<i>Helicobacter pylori</i> prevalence in Indonesia: Higher infection risk in Eastern region population

Hasan Maulahela; Dalla Doohan; Yudith Annisa Ayu Rezkhita; Ari Fahrial Syam; Langgeng Agung Waskito; Camilia Metadea Aji Savitri; Marselino Richardo; Abdul Rahman; Yoma Sari Namara; Hamzah Shatri; Andri Sanityoso; Gontar Alamsyah Siregar; Eko Sudarmo; Tomohisa Uchida; Ratha-korn Vilaichone; Yoshio Yamaoka; Muhammad Miftahussurur

doi:10.12688/f1000research.127094.2

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Research Article

Revised

Helicobacter pylori prevalence in Indonesia: Higher infection risk in Eastern region population

[version 2; peer review: 2 approved with reservations]

Hasan Maulahela¹^*, Dalla Doohan^2-4^*, Yudith Annisa Ayu Rezkhita^2,5, [...] Ari Fahrial Syam¹, Langgeng Agung Waskito^2,6,7, Camilia Metadea Aji Savitri^2,8, Marselino Richardo⁹, Abdul Rahman¹⁰, Yoma Sari Namara¹¹, Hamzah Shatri¹², Andri Sanityoso¹², Gontar Alamsyah Siregar¹³, Eko Sudarmo¹⁴, Tomohisa Uchida¹⁵, Ratha-korn Vilaichone¹⁶, Yoshio Yamaoka⁸, Muhammad Miftahussurur ^2,17

Hasan Maulahela¹^*, Dalla Doohan^2-4^*, [...] Yudith Annisa Ayu Rezkhita^2,5, Ari Fahrial Syam¹, Langgeng Agung Waskito^2,6,7, Camilia Metadea Aji Savitri^2,8, Marselino Richardo⁹, Abdul Rahman¹⁰, Yoma Sari Namara¹¹, Hamzah Shatri¹², Andri Sanityoso¹², Gontar Alamsyah Siregar¹³, Eko Sudarmo¹⁴, Tomohisa Uchida¹⁵, Ratha-korn Vilaichone¹⁶, Yoshio Yamaoka⁸, Muhammad Miftahussurur ^2,17

^* Equal contributors

PUBLISHED 16 Jan 2024

Author details Author details

¹ Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, 10430, Indonesia
² Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangg, Surabaya, 60286, Indonesia
³ Department of General Surgery, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60132, Indonesia
⁴ Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, 60132, Indonesia
⁵ Department of Internal Medicine, Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, 60115, Indonesia
⁶ Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60132, Indonesia
⁷ Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, 60132, Indonesia
⁸ Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, 870-1124, Japan
⁹ Department of Internal Medicine, Merauke City General Hospital, Merauke, 99613, Indonesia
¹⁰ Department of Internal Medicine, Kolaka General Hospital, Kolaka, 93914, Indonesia
¹¹ Department of Internal Medicine, Anutapura General Hospital, Palu, 94225, Indonesia
¹² Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, 10430, Indonesia
¹³ Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, 20155, Indonesia
¹⁴ Department of Internal Medicine, Dr. Hasan Busori General Hospital, Ternate, 97721, Indonesia
¹⁵ Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, 870-1124, Japan
¹⁶ Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Thammasat University Hospital, Khlong Nueng, Pathumthani, 12120, Thailand
¹⁷ Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60132, Indonesia

Hasan Maulahela
Roles: Conceptualization, Investigation, Writing – Original Draft Preparation

Dalla Doohan
Roles: Formal Analysis, Methodology, Writing – Original Draft Preparation

Yudith Annisa Ayu Rezkhita
Roles: Conceptualization, Project Administration, Writing – Review & Editing

Ari Fahrial Syam
Roles: Conceptualization, Project Administration, Resources, Writing – Review & Editing

Langgeng Agung Waskito
Roles: Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Camilia Metadea Aji Savitri
Roles: Formal Analysis, Investigation, Writing – Original Draft Preparation

Marselino Richardo
Roles: Investigation, Resources, Validation, Writing – Original Draft Preparation

Abdul Rahman
Roles: Investigation, Resources, Validation, Writing – Original Draft Preparation

Yoma Sari Namara
Roles: Investigation, Resources, Validation, Writing – Original Draft Preparation

Hamzah Shatri
Roles: Investigation, Resources, Validation, Writing – Original Draft Preparation

Andri Sanityoso
Roles: Investigation, Resources, Validation, Writing – Original Draft Preparation

Gontar Alamsyah Siregar
Roles: Methodology, Project Administration, Writing – Review & Editing

Eko Sudarmo
Roles: Investigation, Resources, Validation, Writing – Original Draft Preparation

Tomohisa Uchida
Roles: Data Curation, Formal Analysis, Methodology, Supervision

Ratha-korn Vilaichone
Roles: Conceptualization, Supervision, Writing – Review & Editing

Yoshio Yamaoka
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Resources, Writing – Review & Editing

Muhammad Miftahussurur
Roles: Conceptualization, Project Administration, Supervision, Writing – Review & Editing

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Abstract

Background

Helicobacter pylori (H. pylori) infection status in Indonesia might be higher than the actual prevalence. A comprehensive epidemiologic study is necessary to explore infection susceptibility by demographic characteristics, especially between Indonesia’s Eastern and Western regions.

Methods

We included our recent survey and data from our previous studies with 1,172 endoscopic examinations from 19 cities throughout Indonesia from January 2014 to March 2017. H. pylori infection was diagnosed based on a combination of four different tests. Using a criterion of one positive result between four tests, we found that 190 subjects (190/1,158; 16.4%) were H. pylori positive. A total of 939 subjects who has complete data were analyzed for risk factors of H. pylori infection.

Results

Prevalence was slightly higher in the Eastern region compared with the Western region of Indonesia (79/277; 59.4% vs. 54/529; 40.6%). Living in the Eastern region imposes a higher risk of infection (OR 5.33, 95%CI 1.17–24.26). Timor ethnicity had the highest prevalence (15/28; 53.6%), followed by Buginese ethnicity (21/74; 28.4%), and Papuan ethnicity (18/64; 28.1%) in the Eastern region. As an ethnicity with a high prevalence (37/109; 33.9%), Batak was an outlier among the low prevalence areas in the Western region. In general, age, living in the Eastern region, Batak ethnicity, Protestant, Catholic, and alcohol drinking were independent risk factors associated with H. pylori infection in Indonesia (OR 1.03, 95%CI 1.02–1.05; OR 5.33, 95%CI 1.17–24.26; OR 5.89, 95%CI 1.58–21.94; OR 5.47, 95%CI 2.16–13.86; OR 5.05, 95%CI 1.43–17.80; OR 2.30, 95%CI 1.14–4.61, respectively).

Conclusions

Several ethnicities and habits were concluded to increase the risk of infection as the interaction of host, agent, and environment is inseparable in affecting disease susceptibility.

Keywords

H. pylori, prevalence, ethnic, Eastern and Western region, infectious disease

Corresponding authors: Ratha-korn Vilaichone, Yoshio Yamaoka, Muhammad Miftahussurur

Competing interests: No competing interests were disclosed.

Grant information: This report is based on work supported partly by grants from Grants-in-Aid for Scientific Research from Japan’s Ministry of Education, Culture, Sports, Science, and Technology (MEXT) (16H05191, 16H06279, 18KK0266, and 19H03473) to YY.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2024 Maulahela H et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Maulahela H, Doohan D, Rezkhita YAA et al. Helicobacter pylori prevalence in Indonesia: Higher infection risk in Eastern region population [version 2; peer review: 2 approved with reservations]. F1000Research 2024, 11:1581 (https://doi.org/10.12688/f1000research.127094.2) First published: 23 Dec 2022, 11:1581 (https://doi.org/10.12688/f1000research.127094.1) Latest published: 16 Jan 2024, 11:1581 (https://doi.org/10.12688/f1000research.127094.2)

Revised Amendments from Version 1

The manuscript has been revised based on the reviewer comments. The statistical analysis result has been added.

To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.

Introduction

Helicobacter pylori, a stomach-living bacteria, infects more than half of the world’s population.¹ While most individuals were asymptomatic, only 10% – 20% had symptoms, including a 1% – 2% chance of developing gastric malignancy.²^–⁴ H. pylori infection is associated with various diseases, including chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer.²^,⁵^–⁷ H. pylori infection was strongly related to hygiene and sanitation,⁸^,⁹ and transmission was believed to be acquired in childhood.¹⁰ Even though no exact prevalence had been known, it was reported to be higher in developing countries.¹¹ Moreover, it is varied between different geographical areas. The variety raised the question of whether particular hosts, agents, and environmental factors increased the risk of infection. Recently, the prevalence of H. pylori infection decreased worldwide due to sanitation improvements in most countries.¹ Despite its decreasing prevalence, the prevalence and risk factor analysis updates in countries are still necessary since H. pylori is the one of the microbiota recognized by the World Health Organization (WHO) to cause cancer. Hence, knowing the prevalence might be able to prevent this.

Indonesia is a developing country in Southeast Asia, with thousands of islands complemented by substantial ethnic diversity. Therefore, it is challenging to determine the accurate prevalence therein. Studies reported that Indonesia had a low prevalence of H. pylori infection.¹² Despite the low overall prevalence, there were vast differences in H. pylori infection between regions and ethnicities. For example, the prevalence in Jayapura, Papua Island and Medan, Sumatra Island was significantly higher than in cities on Java Island.¹² Several islands in Indonesia were huge and lived by multiple ethnicities with a varied prevalence that guaranteed further analysis. Apart from ethnicities, habits also relate significantly to someone’s susceptibility to infection since the whole interaction of the host, agent and environment is inseparable. Moreover, previous studies also mentioned the significantly high risk of Papuan and Buginese ethnics, Protestant religion, and water drinking sources to H. pylori infection in Indonesia.¹² Different areas have different habits; hence it will show a difference in disease susceptibility.

Preceding studies on H. pylori infection’s prevalence in Indonesia might be the tip of the iceberg. There is plenty to be revealed about the association between sociodemographic characteristics and H. pylori infection. Prevalence was scanty as the previous study only used small samples, while Indonesia is a vast country with a 267 million population. Aside from population number, the heterogeneity of ethnics, religions, and habits also affect the susceptibility to H. pylori infection. Hence, this study will extensively analyze H. pylori infection prevalence, especially in Indonesia’s Eastern and Western regions.

Methods

Study population

This study continues our previous Indonesia endoscopic study.¹²^,¹³ In addition, we included our most recent endoscopy samples taken from August 2016 until March 2017. Samples were taken in four cities with a total of 193 samples: 50 subjects from Kolaka and 56 subjects from Palu in Sulawesi Island, 43 subjects from Merauke in Papua Island, and 44 subjects from Ternate in Maluku Island (117 male and 76 female subjects, mean age 44.1 ± 12.1 years). Merauke and Kolaka samples were taken during August – September 2016, while Palu and Ternate samples were taken in March 2017. To provide a thorough analysis, we also included samples from our previous preliminary study of the prevalence of H. pylori infection, taken from six big cities in Indonesia,¹² the prevalence in Malay ethnic¹⁴ and previous surveys for antibiotic resistance.¹³ All studies used the same data extraction method as this study. Samples were taken in five cities in Sumatra Island; Aceh (n = 38), Medan (n = 82), Dolok Sanggul (n = 47), Gunung Sitoli (n = 32), Padang (n = 33), Palembang (n = 38), one city in Kalimantan Island; Pontianak (n = 90), three cities in Java Island; Cimacan (n = 22), Jakarta (n = 62), Surabaya (n = 316), one city in Bali Island; Bangli (n = 61), one city in East Nusa Tenggara; Kupang (n = 35), four cities in Sulawesi Island; Manado (n = 57), Makassar (n = 30), Kolaka (n = 50), Palu (n = 56), two cities in Papua Island; Jayapura (n = 22) and Merauke (n = 43), and one city in the Moluccas; Ternate (n = 44) (Figure 1). Finally, we included 1,158 samples collected throughout Indonesia.

Figure 1. Map of collecting area in Indonesia.

Biopsy specimens were obtained from 1,158 patients in Indonesia (created with BioRender.com).

A qualitative questionnaire was given for demographic data analysis (can be found as Underlying data⁷¹). Questionnaires were made by us and have been unchanged since the first use of the survey in 2013. Subjects signed consent prior to answering the questionnaire and endoscopic examination. When subjects finished answering all questions in the questionnaire, it was concluded as finished. All recruited subjects underwent an endoscopic examination in the referral hospitals having endoscopic facilities by experienced endoscopists, and a total of four gastric biopsies were collected. Three gastric biopsies were taken from the lesser curvature of the antrum, and one gastric biopsy was taken from the greater curvature of the corpus. One antrum biopsy tissue was used for the rapid urease test, and one was kept in a transport medium and immediately stored at –20°C until used. For histological examination, we used one antrum biopsy tissue and one from the corpus, and both were kept in 10% neutral buffered formalin until used.

Ethical approvals were obtained from the Ethics Committee of Dr. Soetomo Teaching Hospital, Surabaya, Indonesia (221/Panke.KKE/IX/2012. date: September 25^th, 2012), Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia (206/112/P1/ETIK/2014. date: April 7^th, 2014), Dr. Wahidin Sudirohusodo Hospital, Makassar, Indonesia (208/H4.8.4.5.31/PP36-KOMETIK/2015. date: February 16^th, 2015), and Oita University Faculty of Medicine, Yufu, Japan (P-12-10. date: January 18^th, 2013). Objectives and procedures of the study were explained and written informed consent was obtained under the guidelines of the Declaration of Helsinki.

H. pylori infection detection methods

H. pylori infection was diagnosed based on the combination of four tests: rapid urease test, histology, immunohistochemistry, and bacterial culture. Patients were considered H. pylori-positive if at least one test showed positive and negative when all tests showed negative results.

As previously described, one antrum biopsy specimen was used for culture.¹²^–¹⁶ Briefly, homogenized antrum specimens were inserted onto H. pylori selective plates (Nissui Pharmaceutical Co., Ltd., Tokyo, Japan; Ref. Number 51035), which were then cultured at 37°C under microaerophilic conditions for up to 10 days (5% CO₂, 10% O₂, and 85% N₂). Sub-culture was performed on Brucella Agar medium (Becton Dickinson, Sparks, MD, USA; Ref. Number 211086) complemented with 7% horse blood but without antibiotics. H. pylori was detected by bacterial colony morphology, Gram staining, and positive reaction of oxidase, catalase, and urease. H. pylori strains were kept at –80°C in Brucella Broth medium supplemented with 10% horse serum (Biosera, France, Code Number BS-110) and 10% glycerol (Becton Dickinson, Sparks, MD, USA, Ref. Number 228220).

All biopsy specimens for histological examination were fixed in 10% buffered formalin and embedded in paraffin. Hematoxylin eosin and May-Giemsa stain were used to stain serial sections. An experienced pathologist (TU) evaluated gastric biopsies using the updated Sydney system.¹⁷ Immunohistochemistry (IHC) was performed as previously described.¹⁸^,¹⁹ Tissue sections were incubated overnight at 4°C with α-H. pylori antibody (DAKO, Denmark; Ref. Number B0471), polyclonal rabbit anti-CagA antibody (b-300) (Santa Cruz Biotechnology Cat# sc-25766, RRID:AB_2184120) or α-EAS Ab diluted for 1:2,000 with diluting solution (DAKO, Denmark) after antigen was retrieved and endogenous peroxidase activity was inactivated. After washing, sections were incubated with biotinylated goat anti-rabbit or anti-rat IgG (Nichirei Biosciences, Inc., Japan; Code. Number 424022), followed by incubation with avidin-conjugated horseradish peroxidase solution (Vectastain Elite ABC kit; Vector Laboratories Inc., Burlingame, CA, USA; Ref. Number PK-6100). H₂O₂/diaminobenzidine substrate solution was used to detect peroxidase activity. H. pylori were identified by Giemsa staining and anti-H. pylori antibody-positive immunostaining with bacterial loads greater than or equal to grade 1 was considered positive for H. pylori.¹⁷

Statistical analysis

The IBM SPSS Statistics version 23 (RRID:SCR_016479) (IBM Corp., Armonk, NY, USA) was used for statistical analyses. Separate variables were tested using the chi-square test, while continuous variables were tested using Mann-Whitney U and t-tests. A logistic regression model was used to calculate the odds ratios (OR) for H. pylori infection. A multivariate logistic regression model was used to calculate odds ratios including age, sex, H. pylori infection status, demographic, and environmental data. Both OR and 95% confidence interval (CI) were used to estimate the risk of infection.

Results

Prevalence of H. pylori infection in Western vs. Eastern Indonesia

In analyzing prevalence, we included 1,158 samples. We found that H. pylori infection prevalence in Palu (Sulawesi), Ternate (Moluccas), Merauke (Papua), and Kolaka (Sulawesi) were 12.5% (7/56), 4.5% (2/44), 20.9% (9/43), and 16.0% (8/50), respectively. When we included all data, the prevalence of H. pylori infection in Indonesia was found to be highest in East Nusa Tenggara (51.4%), followed by Papua Island (30.7%), Sumatra Island (24.4%), Sulawesi Island (18.1%), Bali Island (18.0%), Kalimantan Island (8.9%), Java Island (7.4%), and Moluccas Islands (4.5%). However, positivity rates varied between cities on the same island. In Papua Island, Jayapura had a higher prevalence than Merauke (50.0% vs. 20.9%). Furthermore, Makassar (36.7%) had a twice higher prevalence than other cities on Sulawesi Island, such as Kolaka (16.0%), Palu (12.5%), and Manado (15.8%). Table 1⁷¹ shows the complete distribution of H. pylori positivity rates in islands and cities in Indonesia.

Table 1. H. pylori infection in different locations throughout Indonesia (n= 1,158).

Island/City	Total	Diagnostic method
Island/City	Total	RUT	Histology	IHC	Culture	At least one
Western Indonesia region	760					104 (13.7)
Sumatra Island	270					66 (24.4)
Medan*	82	38 (46.3)	17 (20.7)	18 (22.0)	17 (20.7)	41 (50.0)
Aceh**	38	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Gunungsitoli***	32	2 (6.3)	1 (3.1)	1 (3.1)	1 (3.1)	2 (6.3)
Padang***	33	1 (3.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (3.0)
Palembang***	38	1 (2.6)	1 (2.6)	1 (2.6)	1 (2.6)	2 (5.3)
Dolok Sanggul***	47	11 (23.4)	13 (27.7)	17 (34.0)	10 (21.3)	20 (42.6)
Java Island	401					30 (7.4)
Cimacan***	22	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Jakarta**	62	2 (3.2)	4 (6.5)	4 (6.5)	1 (1.6)	9 (14.5)
Surabaya*	316	12 (3.8)	15 (4.7)	14 (4.4)	12 (3.8)	21 (6.6)
Kalimantan Island
Pontianak*	90	6 (6.7)	4 (4.4)	4 (4.4)	5 (5.6)	8 (8.9)
Eastern Indonesia region	398					86 (21.6)
Sulawesi Island	193					35 (18.1)
Kolaka	50	8 (16.0)	8 (16.0)	8 (16.0)	7 (14.0)	8 (16.0)
Makassar*	30	9 (30.0)	6 (20.0)	6 (20.0)	6 (20.0)	11 (36.7)
Manado**	57	8 (14.0)	7 (12.3)	7 (12.3)	7 (12.3)	9 (15.8)
Palu	56	6 (8.0)	4 (7.1)	4 (7.1)	6 (8.0)	7 (12.5)
Papua Island	65					20 (30.7)
Jayapura*	22	9 (40.9)	9 (40.9)	9 (40.9)	9 (40.9)	11 (50.0)
Merauke	43	9 (20.9)	7 (16.3)	9 (20.9)	9 (20.9)	9 (20.9)
Moluccas
Ternate	44	2 (4.5)	1 (2.3)	1 (2.3)	1 (2.3)	2 (4.5)
Bali Island
Bangli**	61	10 (16.4)	7 (11.5)	7 (11.5)	6 (9.8)	11 (18.0)
East Nusa Tenggara
Kupang**	35	14 (40.0)	12 (34.3)	12 (34.3)	14 (40.0)	18 (51.4)

* Corresponds to our previous study.¹²

** Corresponds to our previous study.¹³

*** Corresponds to our previous study in Sumatra.¹⁴

In this analysis, we divided Indonesia into Eastern and Western regions. The regions were divided based on the Wallace line that separates biogeographical realms between Australia and Asia.²⁰ The Western region consists of Sumatra, Kalimantan, and Java Islands, while the Eastern region consists of Sulawesi, Papua, Moluccas, East Nusa Tenggara, and Bali Islands. Overall, the prevalence was higher in the Eastern region than in the Western region (86/398; 21.6% vs. 104/761; 13.7%). In the Western region, the prevalence of H. pylori infection was only high in two cities, Medan (41/82; 50.0%) and Dolok Sanggul (20/47; 42.6%), both located in North Sumatra province, while in the Eastern region, the prevalence was the highest in Kupang, Timor Island (18/35; 51.4%).

H. pylori positivity rate in each ethnic group

We examined the prevalence of H. pylori infection in Indonesia’s ethnic groups (Table 2). Among 17 ethnicities, the Batak ethnic from the Western region had the highest prevalence of H. pylori infection in Indonesia (48.6%). While in the Eastern region, Timor ethnicity was the highest (44.2%). Batak in the Western region and Timor in the Eastern region were the two ethnicities with the highest prevalence, 48.6% and 44.2%, respectively. Most Indonesian ethnicities analyzed in this study had a low prevalence of H. pylori infection. There were two ethnicities with 0.0% prevalence (Acehnese and Sundanese), as we reported previously.¹³^–¹⁵ The notable phenomenon is that in the middle of low H. pylori infection prevalence on an island, there was ethnicity with high prevalence. For example, Batak, as a predominant ethnicity in North Sumatra, was the only ethnicity in Sumatra with a notably high H. pylori prevalence, compared to other predominant ethnics in other cities in Sumatra, such as Acehnese (0.0%), Malay (5.4%), Minangkabau (2.8%), and Nias (6.1%). Buginese also had the highest H. pylori prevalence in Sulawesi Island (21/81; 25.9%), in contrast to Minahasan and Tolaki ethnic, which showed lower prevalence (15.7% and 4.3%, respectively).

Table 2. H. pylori infection in each ethnic group (n = 1,158).

Ethnic*	Total	Diagnostic method
Ethnic*	Total	RUT	Histology	IHC	Culture	At least one
Acehnese	37	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Balinese	65	11 (16.9)	7 (10.8)	7 (10.8)	7 (10.8)	12 (18.5)
Batak	144	51 (35.4)	34 (23.6)	38 (26.4)	28 (19.4)	70 (48.6)
Buginese	103	20 (19.4)	16 (15.5)	16 (15.5)	17 (16.5)	22 (21.4)
Chinese	156	11 (7.1)	9 (5.8)	8 (5.1)	10 (6.4)	16 (10.3)
Dayak	47	2 (4.3)	2 (4.3)	2 (4.3)	2 (4.3)	3 (6.4)
Javanese	235	2 (0.9)	4 (1.7)	4 (1.7)	1 (0.4)	7 (3.0)
Kaili	12	1 (8.3)	0 (0.0)	0 (0.0)	1 (8.3)	2 (16.7)
Malay	37	2 (5.4)	2 (5.4)	2 (5.4)	2 (5.4)	3 (8.1)
Maluku	46	3 (6.5)	3 (6.5)	3 (6.5)	3 (6.5)	4 (8.7)
Minahasan	53	8 (15.1)	7 (13.2)	7 (13.2)	7 (13.2)	9 (17.0)
Minangkabau	36	1 (2.8)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.8)
Nias	33	2 (6.1)	1 (3.0)	1 (3.0)	1 (3.0)	2 (6.1)
Papuan	65	18 (27.7)	16 (24.6)	18 (27.7)	18 (27.7)	19 (29.2)
Sundanese	22	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Timor	43	15 (34.9)	14 (32.6)	14 (32.6)	15 (34.9)	19 (44.2)
Tolaki	24	1 (4.2)	1 (4.2)	1 (4.2)	0 (0.0)	1 (4.2)

* With no respect to the location of the survey or the place of the samples were taken. The data presented in this analysis includes the samples from our previous studies in Indonesia¹²^–¹⁴ with the addition of samples acquired from our most recent surveys in four cities.

Sociodemographic and risk comparison between Western and Eastern region

We excluded samples with incomplete questionnaire data. A total of 939 samples were included for further analysis. We analyzed the risk factors in both regions (found as Underlying data⁷¹). Both sexes have a similar proportion of H. pylori-positive and negative (14.4% male and 13.9% female subjects). The age of the H. pylori-positive subjects was significantly higher than the negative ones (50.5 ± 13.1 vs. 45.2 ± 13.8 years; P<0.001). Increased age reflects an increased risk for H. pylori infection (P<0.001).

We used logistic regression analysis adjusted to sex and age to calculate the association of risk factors and H. pylori infection in Indonesia (Table 3). No significant relationship was found between sex and infection risk (OR 1.09, 95%CI 0.75–1.59). While Islam is the predominant religion in Indonesia, Protestant, Catholic, and Hinduism had a significantly higher risk of infection (Protestant, OR 5.43, 95%CI 3.42–8.62; Catholic, OR 2.68, 95%CI 1.27–5.69; Hinduism, OR 3.47, 95%CI 1.62–7.44), respectively. Analysis of ethnicity by using Javanese as the reference category showed that Chinese, Maluku, Minahasan, Balinese, Buginese, Papuan, Batak, and Timor ethnic had a higher risk of getting infected (Chinese, OR 3.50, 95%CI 1.04–13.90; Maluku, OR 4.49, 95%CI 1.10–19.24; Minahasan, OR 8.42, 95%CI 2.41–29.46; Balinese, OR 9.71, 95%CI 12.95–31.96; Buginese, OR 15.19, 95%CI 4.97–46.48; Papuan, OR 19.25, 95%CI 6.16–60.15; Batak, OR 20.23, 95%CI 6.92–59.11; Timor, OR 34.66, 95%CI 10.34–116.11). No association was found between infection and marital status. Most infected subjects have a monthly income of less than 2.5 million Rupiah (approximately USD 172.2; USD 1 equals IDR 14,520). We used an income range of IDR 2.5 to 5 million as a reference category and found no significant association between monthly income and H. pylori infection status. Almost a quarter of the infected subjects (30/133; 22.6%) were smokers. However, no significant association was found between smoking and H. pylori infection status (OR 1.40, 95%CI 0.89–2.20). A total of 18 subjects (18/133; 13.5%) were alcohol consumers, and a significant association was found between H. pylori infection with alcohol drinking (OR 2.46, 95%CI 1.37–4.39). We also analyzed the source of water consumed by subjects. We divided water sources into three categories; mineral water (commercially packaged water), boiled, and others (water from rainwater, river, and wells, which are consumed directly without boiling beforehand). People who consume boiled water have a higher risk of infection (OR 1.68, 95%CI 1.14–2.47).

Table 3. The risk for H. pylori infection.

Characteristics	Total	H. pylori-negative n (%)	H. pylori-positive n (%)	Crude OR	Adjusted OR	95% Confidence Interval
Sex
Male	542	464 (85.6)	78 (14.4)	1.05	1.09	0.75 – 1.59
Female	397	342 (86.1)	55 (13.9)	1.00	1.00
Age, years	939	805 (85.9)	132 (14.1)	1.03	1.03	1.02 – 1.04
Religion
Islam	474	445 (93.9)	29 (6.1)	1.00	1.00
Protestant	315	234 (74.3)	81 (25.7)	5.31	5.43	3.42 – 8.62
Catholic	74	63 (85.1)	11 (14.9)	2.68	2.68	1.27 – 5.69
Hinduism	62	51 (82.3)	11 (17.7)	3.31	3.47	1.62 – 7.44
Buddhism	14	13 (92.9)	1 (7.1)	1.18	0.95	0.12 – 7.613
Ethnicities
Javanese	179	175 (97.8)	4 (2.2)	1.000
Minangkabau	86	35 (97.2)	1 (2.8)	1.25	1.20	0.14 – 11.52
Tolaki	23	22 (95.7)	1 (4.3)	1.99	1.91	0.21 – 18.60
Dayak	47	45 (95.7)	2 (4.3)	1.94	2.05	0.35 – 10.95
Malay	37	35 (94.6)	2 (5.4)	2.50	2.59	0.44 – 14.18
Nias	33	31 (93.9)	2 (6.1)	2.82	3.05	0.50 – 16.08
Chinese	75	69 (92.0)	6 (8.0)	3.80	3.50	1.04 – 13.90
Maluku	42	38 (90.5)	4 (9.5)	4.61	4.49	1.10 – 19.24
Kaili	7	6 (85.7)	1 (14.3)	7.29	9.00	0.70 – 75.51
Minahasan	51	43 (84.3)	8 (15.7)	8.14	8.42	2.41 – 29.46
Balinese	62	51 (82.3)	11 (17,7)	9.44	9.71	2.95 – 31.96
Buginese	81	60 (74.1)	21 (25.9)	15.31	15.19	4.97 – 46.48
Papuan	65	47 (72.3)	18 (27.7)	16.76	19.25	6.16 – 60.15
Batak	109	72 (66.1)	37 (33.9)	22.48	20.23	6.92 – 59.11
Timor	34	19 (55.9)	15 (44.1)	34.54	34.66	10.34 – 116.11
Acehnese	37	37 (100)	0 (0)			0.000 –.
Sundanese	21	21 (100)	0 (0)			0.000 –.
Location
Western Region	583	529 (90.7)	54 (9.3)	1.00
Eastern Region	356	277 (77.8)	79 (22.2)	2.79	3.00	2.04 – 4.40
Marital status
Married	835	710 (85.0)	125 (15.0)	0.47	0.79	0.36 – 1.75
Not married	104	96 (92.3)	8 (7.7)	1
Monthly income
IDR <2.5 million	451	383 (84.9)	68 (15.1)	1.21	1.20	0.80 – 1.80
IDR 2.5-5 million	367	320 (87.2)	47 (12.8)	1.00
IDR >5 million	121	103 (85.1)	18 (14.9)	1.19	1.23	0.68 – 2.22
Smoking
Yes	173	143 (82.7)	30 (17.3)	1.35	1.40	0.89 – 2.20
No	766	663 (86.6)	103 (13.4)	1.00
Alcohol drinking
Yes	77	59 (76.6)	18 (23.4)	1.98	2.46	1.37 – 4.39
No	862	747 (86.7)	115 (13.3)	1.00
Source of water
Mineral	549	488 (88.9)	61 (11.1)	1.00
Boiled	345	279 (80.9)	66 (19.1)	1.89	1.68	1.14 – 2.47
Others	45	39 (86.7)	6 (13.3)	1.23	1.18	0.48 – 2.93

Hence, we analyze the significant results from bivariate analysis, through a multivariate logistic regression model to calculate the odds ratios (OR) that included the subject’s demographic data and H. pylori infection status (found as Underlying data⁷¹). We found that in general, age, living in the Eastern region, Batak ethnic, Protestant, Catholic, and alcohol drinking were independent risk factors associated with H. pylori infection in Indonesia (OR 1.03, 95%CI 1.02–1.05; OR 5.33, 95%CI 1.17–24.26; OR 5.89, 95%CI 1.58–21.94; OR 5.47, 95%CI 2.16–13.86; OR 5.05, 95%CI 1.43–17.80; OR 2.30, 95%CI 1.14–4.61, respectively). We performed multivariate analyses in separate regions. We found no significant association between demographic characteristics and infection in the Western region. In the Eastern region, where the prevalence was generally higher than in the Western region (79/356; 22.2%), age, Buginese ethnicity, and Protestant, were independent risk factors associated with infection (OR 1.04, 95%CI 1.02–1.06; OR 10.53, 95%CI 1.28–85.56; OR 4.49, 95%CI 1.21–16.54, respectively).

Discussion

Investigation of H. pylori prevalence in Indonesia has been done over the years.²¹^–²⁶ The prevalence of a disease is inseparable from risk factors, especially in different geographic areas. Despite a high prevalence in certain area of the Western region, we found that living in the Eastern region of Indonesia increases the risk of H. pylori infection. In general, the Western region had low H. pylori prevalence. There were no positive H. pylori subjects of Aceh and Sundanese ethnic; both reside in the Western region, while Timor, Papuan, and Buginese, all ethnicities primarily originated from the Eastern region, were the ethnicities dominating the highest prevalence in Indonesia. Moreover, none of the subjects from those three ethnicities who reside in the Western region had a positive H. pylori infection (found as Underlying data⁷¹). Papuan, the predominant ethnicity in Papua Island, is one of the ethnicities with high prevalence, which concord with a previous study in a neighboring country, Papua New Guinea.²⁷ Higher H. pylori infection prevalence in the Eastern region is also congruent with the high prevalence in Australia, especially in the Australian indigenous community²⁸^,²⁹ and New Zealand’s Maori and the Pacific.³⁰^,³¹ The diversity between the Eastern and Western regions was noticed years ago and was divided by Wallace’s line.³²

In general, we found Indonesia’s overall prevalence of 14.2% lower than other neighboring countries such as Thailand,³³^,³⁴ Myanmar,¹⁶^,³⁵^,³⁶ Cambodia,³⁷ and Vietnam.³⁸ It was lower than our previous study (14.2% vs. 22.1%, respectively).¹² Nevertheless, the low prevalence was almost similar to Malaysia.³⁹ While every other ethnicity in the Western region had a low prevalence, Batak ethnic, the indigenous ethnics in Sumatra Island, exhibit high H. pylori prevalence. Regardless of Batak’s high prevalence, analysis done separately in the Western region did not show susceptibility to infection in any ethnicity. On the other hand, Buginese who resides in the Eastern region showed an increased risk of infection. Several factors could contribute to this phenomenon, including the host, the agent’s virulence, and environmental factors. Host genetic variants were presumably responsible for inter-ethnic susceptibility to H. pylori infection. Previous studies reported that several single nucleotide polymorphisms might be related to Malay ethnic protection against H. pylori infection.⁴⁰^,⁴¹ Malay ethnic descendants in Indonesia mainly reside in Sumatra and Java Island, consisting of Aceh, Minangkabau, and Malay. Sundanese and Javanese were also believed to have a similar ancestral line.¹⁴^,⁴² All these ethnicities showed low H. pylori infection prevalence in this study. The similarities in between the ethnicities were due to human migration. Modern humans originated from Africa, probably through a coastal route and finally arrived in South East Asia.⁴³^,⁴⁴ On the agent side, H. pylori possess various virulence factors responsible for its capability to adapt and successfully colonize the hostile environment of the human stomach.⁴⁵^,⁴⁶ However, this study did not analyze H. pylori strains infecting the subjects.

Several sociodemographic factors are essential in H. pylori infection.⁴⁷ Of note, we found religion as a significant social factor for H. pylori infection in Indonesia. Our result showed that Protestants and Catholics increased the risk of being infected with H. pylori. This result concurred with our previous study, where Protestantism had the highest risk for H. pylori infection in Indonesia.¹² In addition to religion, alcohol drinking is a risk factor for H. pylori infection, especially in the Western region. However, according to Indonesia’s Basic Health Research (Riskesdas) in 2018, the Eastern region generally had higher alcohol consumption, ranging from the lowest of 4.1% in West Sulawesi to the highest of 16.0% in South Sulawesi.⁴⁸ The relationship between alcohol consumption and certain religions to H. pylori infection found in this study might be related to Islam prohibiting Muslims from consuming alcohol where other religions do not. Moreover, certain ethnicities tended to consume alcohol regularly, as depicted by the Batak ethnicity, who consumed it in daily life and ceremonials.⁴⁹ Alcoholic beverages may affect the human stomach directly or indirectly by influencing gastric acid secretion and hence, disturbs normal gastric mucosa physiology.⁵⁰ It contributes to gastric mucosa’s damaging process, resulting in altered mucosal defense.⁵¹ Alcohol also interferes with muscle activity surrounding the stomach, resulting in delayed gastric emptying.⁵² However, the concrete relation between alcohol consumption and H. pylori infection remains unclear as some studies reported it as a protective factor,⁵²^,⁵³ while others showed an increased risk of infection.⁵⁴^,⁵⁵

According to Indonesia’s Basic Health Research (Riskesdas), in 2018, 24.3% of Indonesians smoked daily.⁴⁸ There have been conflicting results on whether smoking could increase the risk of H. pylori infection.⁵⁶^–⁵⁹ Nevertheless, we found no association between the two. A pooled analysis also found the same result.⁵⁶ Studies have found that nicotine increases acid and pepsin secretion, hence making H. pylori harder to thrive in the stomach.⁵⁸ However, in people who are already infected with H. pylori, smoking was found to increase the risk of developing gastric cancer.⁵⁶^,⁶⁰^,⁶¹ Substances in the cigarette contain surmountable carcinogenic compounds that impair gastric mucosa through oxidative stress and allow chronic inflammation. Eventually, a precursor lesion of gastric cancer, such as atrophic gastritis, intestinal metaplasia or dysplasia, will be formed.⁵⁶^,⁶¹

In this study, the age of H. pylori-positive subjects was higher than the negative ones. Some studies reported that H. pylori infection was more common in older people,⁶²^–⁶⁴ while others mentioned that infections are more common in younger age.⁶⁵ H. pylori infection was established in childhood through person-to-person or fecal-oral route.⁶⁶ Hence, the living condition with hygiene and sanitation level is highly correlated with the infection.⁶⁷ As the hygiene and sanitation standards are improved in the 21^st century, the low prevalence at a younger age might originate from decreased microbial acquisition during childhood.⁶⁴^,⁶⁸^,⁶⁹ Drinking water sources have also been discussed to be a source of infection. The prevalence was seen to be higher in individuals using unprotected water sources.⁸^,⁷⁰ Although, in our study, there was no correlation between water source and H. pylori infection. Lower income was an independent infection risk factor in the Eastern region, whereas H. pylori were heavily associated with lower income.⁵⁷^,⁶⁷ However, lifestyle characteristics might be a better indicator of socioeconomic status. Although the exact transmission mode is still unknown, individual and familial characteristics must be assessed to determine the risk of contracting the infection.

We have multiple limitations in this study. There were differences in sample numbers between cities; hence, it still could not reflect the actual prevalence. Subjects included in this study were patients referred to endoscopic centers, indicating that our study is only the tip of the iceberg. Moreover, we excluded subjects with incomplete questionnaire data. A future study with adequate samples and complete demographic characteristics is necessary to provide a more accurate prevalence. We did not conclude the detailed analysis on which H. pylori strains infect our subjects. There was also a possibility of false negative/positive testing. However, this is the first comprehensive study of H. pylori prevalence and risk factors in Indonesia with almost a thousand samples. Knowing the risk factors would help disease prevention in the country.

Conclusions

Living in the Eastern region of Indonesia imposes a higher risk of H. pylori infection. Moreover, specific ethnicities, religions, and habits were risk factors. Understanding the distribution of H. pylori infection according to geographical location and sociodemographic factors is essential for clinicians to increase the awareness of H. pylori infection and determine the infection status in daily practice.

Data availability

Underlying data

Figshare: Helicobacter pylori Prevalence in Indonesia West and East Region. https://doi.org/10.6084/m9.figshare.21514893.⁷¹

This project contains the following underlying data:

- Helicobacter pylori Prevalence in Indonesia_Data.xlsx (sociodemographic data of participants)
- Publication License Oct-14-2022.pdf
- PrevIndo_Underlying data.docx (includes risk factor comparison between Western and Eastern regions and multivariate analysis of risk factor associated with H. pylori infection)
- Indonesian Helicobacter Pylori Project_questionnaire.doc

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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