Is Helicobacter pylori infection protective against esophageal cancer?

Table 1 Risk factors of esophageal squamous cell carcinoma and adenocarcinoma

Squamous cell carcinoma	Adenocarcinoma
Male gender	Male gender
Alcohol	Tobacco smoking
Tobacco smoking	Obesity (BMI > 25 kg/m2)
HPV infection	Barrett’s esophagus
Low intake of fruits and vegetables	GERD
Consumption of hot beverages, pickled vegetables, processed and red meat	Low intake of fruits and vegetables
	Consumption of processed and red meat
Low socioeconomic status	High socioeconomic status
Genetic factors: Howel-Evans syndrome, Fanconi anemia, Bloom syndrome	Genetic factors: Familial Barrett’s esophagus

BMI: Body mass index; GERD: Gastroesophageal reflux disease; HPV: Human papillomavirus.

Table 2 Summary of meta-analyses regarding the association between Helicobacter pylori infection and esophageal cancer

Authors	Year of publication	Number of studies	Association of H. pylori infection with ESCC	Association of H. pylori infection with EAC
Gao et al[19]	2019	35	No significant association in the general population: OR 0.84 (95%CI: 0.64-1.09)/OR 0.74 (95%CI: 0.54-0.97); Inverse relationship in the Middle Eastern population: OR: 0.34 (95%CI: 0.22-0.52 or 0.26-0.44); Positive association with the North American population: OR: 1.83 (95%CI: 1.17-2.87)	Inverse relationship: OR 0.55 (95%CI: 0.43-0.70)/OR 0.23 (95%CI: 0.15-0.36)
Nie et al[20]	2014	28	No significant association with the general population: OR 1.16 (95%CI: 0.83-1.60); Inverse association with Asian population: OR 0.74 (95%CI: 0.57–0.97); Positive association with non-Asian population: OR 1.41 (95%CI: 1.02–1.94)	Inverse relationship: OR 0.57 (95%CI: 0.44-0.73)
Xie et al[21]	2013	27	No significant association in the general population: OR 0.83 (95%CI: 0.63-1.03); Inverse relationship with the East Asian population: OR 0.66 (95%CI: 0.43-0.89)	Inverse relationship: OR 0.59 (95%CI: 0.51-0.68)
Islami and Kamangar[22]	2008	19	No significant association: OR 1.10 (95%CI: 0.78-1.55)	Inverse relationship: OR 0.56 (95%CI: 0.46-0.68)
Zhuo et al[23]	2008	195	No significant association: OR 0.80 (95%CI: 0.45-1.43), Z = 0.75, P > 0.05	Inverse relationship: OR 0.58 (95%CI: 0.48-0.70), Z = 5.79, P < 0.01
Rokkas et al[24]	2007	72	No significant association: OR 0.85 (95%CI: 0.55-1.33), P = 0.48	Inverse relationship: OR 0.52 (95%CI: 0.37-0.73), P < 0.001

H. pylori: Helicobacter pylori; ESCC: Esophageal squamous cell carcinoma; EAC: Esophageal adenocarcinoma; OR: Odds ratio.

Table 3 Mechanisms underlying the protective role of Helicobacter pylori infection against esophageal adenocarcinoma

Mechanism	Description	Implications
Development of atrophic gastritis	The inflammatory processes in chronic H. pylori infection can cause gastric atrophy by loss of gastric glands and partial replacement by intestinal epithelium. This reduces the number of parietal cells which secrete hydrochloric acid, the main constituent of gastric acid	Lower gastric acidity reduces the risk of GERD and BE, risk factors for EAC
Alteration of plasma ghrelin levels	H. pylori-induced gastric atrophy leads to reduced gastric ghrelin production, subsequently decreasing plasma ghrelin levels. Contrastingly, eradication of H. pylori increases ghrelin levels, thus leading to obesity. Thus, H. pylori infection is inversely related to obesity	Ghrelin is a key regulator of obesity and has been implicated in the pathogenesis and differentiation of esophageal cancers. Obesity can predispose individuals to GERD, which is a risk factor for both BE and EAC
Induction of cancer cell apoptosis	In vitro, H. pylori induces apoptosis in Barrett’s-derived EAC cells at a higher rate than in healthy esophageal cells. H. pylori activates the Fas-caspase cascade by increasing Fas protein expression in EAC cells, which leads to apoptosis through the fragmentation of cellular DNA	H. pylori infection can induce apoptosis and thus reduce the rate of esophageal cancer progression

H. pylori: Helicobacter pylori; GERD: Gastroesophageal reflux disease; BE: Barrett’s esophagus; EAC: Esophageal adenocarcinoma.