ŧ Chi-square test

* Kruskal Wallis test

During a median follow-up of 12.2 years, we recorded 322 new cases of PUD (1.56 cases/1000 person-years). The association between tertiles of UPF consumption and risk of PUD is reported in Table 2. Participants in the highest tertile of UPF consumption had a 52% increased relative risk of PUD compared to participants in the lowest tertile (HR = 1.52, 95%CI: 1.15, 2.00), with a significant dose-response relationship (Ptrend=0.002). A linear association between the UPF consumption and the occurrence of PUD was also confirmed when we included in the Cox regression model the exposure as a continuous variable. We observed a 7% increase in relative risk for every 100 g/day of UPF consumed (HR = 1.07, 95% CI: 1.03, 1.12). Furthermore, when we accounted for changes in UPF consumption (repeated-measures analysis), using the updated data on food consumption after 10 years of follow-up, the association remained statistically significant. Compared with participants in the lowest tertile, those in the highest tertile had a 39% increased risk of PUD (OR = 1.39, 95% CI: 1.03, 1.87; Ptrend = 0.001).

Table 2 Association between consumption of ultra-processed foods and risk of peptic ulcer

	Tertiles of energy-adjusted UPF consumption			
	First
(≤212 g/day)	Second
(212–318 g/day)	Third
(>318 g/day)	P for trend	HR (95% CI)	P value	
No. of cases/no. of person-y	102/69,206	94/69,414	126/68,218				
No. of cases/no. of participants	102/6022	94/6022	126/6022				
Crude model	ref.	1.01 (0.76; 1.35)	1.47 (1.12; 1.92)	0.003			
Multivariable model	ref.	1.09 (0.81; 1.47)	1.52 (1.15; 2.00)	0.002			
Multivariable model (without BMI)	ref.	1.10 (0.82; 1.47)	1.51 (1.15; 2.00)	0.002			
Multivariable model (without energy intake)	ref.	1.05 (0.78; 1.40)	1.49 (1.13; 1.96)	0.003			
Multivariable model (linear, 100 g/day)					1.07 (1.03; 1.12)	0.001	
Repeated measure multivariable model	ref.	1.07 (0.79; 1.47)	1.39 (1.03; 1.87)	0.001			
Multivariable model: adjusted for sex, age (decades), bmi (quartiles), calendar year of recruitment (1999–2001, 2002–2004, 2005–2007, 2008–2010, and from 2011 onwards), health career (yes/no), education (3-4, 5-6, 9 years), marital status (unmarried, married, other, missing), packs of cigarettes (0, 1-12 packs/year, 13-24 packs/year, >24 packs/year, missing), energy intake (quartiles), known Helicobacter pylori infection (yes/no), gastroesophageal reflux (yes/no), hiatal hernia (yes/no), aspirin (yes/no), analgesics (yes/no), coffee (no, 1-2 cups/day, >2 cups/day), alcohol from wine and beer (quartile), and stratified for smoking (categories) and physical activity (quartiles)

The observed HR of 1.52 in our analysis could hypothetically be explained by the presence of an unmeasured confounder associated with UPF consumption and PUD with a HR of 1.78-fold each, beyond the measured confounders, but a weaker confounder could not. Similarly, the lowest confidence interval could be moved to include the null by an unmeasured confounder associated with both UPF consumption and PUD by a HR of 1.36-fold each, above and beyond the measured confounders, but weaker confounding could not do so.

Figure 2 shows the cumulative risk for developing PUD over time across tertiles of UPF consumption. The highest tertile of UPF consumption was associated with higher incidence of PUD.

Fig. 2 Nelson-Aalen estimate of the incidence of peptic ulcer disease according to tertiles of ultra-processed consumption

We also performed a sensitivity analysis to test the robustness of our results, but we did not observe any substantial change in the magnitude of the association in any of the examined scenarios (Table 3).

Table 3 Sensitivity analysis

		Tertiles of energy-adjusted UPF consumption	
No. of cases/no. of person-y	T1	T2	T3	P for trend	
Overall results	322/206,837	1 (ref.)	1.09 (0.81; 1.47)	1.52 (1.15; 2.00)	0.002	
Willett’s energy limits (<800 kcal/d or >4000 kcal/d in men and <500 kcal/d or >3500 kcal/d in women)	298/192,450	1 (ref.)	0.99 (0.73; 1.35)	1.44 (1.08; 1.91)	0.008	
Including participants with prevalent diabetes, CVD or cancer	341/217,437	1 (ref.)	1.06 (0.80; 1.41)	1.47 (1.17; 1.92)	0.003	
Excluding participants taking aspirin and analgesics	271/183,571	1 (ref.)	1.09 (0.79; 1.50)	1.57 (1.17; 2.13)	0.003	
Excluding participants with prevalent gastrointestinal disorders	316/204,812	1 (ref.)	1.07 (0.80; 1.45)	1.48 (1.12; 1.95)	0.004	
Excluding participants with obesity	303/198,598	1 (ref.)	1.12 (0.82; 1.52)	1.61 (1.21; 2.15)	0.001	
Excluding participants with alcohol consumption >25 g/d for women or >50 g/d for men	314/203,550	1 (ref.)	1.12 (0.83; 1.50)	1.51 (1.14; 2.00)	0.003	
Additionally adjusted for sodium intake	322/206,837	1 (ref.)	1.10 (0.82; 1.48)	1.55 (1.16; 2.06)	0.002	
Additionally adjusted for Mediterranean diet	322/206,837	1 (ref.)	1.08 (0.80; 1.46)	1.50 (1.13; 1.99)	0.003	
Multivariable model: adjusted for sex, age (decades), bmi (quartiles), calendar year of recruitment (1999–2001, 2002–2004, 2005–2007, 2008–2010, and from 2011 onwards), health career (yes/no), education (3-4, 5-6, 9 years), marital status (unmarried, married, other, missing), packs of cigarettes (0, 1-12 packs/year, 13-24 packs/year, >24 packs/year, missing), energy intake (quartiles), Helicobacter infection (yes/no), gastroesophageal reflux (yes/no), hiatal hernia (yes/no), aspirin (yes/no), analgesics (yes/no), coffee (no, 1-2 cups/day, >2 cups/day), alcohol from wine and beer (quartile), and stratified for smoking (categories) and physical activity (quartiles)

Discussion

In this prospective cohort study, we found that a higher consumption of UPF was associated with the risk of incident PUD. This result remained consistent in the sensitivity analysis even when excluding participants taking NSAIDs and aspirin and with gastrointestinal disorders, including a known H. pylori infection. However, it should be kept in mind that H. pylori infection is often asymptomatic. Therefore, it is highly likely that many participants did not know they were infected. The further adjustment for the adherence to the Mediterranean diet, dietary pattern rich in unsaturated fatty acids, fiber, vitamins and minerals and antioxidants, and low in salt, did not affect the result. Thus, our findings support the hypothesis that the consumption of UPF could be an environmental factor that increases the risk of PUD. Recent systematic reviews and meta-analyses reported an increased risk of functional gastrointestinal disorders or diseases, including dyspepsia, irritable bowel syndrome [13], and Crohn’s disease [30], associated with higher consumption of UPF. Furthermore, a recent case-control study showed the consumption of UPF associated with a higher risk of stomach adenocarcinoma [31]. However, to the best of our knowledge, this is the first study investigating the association between UPF consumption and PUD.

Several mechanisms could explain the relationship between UPF and PUD. Recent meta-analysis reported that a higher UPF consumption contributed to increase dietary intake of salt and refined carbohydrates, and to reduce the intakes of fiber, vitamins, and antioxidants [32]. Our data confirmed these findings, also showing higher alcohol intake among those who consumed higher amounts of UPF, presumably due to higher consumption of distilled spirits and liquor (alcoholic beverages that fall under the definition of UPF). Epidemiological studies have reported these components in the diet to be positive or negative associated with PUD risk. In addition, results from animal studies have corroborated these findings, providing evidence on possible mechanisms. In particular, some diet components may undermine the integrity of the mucosal barrier, resulting in inflammation and damage, and subsequently, erosion of the gastric mucosa. The mucosal damage could enhance H. pylori colonization and the presence of certain nutrients in the gastric lumen may influence the expression of H. pylori virulence factors associated with the development of PUD and other gastroduodenal diseases [33]. In vivo studies shown salt to alter the viscosity and composition of the protective mucosal barrier [34, 35], potentially exposing the mucosa to the toxic effects of acid and intragastric enzymes, resulting in mucosal damage and inflammation [36]. Moreover, salt has been also shown to facilitate H. pylori colonization both in human and animals [37–39] and increase gene expression of virulence factors which resulted in more virulent bacterial strains [40]. Prospective and geographical studies have confirmed the role of salt, documenting an increased risk of gastric ulcer associated with higher salt intake [20, 41]. Other prospective studies reported the intakes of refined carbohydrates and fiber, especially soluble fiber from fruits, vegetables, and legumes, associated with higher and lower risk of duodenal ulcer, respectively [18, 19]. These findings were corroborated by additional studies showing an increased risk of H. pylori infection associated with carbohydrate/sugar intake and diet glycemic index [42, 43]. Moreover, in patients with duodenal ulcer, it has been observed that the liquid phase of a meal is emptied more rapidly into the duodenum, compared with controls [35]. A rapid rate of gastric emptying in the presence of gastric hypersecretion may play an important role in the pathogenesis of duodenal ulcer. Dietary fiber might delay the gastric emptying explaining its apparent benefit. The relationship between alcohol intake and PUD risk is uncertain. However, alcohol is known to dose-dependently damage the gastric mucosa through numerous mechanisms, including alterations in epithelial transport, disruption of the intercellular junction and mucosal barrier, which allow hydrogen ions to penetrate the mucosa [44]. Moreover, ethanol activates an inflammatory reaction that also participates in gastric mucosal damage [45]. Histological studies indicate that after ethanol administration in concentrations comparable to distillates and spirits (20% and 40% ethanol), the mucosal layer and mucin content of the lining epithelial cells decreased significantly. In addition, the presence of acids aggravated the injury and induced bleeding. The restoration of mucosal damage was completed in 24 h [46]. Alcoholic beverages such as wine and beer may be less harmful to the gastroduodenal mucosa both for lower ethanol content and for the presence of polyphenols, which have shown anti-ulcer effects such as reducing acid secretion, inhibiting pepsin level and activity, and increasing gastric mucus and bicarbonate secretion, as well as enhancing cytoprotective, antioxidative, anti-inflammatory, and antibacterial mucosal defenses against peptic ulcer [47]. Finally, it has been suggested that some vitamins, whose intakes were lower in participants consuming larger amounts of UPF, may protect against PUD through several mechanisms. In animal models, vitamin A increased gastric and duodenal mucus production. Moreover, dietary supplementation of vitamin A reduced the incidence of stress- and aspirin-induced ulcers in rats [48]. Vitamin E, particularly tocopherol and tocotrienol, conferred its protection against ulcerogenic factors/agents mainly through its antioxidant and anti-inflammatory mechanisms [49]. In addition, vitamin C attenuated the oxidative damage induced by NSAIDs and H. pylori to the gastric mucosa [50, 51]. Note, however, that so far only vitamin A intake has been found to be associated with a lower risk of duodenal ulcer in humans [18].

We are well aware that our study is not free of limitations. First, the ulcer diagnosis was self-reported and validation study showed partial validity. Therefore, we have to acknowledge the existence of some misclassification, taking in mind that some of self-reported diagnoses of PUD are gastritis or esophagitis. Nevertheless, the plausible biological mechanisms explained before can be applied as well. Second, we had no information on ulcer location and therefore could not investigate the impact of UPF on gastric and duodenal ulcer risk separately. Third, we had no information on the use of proton pump inhibitors that may have influenced the risk of PUD. However, we controlled the analysis for gastrointestinal disorders, like hiatal hernia and gastroesophageal reflux, that generally require the use of proton pump inhibitors. Fourth, like any FFQ, the one used in this study has the limitation of investigating the consumption of only the foods listed. We are aware that consumption was not specifically required for all commercially available UPF. This may have led to an underestimation of exposure. Nevertheless, this is a validated FFQ investigating a large number of food items (n = 136). Fifth, SUN cohort involves mainly graduate participants, limiting the generalizability of our results. Sixth, since this was a cohort of Spanish graduates, we can assume that almost all participants were Caucasian, and therefore these results cannot be transferred to other ethnicities without prior confirmation. Finally, as in any observational study, we cannot rule out residual confounding. However, adjusted for a wide range of potential confounders using different statistical methods, and the results were consistent. In addition, the E-values for the point estimate supported the observed association. The point estimate could be theoretically explained only by an unmeasured confounder with a hazard ratio of at least 1.78-fold for PUD and for ultra-processed food consumption.

Our study has several strengths. First, the study addresses a topic not previously covered. Second, the study prospective nature, as the assessment of participants’ dietary habits was carried out before the onset of the disease, which reflects the optimal temporal relation between exposure and disease occurrence. Third, the repeated measurements of exposure variable allowed to take into consideration dietary changes occurred overtime. Fourth, we controlled our analysis for NSAID and aspirin use and for the presence of gastroduodenal disorders, including known H. pylori infection, risk factors for PUD. However, as mentioned earlier, it is likely that many participants did not know they were infected due to lack of symptoms. Therefore, it is not possible to extrapolate detailed information about the underlying mechanisms. Fifth, the high cohort response rate. Sixth, the high educational level of participants, which may have facilitated better understanding of the food frequency questionnaire. Seventh, the food frequency questionnaire used to assess dietary habits has been repeatedly validated [52, 53].

In conclusion, our data suggest that the consumption of UPF may be associated with the risk of PUD and other gastric disorders. Given the importance of the topic - individuals with PUD have an increased risk of developing gastric cancer [54] - further studies confirming our findings are strongly requested. Nevertheless, UPF consumption should still be discouraged because of the known negative associations with health status.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We thank the SUN participants for their continued participation and collaboration with the project.

Author contributions

Conceptualization, A.L. and M.B.-R.; methodology, A.L.; validation, C.DLF-A., M.V., and M.B.-R.; formal analysis, A.L.; writing—original draft preparation, A.L.; writing—review and editing, A.L., C.DLF-A., M.V., C.S.-O., M.Á.M.-G., F.M., and M.B.-R.; supervision, M.B.-R.; funding acquisition, M.Á.M.-G. and M.B.-R. All authors have read and agreed to the published version of the manuscript.

Funding

Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement. This research was funded by the Spanish Government—Instituto de Salud Carlos III with the co-funding from the European Union, grants: PI20/00564, and PI23/01332; and the Centro de Investigacion Biomedica en Fisiopatología de la Obesidad y Nutrición [CIBERobn, group: CB12/03/30017].

Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement.

Declarations

Ethical approval

The project conformed to the guidelines established in the Declaration of Helsinki, and the Human Research Ethical Committee at the University of Navarra approved all the study procedures (091/2008). Voluntary completion of the first questionnaire was considered to imply informed consent.

Conflict of interest

The authors declare that they have no conflict of interest.
==== Refs
References

1. Gibney MJ Ultra-processed foods: definitions and Policy issues Curr Dev Nutr 2019 3 2 nzy077 10.1093/cdn/nzy077 30820487
Gibney MJ (2019) Ultra-processed foods: definitions and Policy issues. Curr Dev Nutr 3(2):nzy077. 10.1093/cdn/nzy07730820487 10.1093/cdn/nzy077
2. Rauber F Steele EM Louzada MLC Millett C Monteiro CA Levy RB Ultra-processed food consumption and indicators of obesity in the United Kingdom population (2008–2016) PLoS ONE 2020 15 5 e0232676 e0232676 10.1371/journal.pone.0232676 32357191
Rauber F, Steele EM, Louzada MLC, Millett C, Monteiro CA, Levy RB (2020) Ultra-processed food consumption and indicators of obesity in the United Kingdom population (2008–2016). PLoS ONE 15(5):e0232676–e0232676. 10.1371/journal.pone.023267632357191 10.1371/journal.pone.0232676
3. Martínez Steele E Baraldi LG Louzada ML Moubarac JC Mozaffarian D Monteiro CA Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study BMJ Open 2016 6 3 e009892 10.1136/bmjopen-2015-009892 26962035
Martínez Steele E, Baraldi LG, Louzada ML, Moubarac JC, Mozaffarian D, Monteiro CA (2016) Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study. BMJ Open 6(3):e009892. 10.1136/bmjopen-2015-00989226962035 10.1136/bmjopen-2015-009892
4. Moubarac JC Batal M Louzada ML Martinez Steele E Monteiro CA Consumption of ultra-processed foods predicts diet quality in Canada Appetite 2017 108 512 520 10.1016/j.appet.2016.11.006 27825941
Moubarac JC, Batal M, Louzada ML, Martinez Steele E, Monteiro CA (2017) Consumption of ultra-processed foods predicts diet quality in Canada. Appetite 108:512–520. 10.1016/j.appet.2016.11.00627825941 10.1016/j.appet.2016.11.006
5. Rauber F, da Costa Louzada ML, Steele EM, Millett C, Monteiro CA, Levy RB (2018) Ultra-processed Food Consumption and chronic non-communicable diseases-related Dietary Nutrient Profile in the UK (2008–2014). Nutrients 10(5). 10.3390/nu10050587
6. Mendonca RD Pimenta AM Gea A de la Fuente-Arrillaga C Martinez-Gonzalez MA Lopes AC Bes-Rastrollo M Ultraprocessed food consumption and risk of overweight and obesity: the University of Navarra Follow-Up (SUN) cohort study Am J Clin Nutr 2016 104 5 1433 1440 10.3945/ajcn.116.135004 27733404
Mendonca RD, Pimenta AM, Gea A, de la Fuente-Arrillaga C, Martinez-Gonzalez MA, Lopes AC, Bes-Rastrollo M (2016) Ultraprocessed food consumption and risk of overweight and obesity: the University of Navarra Follow-Up (SUN) cohort study. Am J Clin Nutr 104(5):1433–1440. 10.3945/ajcn.116.13500427733404 10.3945/ajcn.116.135004
7. Rauber F Chang K Vamos EP da Costa Louzada ML Monteiro CA Millett C Levy RB Â Ultra-processed food consumption and risk of obesity: a prospective cohort study of UK Biobank Eur J Nutr 2021 60 4 2169 2180 10.1007/s00394-020-02367-1 33070213
Rauber F, Chang K, Vamos EP, da Costa Louzada ML, Monteiro CA, Millett C, Levy RB (2021) Â Ultra-processed food consumption and risk of obesity: a prospective cohort study of UK Biobank. Eur J Nutr 60(4):2169–2180. 10.1007/s00394-020-02367-133070213 10.1007/s00394-020-02367-1
8. Mambrini SP, Menichetti F, Ravella S, Pellizzari M, De Amicis R, Foppiani A, Battezzati A, Bertoli S, Leone A (2023) Ultra-processed Food Consumption and Incidence of Obesity and cardiometabolic risk factors in adults: a systematic review of prospective studies. Nutrients 15(11). 10.3390/nu15112583
9. Llavero-Valero M Escalada-San Martín J Martínez-González MA Basterra-Gortari FJ de la Fuente-Arrillaga C Bes-Rastrollo M Ultra-processed foods and type-2 diabetes risk in the SUN project: a prospective cohort study Clin Nutr 2021 40 5 2817 2824 10.1016/j.clnu.2021.03.039 33933748
Llavero-Valero M, Escalada-San Martín J, Martínez-González MA, Basterra-Gortari FJ, de la Fuente-Arrillaga C, Bes-Rastrollo M (2021) Ultra-processed foods and type-2 diabetes risk in the SUN project: a prospective cohort study. Clin Nutr 40(5):2817–2824. 10.1016/j.clnu.2021.03.03933933748 10.1016/j.clnu.2021.03.039
10. Leone A, Martínez-González M, Craig W, Fresán U, Gómez-Donoso C, Bes-Rastrollo M (2021) Pre-gestational consumption of Ultra-processed Foods and Risk of Gestational Diabetes in a Mediterranean Cohort. SUN Project Nutrients 13(7). 10.3390/nu13072202
11. Srour B Fezeu LK Kesse-Guyot E Alles B Mejean C Andrianasolo RM Chazelas E Deschasaux M Hercberg S Galan P Monteiro CA Julia C Touvier M Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Sante) BMJ 2019 365 l1451 10.1136/bmj.l1451 31142457
Srour B, Fezeu LK, Kesse-Guyot E, Alles B, Mejean C, Andrianasolo RM, Chazelas E, Deschasaux M, Hercberg S, Galan P, Monteiro CA, Julia C, Touvier M (2019) Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Sante). BMJ 365:l1451. 10.1136/bmj.l145131142457 10.1136/bmj.l1451
12. Juul F Vaidean G Lin Y Deierlein AL Parekh N Ultra-processed Foods and Incident Cardiovascular Disease in the Framingham offspring study J Am Coll Cardiol 2021 77 12 1520 1531 10.1016/j.jacc.2021.01.047 33766258
Juul F, Vaidean G, Lin Y, Deierlein AL, Parekh N (2021) Ultra-processed Foods and Incident Cardiovascular Disease in the Framingham offspring study. J Am Coll Cardiol 77(12):1520–1531. 10.1016/j.jacc.2021.01.04733766258 10.1016/j.jacc.2021.01.047
13. Lane MM Davis JA Beattie S Gómez-Donoso C Loughman A O’Neil A Jacka F Berk M Page R Marx W Rocks T Ultraprocessed food and chronic noncommunicable diseases: a systematic review and meta-analysis of 43 observational studies Obes Rev 2021 22 3 e13146 10.1111/obr.13146 33167080
Lane MM, Davis JA, Beattie S, Gómez-Donoso C, Loughman A, O’Neil A, Jacka F, Berk M, Page R, Marx W, Rocks T (2021) Ultraprocessed food and chronic noncommunicable diseases: a systematic review and meta-analysis of 43 observational studies. Obes Rev 22(3):e13146. 10.1111/obr.1314633167080 10.1111/obr.13146
14. Schnabel L Buscail C Sabate JM Bouchoucha M Kesse-Guyot E Allès B Touvier M Monteiro CA Hercberg S Benamouzig R Julia C Association between Ultra-processed Food Consumption and Functional Gastrointestinal disorders: results from the French NutriNet-Santé cohort Am J Gastroenterol 2018 113 8 1217 1228 10.1038/s41395-018-0137-1 29904158
Schnabel L, Buscail C, Sabate JM, Bouchoucha M, Kesse-Guyot E, Allès B, Touvier M, Monteiro CA, Hercberg S, Benamouzig R, Julia C (2018) Association between Ultra-processed Food Consumption and Functional Gastrointestinal disorders: results from the French NutriNet-Santé cohort. Am J Gastroenterol 113(8):1217–1228. 10.1038/s41395-018-0137-129904158 10.1038/s41395-018-0137-1
15. Lo CH Khandpur N Rossato SL Lochhead P Lopes EW Burke KE Richter JM Song M Ardisson Korat AV Sun Q Fung TT Khalili H Chan AT Ananthakrishnan AN Ultra-processed Foods and Risk of Crohn’s Disease and Ulcerative Colitis: a prospective cohort study Clin Gastroenterol Hepatol 2022 20 6 e1323 e1337 10.1016/j.cgh.2021.08.031 34461300
Lo CH, Khandpur N, Rossato SL, Lochhead P, Lopes EW, Burke KE, Richter JM, Song M, Ardisson Korat AV, Sun Q, Fung TT, Khalili H, Chan AT, Ananthakrishnan AN (2022) Ultra-processed Foods and Risk of Crohn’s Disease and Ulcerative Colitis: a prospective cohort study. Clin Gastroenterol Hepatol 20(6):e1323–e1337. 10.1016/j.cgh.2021.08.03134461300 10.1016/j.cgh.2021.08.031
16. Narula N Wong ECL Dehghan M Mente A Rangarajan S Lanas F Lopez-Jaramillo P Rohatgi P Lakshmi PVM Varma RP Orlandini A Avezum A Wielgosz A Poirier P Almadi MA Altuntas Y Ng KK Chifamba J Yeates K Puoane T Khatib R Yusuf R Boström KB Zatonska K Iqbal R Weida L Yibing Z Sidong L Dans A Yusufali A Mohammadifard N Marshall JK Moayyedi P Reinisch W Yusuf S Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study BMJ 2021 374 n1554 10.1136/bmj.n1554 34261638
Narula N, Wong ECL, Dehghan M, Mente A, Rangarajan S, Lanas F, Lopez-Jaramillo P, Rohatgi P, Lakshmi PVM, Varma RP, Orlandini A, Avezum A, Wielgosz A, Poirier P, Almadi MA, Altuntas Y, Ng KK, Chifamba J, Yeates K, Puoane T, Khatib R, Yusuf R, Boström KB, Zatonska K, Iqbal R, Weida L, Yibing Z, Sidong L, Dans A, Yusufali A, Mohammadifard N, Marshall JK, Moayyedi P, Reinisch W, Yusuf S (2021) Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study. BMJ 374:n1554. 10.1136/bmj.n155434261638 10.1136/bmj.n1554
17. Loscalzo J, Fauci AS, Kasper DL, Hauser S, Longo DL, Jameson JL (2022) Harrison’s principles of internal medicine. Principles of internal medicine, Twenty First edition. edn. New York
18. Aldoori WH Giovannucci EL Stampfer MJ Rimm EB Wing AL Willett WC Prospective study of diet and the risk of duodenal ulcer in men Am J Epidemiol 1997 145 1 42 50 10.1093/oxfordjournals.aje.a009030 8982021
Aldoori WH, Giovannucci EL, Stampfer MJ, Rimm EB, Wing AL, Willett WC (1997) Prospective study of diet and the risk of duodenal ulcer in men. Am J Epidemiol 145(1):42–50. 10.1093/oxfordjournals.aje.a0090308982021 10.1093/oxfordjournals.aje.a009030
19. Katschinski BD Logan RF Edmond M Langman MJ Duodenal ulcer and refined carbohydrate intake: a case-control study assessing dietary fibre and refined sugar intake Gut 1990 31 9 993 996 10.1136/gut.31.9.993 2170250
Katschinski BD, Logan RF, Edmond M, Langman MJ (1990) Duodenal ulcer and refined carbohydrate intake: a case-control study assessing dietary fibre and refined sugar intake. Gut 31(9):993–996. 10.1136/gut.31.9.9932170250 10.1136/gut.31.9.993
20. Kato I Nomura AM Stemmermann GN Chyou PH A prospective study of gastric and duodenal ulcer and its relation to smoking, alcohol, and diet Am J Epidemiol 1992 135 5 521 530 10.1093/oxfordjournals.aje.a116319 1570818
Kato I, Nomura AM, Stemmermann GN, Chyou PH (1992) A prospective study of gastric and duodenal ulcer and its relation to smoking, alcohol, and diet. Am J Epidemiol 135(5):521–530. 10.1093/oxfordjournals.aje.a1163191570818 10.1093/oxfordjournals.aje.a116319
21. Martinez-Gonzalez MA The SUN cohort study (Seguimiento University of Navarra) Public Health Nutr 2006 9 1a 127 131 10.1079/PHN2005935 16512960
Martinez-Gonzalez MA (2006) The SUN cohort study (Seguimiento University of Navarra). Public Health Nutr 9(1a):127–13116512960 10.1079/PHN2005935
22. Martin-Moreno JM Boyle P Gorgojo L Maisonneuve P Fernandez-Rodriguez JC Salvini S Willett WC Development and validation of a food frequency questionnaire in Spain Int J Epidemiol 1993 22 3 512 519 10.1093/ije/22.3.512 8359969
Martin-Moreno JM, Boyle P, Gorgojo L, Maisonneuve P, Fernandez-Rodriguez JC, Salvini S, Willett WC (1993) Development and validation of a food frequency questionnaire in Spain. Int J Epidemiol 22(3):512–519. 10.1093/ije/22.3.5128359969 10.1093/ije/22.3.512
23. Monteiro CA Cannon G Levy R Moubarac J-C Jaime P Martins AP Canella D Louzada M Parra D NOVA. The star shines bright World Nutr 2016 7 1–3 28 38
Monteiro CA, Cannon G, Levy R, Moubarac J-C, Jaime P, Martins AP, Canella D, Louzada M, Parra D (2016) NOVA. The star shines bright. World Nutr 7(1–3):28–38
24. Willett WC, Howe GR, Kushi LH (1997) Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 65 (4 Suppl):1220S-1228S; discussion 1229S-1231S. 10.1093/ajcn/65.4.1220S
25. Bes-Rastrollo M Pérez Valdivieso JR Sánchez-Villegas A Alonso A Martínez-González MA Validación Del peso e índice de masa corporal auto-declarados de Los participantes de una cohorte de graduados universitarios Rev Esp Obes 2005 3 6 183 189
Bes-Rastrollo M, Pérez Valdivieso JR, Sánchez-Villegas A, Alonso A, Martínez-González MA (2005) Validación Del peso e índice de masa corporal auto-declarados de Los participantes de una cohorte de graduados universitarios. Rev Esp Obes 3(6):183–189
26. Martinez-Gonzalez MA Lopez-Fontana C Varo JJ Sanchez-Villegas A Martinez JA Validation of the Spanish version of the physical activity questionnaire used in the nurses’ Health Study and the Health professionals’ follow-up study Public Health Nutr 2005 8 7 920 927 10.1079/PHN2005745 16277809
Martinez-Gonzalez MA, Lopez-Fontana C, Varo JJ, Sanchez-Villegas A, Martinez JA (2005) Validation of the Spanish version of the physical activity questionnaire used in the nurses’ Health Study and the Health professionals’ follow-up study. Public Health Nutr 8(7):920–92716277809 10.1079/PHN2005745
27. Hernán MA Hernández-Díaz S Werler MM Mitchell AA Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology Am J Epidemiol 2002 155 2 176 184 10.1093/aje/155.2.176 11790682
Hernán MA, Hernández-Díaz S, Werler MM, Mitchell AA (2002) Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol 155(2):176–184. 10.1093/aje/155.2.17611790682 10.1093/aje/155.2.176
28. VanderWeele TJ Ding P Sensitivity analysis in Observational Research: introducing the E-Value Ann Intern Med 2017 167 4 268 274 10.7326/m16-2607 28693043
VanderWeele TJ, Ding P (2017) Sensitivity analysis in Observational Research: introducing the E-Value. Ann Intern Med 167(4):268–274. 10.7326/m16-260728693043 10.7326/m16-2607
29. Trichopoulou A Costacou T Bamia C Trichopoulos D Adherence to a Mediterranean diet and survival in a Greek population N Engl J Med 2003 348 26 2599 2608 10.1056/NEJMoa025039 12826634
Trichopoulou A, Costacou T, Bamia C, Trichopoulos D (2003) Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 348(26):2599–2608. 10.1056/NEJMoa02503912826634 10.1056/NEJMoa025039
30. Narula N Chang NH Mohammad D Wong ECL Ananthakrishnan AN Chan SSM Carbonnel F Meyer A Food Processing and Risk of Inflammatory Bowel Disease: a systematic review and Meta-analysis Clin Gastroenterol Hepatol 2023 10.1016/j.cgh.2023.01.012 37391059
Narula N, Chang NH, Mohammad D, Wong ECL, Ananthakrishnan AN, Chan SSM, Carbonnel F, Meyer A (2023) Food Processing and Risk of Inflammatory Bowel Disease: a systematic review and Meta-analysis. Clin Gastroenterol Hepatol. 10.1016/j.cgh.2023.01.01237391059 10.1016/j.cgh.2023.01.012
31. Peres SV Silva DRM Coimbra FJF Fagundes MA Auzier JJN Pelosof AG Araujo MS Assumpção PP Curado MP Consumption of processed and ultra-processed foods by patients with stomach adenocarcinoma: a multicentric case-control study in the Amazon and southeast regions of Brazil Cancer Causes Control 2022 33 6 889 898 10.1007/s10552-022-01567-w 35362791
Peres SV, Silva DRM, Coimbra FJF, Fagundes MA, Auzier JJN, Pelosof AG, Araujo MS, Assumpção PP, Curado MP (2022) Consumption of processed and ultra-processed foods by patients with stomach adenocarcinoma: a multicentric case-control study in the Amazon and southeast regions of Brazil. Cancer Causes Control 33(6):889–898. 10.1007/s10552-022-01567-w35362791 10.1007/s10552-022-01567-w
32. Martini D, Godos J, Bonaccio M, Vitaglione P, Grosso G (2021) Ultra-processed Foods and Nutritional Dietary Profile: a Meta-analysis of nationally Representative Samples. Nutrients 13(10). 10.3390/nu13103390
33. Chang WL Yeh YC Sheu BS The impacts of H. Pylori virulence factors on the development of gastroduodenal diseases J Biomed Sci 2018 25 1 68 10.1186/s12929-018-0466-9 30205817
Chang WL, Yeh YC, Sheu BS (2018) The impacts of H. Pylori virulence factors on the development of gastroduodenal diseases. J Biomed Sci 25(1):68. 10.1186/s12929-018-0466-930205817 10.1186/s12929-018-0466-9
34. Kato S Tsukamoto T Mizoshita T Tanaka H Kumagai T Ota H Katsuyama T Asaka M Tatematsu M High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells Int J Cancer 2006 119 7 1558 1566 10.1002/ijc.21810 16646055
Kato S, Tsukamoto T, Mizoshita T, Tanaka H, Kumagai T, Ota H, Katsuyama T, Asaka M, Tatematsu M (2006) High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells. Int J Cancer 119(7):1558–1566. 10.1002/ijc.2181016646055 10.1002/ijc.21810
35. Tatematsu M Takahashi M Fukushima S Hananouchi M Shirai T Effects in rats of sodium chloride on experimental gastric cancers induced by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide J Natl Cancer Inst 1975 55 1 101 106 10.1093/jnci/55.1.101 808633
Tatematsu M, Takahashi M, Fukushima S, Hananouchi M, Shirai T (1975) Effects in rats of sodium chloride on experimental gastric cancers induced by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide. J Natl Cancer Inst 55(1):101–106. 10.1093/jnci/55.1.101808633 10.1093/jnci/55.1.101
36. Takahashi M Hasegawa R Enhancing effects of dietary salt on both initiation and promotion stages of rat gastric carcinogenesis Princess Takamatsu Symp 1985 16 169 182 3916194
Takahashi M, Hasegawa R (1985) Enhancing effects of dietary salt on both initiation and promotion stages of rat gastric carcinogenesis. Princess Takamatsu Symp 16:169–1823916194
37. Tsugane S Tei Y Takahashi T Watanabe S Sugano K Salty food intake and risk of Helicobacter pylori infection Jpn J Cancer Res 1994 85 5 474 478 10.1111/j.1349-7006.1994.tb02382.x 8014104
Tsugane S, Tei Y, Takahashi T, Watanabe S, Sugano K (1994) Salty food intake and risk of Helicobacter pylori infection. Jpn J Cancer Res 85(5):474–478. 10.1111/j.1349-7006.1994.tb02382.x8014104 10.1111/j.1349-7006.1994.tb02382.x
38. Beevers DG Lip GY Blann AD Salt intake and Helicobacter pylori infection J Hypertens 2004 22 8 1475 1477 10.1097/01.hjh.0000133736.77866.77 15257168
Beevers DG, Lip GY, Blann AD (2004) Salt intake and Helicobacter pylori infection. J Hypertens 22(8):1475–1477. 10.1097/01.hjh.0000133736.77866.7715257168 10.1097/01.hjh.0000133736.77866.77
39. Fox JG Dangler CA Taylor NS King A Koh TJ Wang TC High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice Cancer Res 1999 59 19 4823 4828 10519391
Fox JG, Dangler CA, Taylor NS, King A, Koh TJ, Wang TC (1999) High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res 59(19):4823–482810519391
40. Gancz H Jones KR Merrell DS Sodium chloride affects Helicobacter pylori growth and gene expression J Bacteriol 2008 190 11 4100 4105 10.1128/jb.01728-07 18375562
Gancz H, Jones KR, Merrell DS (2008) Sodium chloride affects Helicobacter pylori growth and gene expression. J Bacteriol 190(11):4100–4105. 10.1128/jb.01728-0718375562 10.1128/jb.01728-07
41. Stemmermann G Haenszel W Locke F Epidemiologic pathology of gastric ulcer and gastric carcinoma among Japanese in Hawaii J Natl Cancer Inst 1977 58 1 13 20 10.1093/jnci/58.1.13 833857
Stemmermann G, Haenszel W, Locke F (1977) Epidemiologic pathology of gastric ulcer and gastric carcinoma among Japanese in Hawaii. J Natl Cancer Inst 58(1):13–20. 10.1093/jnci/58.1.13833857 10.1093/jnci/58.1.13
42. Sohouli MH Haghshenas N Pouladi F Sayyari A Olang B Găman MA Kord-Varkaneh H Fatahi S Association between glycemic index and Helicobacter pylori infection risk among adults: a case-control study Nutrition 2021 83 111069 10.1016/j.nut.2020.111069 33348108
Sohouli MH, Haghshenas N, Pouladi F, Sayyari A, Olang B, Găman MA, Kord-Varkaneh H, Fatahi S (2021) Association between glycemic index and Helicobacter pylori infection risk among adults: a case-control study. Nutrition 83:111069. 10.1016/j.nut.2020.11106933348108 10.1016/j.nut.2020.111069
43. Xia Y Meng G Zhang Q Liu L Wu H Shi H Bao X Su Q Gu Y Fang L Yu F Yang H Yu B Sun S Wang X Zhou M Jia Q Zhao H Song K Niu K Dietary patterns are Associated with Helicobacter Pylori infection in Chinese adults: a cross-sectional study Sci Rep 2016 6 32334 10.1038/srep32334 27573193
Xia Y, Meng G, Zhang Q, Liu L, Wu H, Shi H, Bao X, Su Q, Gu Y, Fang L, Yu F, Yang H, Yu B, Sun S, Wang X, Zhou M, Jia Q, Zhao H, Song K, Niu K (2016) Dietary patterns are Associated with Helicobacter Pylori infection in Chinese adults: a cross-sectional study. Sci Rep 6:32334. 10.1038/srep3233427573193 10.1038/srep32334
44. Bor S Bor-Caymaz C Tobey NA Abdulnour-Nakhoul S Orlando RC Esophageal exposure to ethanol increases risk of acid damage in rabbit esophagus Dig Dis Sci 1999 44 2 290 300 10.1023/a:1026646215879 10063914
Bor S, Bor-Caymaz C, Tobey NA, Abdulnour-Nakhoul S, Orlando RC (1999) Esophageal exposure to ethanol increases risk of acid damage in rabbit esophagus. Dig Dis Sci 44(2):290–300. 10.1023/a:102664621587910063914 10.1023/a:1026646215879
45. Gasbarrini A D’Aversa F Di Rienzo T Franceschi F Nutrients affecting gastric barrier Dig Dis 2014 32 3 243 248 10.1159/000357856 24732190
Gasbarrini A, D’Aversa F, Di Rienzo T, Franceschi F (2014) Nutrients affecting gastric barrier. Dig Dis 32(3):243–248. 10.1159/00035785624732190 10.1159/000357856
46. Dinoso VP Chey WY Siplet H Lorber SH Effects of ethanol on the gastric mucosa of the Heidenhain pouch of dogs Am J Dig Dis 1970 15 9 809 817 10.1007/bf02236042 5311761
Dinoso VP, Chey WY, Siplet H, Lorber SH (1970) Effects of ethanol on the gastric mucosa of the Heidenhain pouch of dogs. Am J Dig Dis 15(9):809–817. 10.1007/bf022360425311761 10.1007/bf02236042
47. Zhang W, Lian Y, Li Q, Sun L, Chen R, Lai X, Lai Z, Yuan E, Sun S (2020) Preventative and therapeutic potential of flavonoids in peptic ulcers. Molecules 25(20). 10.3390/molecules25204626
48. Mahmood T Tenenbaum S Niu XT Levenson SM Seifter E Demetriou AA Prevention of duodenal ulcer formation in the rat by dietary vitamin a supplementation JPEN J Parenter Enter Nutr 1986 10 1 74 77 10.1177/014860718601000174
Mahmood T, Tenenbaum S, Niu XT, Levenson SM, Seifter E, Demetriou AA (1986) Prevention of duodenal ulcer formation in the rat by dietary vitamin a supplementation. JPEN J Parenter Enter Nutr 10(1):74–77. 10.1177/01486071860100017410.1177/014860718601000174
49. Kamisah Y Qodriyah HM Chua KH Nur Azlina MF Vitamin E: a potential therapy for gastric mucosal injury Pharm Biol 2014 52 12 1591 1597 10.3109/13880209.2014.902082 25026358
Kamisah Y, Qodriyah HM, Chua KH, Nur Azlina MF (2014) Vitamin E: a potential therapy for gastric mucosal injury. Pharm Biol 52(12):1591–1597. 10.3109/13880209.2014.90208225026358 10.3109/13880209.2014.902082
50. Koc M Imik H Odabasoglu F Gastroprotective and anti-oxidative properties of ascorbic acid on indomethacin-induced gastric injuries in rats Biol Trace Elem Res 2008 126 1–3 222 236 10.1007/s12011-008-8205-9 18726076
Koc M, Imik H, Odabasoglu F (2008) Gastroprotective and anti-oxidative properties of ascorbic acid on indomethacin-induced gastric injuries in rats. Biol Trace Elem Res 126(1–3):222–236. 10.1007/s12011-008-8205-918726076 10.1007/s12011-008-8205-9
51. Shi LQ Zheng RL DNA damage and oxidative stress induced by Helicobacter pylori in gastric epithelial cells: protection by vitamin C and sodium selenite Pharmazie 2006 61 7 631 637 16889072
Shi LQ, Zheng RL (2006) DNA damage and oxidative stress induced by Helicobacter pylori in gastric epithelial cells: protection by vitamin C and sodium selenite. Pharmazie 61(7):631–63716889072
52. de la Fuente-Arrillaga C Ruiz ZV Bes-Rastrollo M Sampson L Martinez-Gonzalez MA Reproducibility of an FFQ validated in Spain Public Health Nutr 2010 13 9 1364 1372 10.1017/s1368980009993065 20105389
de la Fuente-Arrillaga C, Ruiz ZV, Bes-Rastrollo M, Sampson L, Martinez-Gonzalez MA (2010) Reproducibility of an FFQ validated in Spain. Public Health Nutr 13(9):1364–1372. 10.1017/s136898000999306520105389 10.1017/s1368980009993065
53. Fernandez-Ballart JD Pinol JL Zazpe I Corella D Carrasco P Toledo E Perez-Bauer M Martinez-Gonzalez MA Salas-Salvado J Martin-Moreno JM Relative validity of a semi-quantitative food-frequency questionnaire in an elderly Mediterranean population of Spain Br J Nutr 2010 103 12 1808 1816 10.1017/s0007114509993837 20102675
Fernandez-Ballart JD, Pinol JL, Zazpe I, Corella D, Carrasco P, Toledo E, Perez-Bauer M, Martinez-Gonzalez MA, Salas-Salvado J, Martin-Moreno JM (2010) Relative validity of a semi-quantitative food-frequency questionnaire in an elderly Mediterranean population of Spain. Br J Nutr 103(12):1808–1816. 10.1017/s000711450999383720102675 10.1017/s0007114509993837
54. Paragomi P, Dabo B, Pelucchi C, Bonzi R, Bako AT, Sanusi NM, Nguyen QH, Zhang ZF, Palli D, Ferraroni M, Vu KT, Yu GP, Turati F, Zaridze D, Maximovitch D, Hu J, Mu L, Boccia S, Pastorino R, Tsugane S, Hidaka A, Kurtz RC, Lagiou A, Lagiou P, Camargo MC, Curado MP, Lunet N, Vioque J, Boffetta P, Negri E, La Vecchia C, Luu HN (2022) The Association between Peptic Ulcer Disease and gastric Cancer: results from the stomach Cancer Pooling (StoP) Project Consortium. Cancers (Basel) 14(19). 10.3390/cancers14194905
