Helicobacter pylori in human health and disease: Mechanisms for local gastric and systemic effects

Table 1 Association of different diseases with the presence or absence of Helicobacter pylori

Disease	Association	Reference	Type/model of study	Sample size	Statistical analysis	H. pylori detection	Diagnosis of the pathology
Asthma	NA	Holster et al[53], 2012	Cohort study	545 childrens	Chi-square and t-tests. Univariate and multiple logistic regression analysesa	Serum anti-H. pylori inmunoglobulin G, and CagA by ELISA	Positive diagnosed asthma by a medical questionnaire
	Positive	Den Hollander[54], 2016	Cohort study	3797 childrens	Chi-square test. Multivariate logistic regression analysis. Odd ratios 95% CIb	inmunoglobulin G levels in serum	Positive diagnosed asthma by a medical questionnaire
	Inverse	Chen and Blaser[10], 2007	Cohort study	7663 adults	Unconditional logistic regression models. Odd ratios 95%CIa	inmunoglobulin G levels in serum	Positive diagnosed asthma by a medical questionnaire
		Chen and Blaser[55], 2008	Case-control study	7412 individuals	Chi-square and t-testsb	Wampole ELISA	Positive diagnosed asthma by a medical questionnaire
		Sommer et al[57], 1998	Ex vivo study. Isolated T cells from gastric biopsy	Biopsies from 30 patients	Not mentioned	Histological detection	Endoscopic examination
		Bamford et al[56], 1998	Ex vivo study. Isolated T cells from gastric biopsy	n patients = 5, n control = 3	t-testa	Rapid urease test (RUT) or histopathology	-
		Oertli et al[59], 2013	In vivo study. C57BL/6 mice	60 mice	Chi-square. Mann Whitney U-test and Kruskal-Wallis testa	CFU from homogenised tissues	-
		De la Pena-Ponce et al[60], 2017	In vitro study. Airway epithelial cells	Between n=3 to n=10	One way ANOVAa	CagA detection by western blot	-
Inflammatory Bowel Disease	Inverse	Higgins et al[61], 2011	Meta-analysis and In vivo study. C57BL/6 mice	Between n=3 to n=9	Odd ratios 95%CI. P-value < 0.1. One way ANOVA and t-testa	Not mentioned	-
		Lord et al[62], 2018	Cross-sectional study	704 individuals	Odd ratios 95%CIb	Not mentioned	Not mentioned
		Castano-Rodriguez et al[63], 2017	Meta analysis	6130 patients and 74659 controls	Chi-square, t-test, fixed effect model and odd ratios 95%CIb	Histology, culture, rapid urease test, serology and/or urea breath test (UBT)	Not mentioned but differentiated among Crohn's disease, ulcerative colitis, IBD, and unclassified
Celiac Disease	Inverse	Lebwohl et al[65], 2013	Cross-sectional study	136179 individuals	Odd ratios and 95%CIb	Polyclonal inmunochemical stain	Duodenal and gastric biopsies
		Narang et al[18], 2017	Cross-sectional study	324 childrens	Chi-square test or Fisher exact test, and odd ratio and 95%CIa	Giemsa staining and rapid urease test (RUT)	Serum levels of inmunoglobulin A-tissue transglutaminase antibodies (IgA-tTG> 18 U/mL = CD +). Further analysis by upper gastrointestinal endoscopy for biopsies to confirm
		Lucero et al[17], 2017	Case-control study	66 patients and 50 controls	Chi-square test or Fisher exact test, and odd ratio and 95%CIb	Rapid urease test (RUT), histological evaluation and PCR	Duodenal histopathology and inmunoglobulin A-tissue transglutaminase (IgA-tTG) serology
Multiple Sclerosis	Inverse	Yao et al[67], 2016	Meta analysis	1553 patients and 1253 controls	Chi-square test, odd ratio and 95%CIb	ELISA, immunofluorescence and latex agglutination tests	Not mentioned
		Jaruvongvanich.[68], 2016	Meta analysis	1902 individuals	Chi-square test, odd ratios, multivariant models and random-effect modelsa	Urea breath test (UBT), rapid urease test, PCR and ELISA	Diagnosed by neurologist using the McDonald criteria (based on clinical presentations, finding on magnetic resonance imaging and cerebrospinal fluid profile)
	Positive	Efthymiou et al[16], 2016	Cohort study	129 patients, 49 controls	Two-tailed t-testa	Serum anti-H. pylori, anti-VacA, anti-CagA, anti-Hsp60 ELISA	Not mentioned, but relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) are differentiated
Ischemic Heart Diseases	Positive	Liu et al[4], 2015	Meta analysis	5829 patients and ~16000 controls	Fixed and random effect models. Odd ratios and 95%CI. P-value = 0.06	Not mentioned	Medical records
		Shmuely et al[3], 2014	Cohort study	173 patients and 127 controls	Multivariate analysis. Odd ratios 95%CI. t-test and ANOVAa	Serum anti-H. pylori inmunoglobulin G, and CagA by ELISA	Myocardial perfusion imaging in patients with angina symptoms, chest pain, suspected CAD, cardiac related symptoms or risk stratications in patients with known CAD
		Huang et al[72], 2014	Retrospective cohort study	17332 patients and 69328 controls	Chi-square and t-testsa	Not mentioned	Isquemic stroke
Anemia	Positive	Xu et al[6], 2017	Retrospective study	17791 individuals 7804 Hp positive	Chi-square and t-tests. Odd ratios 95%CIa	Serum anti-H. pylori inmunoglobulin G and inmunoglobulin M ELISA	Using haemoglobin level
		Flores et al[76], 2015	In vitro study. AGS human gastric adenocarcinoma cell line	n=7 experiments	One way ANOVA or non-parametric t-testa	CFU from homogenised cells	-
		Flores et al[75], 2017	In vitro study. AGS human gastric adenocarcinoma cell line	n=3 experiments	One way ANOVA or non-parametric t-test a	CFU from homogenised cells	-
		Kato et al[77], 2017	In vitro study. Isolated H. pylori strains from patients and controls (whole genome sequencing)	4 patients and 4 controls	t-testa	Biopsy directly inoculated in growth medium	Measuring serum iron and ferritin
NAFLD	Positive	Chen et al[7], 2017	Cohort study	2263 individuals	Chi-square and t-testsa	13C-labeled urea breath test (UBT)	Using the NALFD criteria suggested by the Chinese Liver Disease Association and Clinical Diagnosis Standards
		Huang et al[78], 2009	In vivo study. C57BL/6 mice	n = 20	Chi-square testa	Gram staining, PCR and urease/catalase reactions	Histopathology and inmunochemical analysis
Insulin resistance	Positive	Aydemir et al[82], 2005	Cross-sectional Study	63 patients	t-testa	Giemsa staining	HOMA-IR
		Gunji et al[83], 2009	Cross-sectional Study	1107 participants (1008 IR- y 99 IR+)	Chi-square and t testsa	Serum anti-H. pylori inmunoglobulin G ELISA	HOMA-IR
		Chen et al[84], 2015	Cohort study	811 individuals	Chi-square or Fisher exact testa	Serum anti-H. pylori inmunoglobulin G ELISA	HOMA-IR
		Polyzos et al[86], 2011	Meta analysis	2120 participants	t-testa	Gastric mucosa histologic examination for H. pylori presence, gastric mucosa rapid urease test (CLO test), serum H. pylori-specific immunoglobulin G antibody concentration (ELISA), serum H. pylori-specific immunoglobulin G antibody concentration (chemiluminescence)	HOMA-IR
		Yildrim et al[89], 2016	Cohort study	41 patients and 27 controls	t-testa	13C-labeled urea breath test (UBT) and gastroscopy	HOMA-IR
		Upala et al[8], 2016	Meta analysis	27544 participants	Chi-square. Odd ratio 95%CIa	Urea breath test (UBT), rapid urease test (RUT), PCR and ELISA	HOMA-IR
Type 2 Diabetes Mellitus	NA	Anastasios et al[93], 2002	Cross-sectional study	67 patients and 105 controls	Chi-square. P-value < 0.05	Giemsa staining	Previously diagnosed patients
	Positive	Li et al[5], 2017	Meta analysis	57397 participants	Fixed and random effect models. Odd ratios and 95%CIa	13C or 14C urea breath test, stool antigen test, anti-H. pylori antibody, rapid urease test, histology or biopsy, culture	Not mentioned
		Bener et al[91], 2007	Case-control study	210 patients	t-testa	Serum anti-H. pylori inmunoglobulin G and inmunoglobulin A ELISA	Using venous blood glucose values or currently taking diabetic medication
		Devrajani et al[92], 2010	Case-control study	74 patients and 74 controls	Chi-squarea	Stool H. pylori-antigen detection by Enzyme immunoassay (EIA)	Fasting blood sugar (FBS) level, random blood sugar (RBS) level and hemoglobin A1c
		Aslan et al[95], 2006	Cross-sectional Study	103 patients	t-testa	Rapid urease test (RUT) and histopathologic examination	Serum glucose concentration and serum insulin levels
		Nasif et al[96], 2016	Cross-sectional Study	100 patients	t-test, Manne Whitney U-testa	Serum anti-H. pylori IgG ELISA	Postprandial glucose level, glycated hemoglobin (HbA1c) and body mass index (BMI). Serum 8-OHdG and Ox-LDL
Periodontitis	Positive	Sujatha et al[106], 2015	Cohort study	40 patients	Fisher exact testa	Rapid urease test, histopathological examination	Periodontal examination
		Pei et al[192], 2015	Cross-sectional study	70 patients ans 70 controls	The ratios were compared using × 2 test and × 2 statistics was adjusted. t-testa	PCR for urease C gene	Probing depth (PD), plaque index (PI) and bleeding index (BI)
		Hu et al[107], 2016	In vitro study. THP-1 cells	28 samples from 14 patients	One way ANOVAa	real-time PCR	Probing depth (PD), plaque index (PLI), bleeding index (BI), attachment loss (AL)

Different studies were analyzed considering the association of Helicobacter pylori (H. pylori) presence/absence with the corresponding disease (type of association), the type of study and model, the sample size, the type of statistical analysis employed, the method used for H. pylori detection and the method used for the disease diagnosis. Positive and inverse associations are indicated.

^aP < 0.05,

^bP < 0.01. NA: Indicates no association; IBD: Inflammatory bowel disease; IR: Insulin resistance.