The interplay between Helicobacter pylori and gastrointestinal microbiota

Figures & data

Table 1. Studies analyzing the role of gastric microbiota in gastric diseases using culture-based methods

Studies	Participants	Sample type	Culture findings		Remarks
Hewetson et al., 1904^Citation64	36 gastric dilatation cases with or without ulceration	Gastric contents	Firmicutes, Proteobacteria, Actinobacteria; yeast	Streptococci, Bacillus coli, Micrococci, Streptococcus pyrogenes, Bacillus subtilis, Staphylococcus albus (epidermiditis), Sarcinae (family clostridiaceae), Bacillus proteus, bacillus, Torula (yeast)	The positive culture rate was 72% in patients with GU compared with a 17% positive culture rate in patients without GU.
Rosenow et al., 1915^Citation69	18 GU	Gastroduodenal ulcer or regional lymph glands	Firmicutes, Proteobacteria, Actinobacteria; yeast	Streptococci, Streptococcus viridans, Staphylococci, Gram-positive bacilli, Gram-negative bacilli, colon bacilli, Bacillus welchii, Diphtheroid bacilli, spore-forming bacilli; yeast	Of the 18 patients, 16 had positive culture results from the ulcer base. The almost constant occurrence of Streptococci in PUD suggests Streptococci (usually viridans) may play a role in the pathogenesis of ulcers.
Seley et al., 1941^Citation113	16 GC, 6 GU, 18 DU, 29 secondary ulcers	Mucosa obtained by surgery	Firmicutes, Proteobacteria, Actinobacteria; yeast	Staphylococcus haemolyticus, S. viridans, non-hemolytic Streptococci, Clostridium welchii, B. coli, Enterococcus, B. friedlanderi (Klebsiella pneumoniae), Staphylococcus aureus, S. albus, B. proteus, Bacillus pyocyaneus, B. subtilis, Neisseria catarrhalis, Corynebacterium hodgkinii, Saccharomyces	Positive cultures in 93.7% of GC, 83.3% of GU, 36.6% of DU, and 37.9% of secondary peptic ulcers; pathogenic bacteria (S. haemolyticus, S. viridans, non-hemolytic streptococci, C. welchii, and Bact. coli) were isolated from 88% of the GC samples vs. 30% of the GU samples.
Barber et al., 1946^Citation65	27 GU, 12 DU, 10 GC	Swab on stomach mucosa	Firmicutes, Proteobacteria, Actinobacteria; yeast	S. viridans, non-hemolytic streptococci, coliform bacilli (Bact. coli, proteus, B. fecalis alcaligenes), S. albus, Neisseriae, Streptococcus pneumoniae, Diphteroid bacilli, S. aureus, S. pyogens, Lactobacilli; M. albicans	Bacteria were isolated from the stomach ± duodenum in 90% of the patients with GC; GU cases had a lower proportion of positive culture results (55%), while swabs were sterile from all 12 cases of DU. M. albicans, non-hemolytic streptococci, and coliform bacilli were isolated from patients with normal or high gastric acidity. All other bacteria were isolated only from cases with achlorhydria.
Cregan et al., 1953^Citation66	10 PUD, 8 GC	Gastric juice	Firmicutes, Proteobacteria	S. mitis, Streptococcus acidominimus, Streptococcus MG, Streptococcus uberis, Streptococcus salivarius, Streptococci, S. pyogenes, β-hemolytic streptococci, not Group A, B, B or G, Serratia liquefaciens, S. aureus, Streptococcus  lactis, Staphylococcus sarophyticus; Lactobacillus spp., Bacillus spp., C. welchii, Bact. coli, Bact. Intermediate type I, Bact. aerogenes type I & II, Paracolon spp., Pseudomonas spp., H. influenzae; Candida spp.	The bacterial load in the stomach was higher in patients with GC, compared with patients without GC, and is probably related to gastric acidity. Oral or fecal commensal flora were usually found in the gastric juice of patients with GC.
Gatehouse et al., 1978^Citation67	49 DU, 14 GU, 35 GC	Gastric juice	Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes; yeast	Lactobacilli, S. viridans, Micrococci, Streptococci fecalis, Diphtheroids, Escherichia coli, Neisseria spp. Clostridium spp., Bacteroides spp., Hemophilus spp., S. albus, Bifidobacteria, Proteus spp., non-hemolytic Streptococci, S. aureus, K. aerogenes, Anerobic streptococci, Veillonella spp., β-hemolytic streptococci; yeasts	The gastric juice was sterile in the healthy controls, in 67% of DU, in 7% of GU, and in 0% of GC samples. Oropharyngeal commensals were frequently isolated in the gastric juice. The microflora of gastric aspirate is associated with gastric pathology and gastric pH. Patients with GC had higher bacterial counts and higher numbers of different bacterial species.
Sjöstedt et al., 1985^Citation68	10 healthy, 10 GC	Gastric juice	Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes; yeast	Staphylococcus, Neisseria, Streptococcus, Bifidobacterium, Lactobacillus, Veilonella, Klebsiella, Escherichia, Pseudomonas, Bacillus, Bacteroides	Patients with GC harbored the most microorganisms in the stomach and the highest number of species. The cancer patients had more non-oropharyngeal species.
Sjöstedt et al., 1987^Citation114	23 GC	Gastric juice, tumor, and non-tumor	Firmicutes, Proteobacteria, Actinobacteria, Fusobacteria, Bacteroidetes	Micrococci, Staphylococci, Streptococci, Hemophilus Neisseria, Bifidobacteria, Lactobacillus, Enterococci, enteric Gram-negative bacteria, Veilonella, Fusobacteria, Leptotrichia, Bacteroides, Clostridium spp.; yeast	The gastric pH correlated with the total number of microorganisms in the gastric juice; significantly higher numbers of different strains and anaerobic microorganisms colonized the tumor compared to the gastric mucosa.
Kato et al., 2006^Citation70	1 gastritis, 1 GU, 5 early GC, 1 gastric adenoma, 1 dyspepsia	Gastric juice and biopsy	Firmicutes, Proteobacteria, Bacteroidetes, Fusobacteria	Streptococcus spp., Staphylococcus spp., Neisseria spp., Bacillus spp., Veillonella spp., Bacteroides fragilis, Fusobacterium, Lactobacillus spp., Peptostreptococcus anaerobius	Impaired gastric acid secretion associated with long-term H. pylori infection enabled non-Helicobacter bacteria to colonize the human stomach. Higher bacterial load (100-fold) correlated with higher pH.

GU: gastric ulcer; GC: gastric cancer; PUD: peptic ulcer disease.

Table 2. Summary of studies examining the relationships between gastric cancer and gastric microbiota

Author, year	Sample size	Country	Microbial diversity	H. pylori in GC	Taxon differences
Dicksved et al., 2009^Citation72	10 GC, 5 dyspepsia	Sweden	No difference	N/A	N/A
Aviles-Jimenez et al., 2014^Citation73	5 NAG, 5 IM, 5 GC	Mexico	α-diversity: NAG > IM > GC	N/A	↑Lactobacillus, Lachnospiraceae from NAG, IM, to GC; ↓Saccaribacteria (TM7), Porphyromonas, Neisseria in GC
Eun et al., 2014^Citation74	11 GC, 10 IM, 10 CG	Korea	↑α-diversity in GC vs. IM & CG (not significant)	N/A	↑ Streptococcus, Lactobacillus, Veillonella, and Prevotella in GC
Wang et al., 2016^Citation75	6 GC, 6 CG	China	No difference in α-diversity	N/A	↑Lactobacillus, Escherichia-Shigella, Nitrospirae, Burkholderia fungorum, and uncultured Lachnospiraceae in GC
Jo et al., 2016^Citation76	34 GC, 29 control	Korea	No difference in α- and β-diversity	N/A	↑Actinobacteria, Staphylococcus epidermidis in GC; ↑ nitrosating/nitrate‐reducing bacteria in GC (not statistically significant)
Yu et al., 2017^Citation77	80 cardia GC, 80 non-cardia GC	80 China, 80 Mexico	↓α-diversity in GC (Chinese cohort), but not in Mexican cohort	↓	↓Proteobacteria, ↑Bacteriodetes, Firmicutes, Fusobacteria, and Spirochetes in tumor (Chinese cohort)
Li et al., 2017^Citation44	8 healthy control, 9 gastritis, 9 IM, 9 GC	Hong Kong	↑ Shannon index in GC vs. gastritis ↓ phylogenetic diversity in GC vs. IM	N/A	↑Flavobacterium, Klebsiella, Serratia marcescens, Stenotrophomonas, Achromobacter, Pseudomonas, Delftia, Ralstonia, Rhizobium, Elizabethkingia meningoseptica, Methyloversatiis, Gp4, Cytophagaceae in GC
Castaño‐Rodríguez et al., 2017^Citation78	12 GC, 20 dyspepsia	Singapore and Malaysia	↑α-diversity in GC	N/A	↑Lactococcus, Veilonella, and Fusobacteriaceae (Fusobacterium and Leptotrichia) in GC
Hsieh et al., 2018^Citation79	9 gastritis, 7 IM, 11 GC	Taiwan	N/A	↓	↑Burkholderia, Enterobacter, and Leclercia, Clostridium, Fusobacterium in non-GC; ↑Lactobacillus in GC, C. colicanis and F. nucleatum represent diagnostic markers for GC
Ferreira et al., 2018^Citation46	discovery cohort: 81 gastritis, 54 GC	Portugal	↓α-diversity in GC	↓	↑Citrobacter, Clostridium, Lactobacillus, Achromobacter, and Rhodococcus in GC patients
Coker et al., 2018^Citation80	21 superficial gastritis, 23 atrophic gastritis, 17 IM, 20 GC	China	↓α-diversity in GC and IM vs. SG	N/A	↑oral flora, Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes in GC; ↓Vogesella, Comamonadaceae and Acinetobacter in GC
Hu et al., 2018^81	6 GC, 5 CG	China	↓bacterial richness in GC, but not Shannon diversity index	N/A	↑ Neisseria, Alloprevotella, Aggregatibacter, Streptococcus mitis and Porphyromonoas endodontalis in GC; ↓Sphingobium yanoikuyae in GC
Liu et al., 2019^82	276 GC	China	↓α-diversity in GC	↓	↓Prevotella copri and Bacteroides uniformis; ↑Prevotella melaninogenica, Streptococcus anginosus and Propionibacterium acnes
Gunathilake et al., 2019^83	288 GC, 288 control	Korea	↓α-diversity in GC	↑	↑Prevotella copri and Propionibacterium acnes in GC; ↑ Lactococcus lactis in controls
Park et al., 2019^84	55 GC, 19 IM, 62 CG	Korea	N/A	N/A	↑Rhizobiales in IM vs. gastritis; ↑Cyanobacteria in H. pylori–negative CG patients
Wu et al., 2020^85	18 GC, 32 superficial gastritis	China	↓α-diversity in GC	N/A	↑Dialister, Helicobacter, Lactobacillus, Rhodococcus, Rudaea and Sediminibacterium in GC; 18 genera were depleted in GC; ↓Bradyrhizobium and Mesorhizobium in tumor vs. non-tumor
Gantuya et al., 2020^86	48 GC, 120 control (20 healthy, 20 gastritis, 40 atrophy, 40 IM)	Mongolia	α-diversity: normal > IM > GC > gastritis and atrophy	↓	↑Enterococcus, Lactobacillus, Carnobacterium, Glutamicibacter, Paeniglutamicibacter, Fusobacterium, and Parvimonas in GC

GC, gastric cancer; CG, chronic gastritis; NAG, non-atrophic gastritis; IM, intestinal metaplasia; N/A, not available.

Figure 1. The interplay between Helicobacter pylori and gastrointestinal (GI) microbiota

(A) Case-control and epidemiology studies demonstrated H. pylori infection is inversely associated with Barrett’s esophagus and esophageal adenocarcinoma. Studies suggest that the healthy esophagus is associated with a Type I microbiome, which is dominated by Streptococcus, while Barrett’s esophagus is associated with a Type II microbiome, containing a lower relative abundance of Streptococcus and a greater proportion of Gram-negative bacteria. Whether H. pylori directly or indirectly influences the esophageal microbiome, and the relationship between H. pylori, Barrett’s esophagus, esophageal adenocarcinoma, and the esophageal microbiome still needs to be elucidated. (B) Schematic plot presentation of the influence of H. pylori on gastric and colonic microbiota. In healthy, non-inflamed mucosa, the gastric mucosa comprises a thick layer of mucus, which serves as a protective barrier and as a highly diverse, specialized niche for colonization of gastric microbiota. In H. pylori–positive patients with chronic (atrophic) gastritis, Helicobacter dominates the gastric mucosa, resulting in reduced microbial diversity. Other bacteria, like Streptococcaceae, Fusobacteriaceae, and Prevotellaceae, may be present to a lesser extent. After a long period of co-infection and co-colonization, combined with the presence of risk factors that determine the gastric dysbiotic parietal cell loss with an increase in pH, the innate immune response and gastric microbiota interactions promote the progression of pre-neoplastic lesions. In the later stages of carcinogenesis, ranging from intestinal metaplasia to gastric adenocarcinoma, a reduction or depletion of H. pylori is seen in the gastric mucosa. In gastric cancer, microbial diversity is reduced, and oral or intestinal-type bacteria are enriched. (C) In chronic H. pylori infections, the H. pylori–experienced dendritic cells retain a semi-mature phenotype and induce immunosuppressive regulatory T cell (Treg) differentiation, rather than Th1 or Th17 cells from naive Th0 cells.^93,136,137 Tregs produced in the gastric mucosa are trafficked to other lymphoid tissues in distant organs to exert a systematic immunoregulatory effect that influences the pathogenesis of various immune-related diseases, such as asthma and inflammatory bowel disease.^{138,139,140,141} The immunoregulatory effect induced by H. pylori strengthens the host’s resilience against microbiome perturbations and may result in increased colonic microbiota diversity. Additionally, chronic H. pylori infection alters the acidic environment in the stomach, permitting more microorganisms to pass through the gastric acid barrier and colonize the distal gut. The gut microbiota may also induce Tregs and in turn, regulate H. pylori–associated immune responses, which includes complex crosstalk between H. pylori and colonic microbiota.

Table 3. Summary of studies examining the effect of Helicobacter pylori infection on colonic microbiota

Detection method	Author, year	Participants	Age	Country	α-diversity	Findings
Cultivation	Bühling et al., 2001^98	51 H. pylori vs. 27 control	Adult	Germany	N/A	↓Anaerobes in H. pylori patients; ↓Enterobacteria, Clostridium innocuum and Veillonella spp. in H. pylori patients; ↑Lactobacilli, esp. Lactobacillus acidophilus in H. pylori patients
	Myllyluoma et al., 2007^99	39 H. pylori vs. 19 control	Adult	Finland	N/A	↓Clostridium histolyticum and anaerobes in H. pylori patients
	Yang et al., 2012^100	38 H. pylori vs. 38 matched control	Child	Taiwan	N/A	↓Bifidobacterium, Bifidobacterium:Escherechia coli ratio; ↑E. coli
	Benavides-Ward et al., 2018^103	28 H. pylori vs. 28 control	Child	Peru	N/A	↑Proteobacteria, Firmicutes and Prevotella in H. pylori patients
Next-Generation Sequencing	Chen et al., 2018^101	70 H. pylori vs. 35 control	Adult	China	↑ richness (Sobs index)	22 genera and 38 bacterial species differ; predicted metabolic pathways differ
	Iino et al., 2018^102	226 H. pylori vs. 524 control (111 non-AG, mild AG, severe AG)	Adult	Japan	N/A	↑Lactobacillus in severe AG vs. mild & non-AG
	Gao et al., 2018^104	24 H. pylori vs. 22 non−H. pylori (negative control + past infection)	Adult	China	Non-significant ↑ Shannon index in gastritis and metaplasia	No differences in β-diversity; some genera differ; ↓Bacteroidetes, ↑Firmicutes and ↑Proteobacteria associated with H. pylori–related gastric lesion progression
	Osaki et al., 2018^105	5 H. pylori–infected children and 13 family members	Child and adult	Japan	N/A	No differences in β-diversity and Firmicutes/Bacteroidetes ratio; some genera differ
	Iino et al., 2019^106	226 H. pylori vs. propensity score matched control	Adult	Japan	↑	β-diversity differs; some genera differ; ↑Streptococcus in severe AG vs. non-AG in H. pylori patients
	Wang et al., 2019^107	128 H. pylori vs. 158 control	Adult	China	No differences	β-diversity differs; some genera differ
	Dash et al., 2019^108	12 H. pylori vs. 48 control	Adult	United ArabEmirates	↑	No difference in β-diversity; some genera differ
	He et al., 2019^54	17 H. pylori vs. 7 control	Adult	China	↑	β-diversity differs; ↑Proteobacteria, Actinobacteria, and Acidobacteria; some genera differ
	Vasapolli et al., 2019^47	6 H. pylori, 15 non−H. pylori	Adult	Germany	N/A	No differences in β-diversity
	Yang et al., 2019^109	50 H. pylori, 42 control	Child	China	No differences	β-diversity differs; some genera differ
	Frost et al., 2019^110	212 H. pylori vs. 212 control	Adult	Germany	↑	β-diversity differs; some genera differ; more enterotype 2 in H. pylori patients; Bacteroides, Barnesiella, Alistipes, and Fusicatenibacter negatively associated with HpSA load
	Cornejo-Pareja et al., 2019^111	40 H. pylori vs. 20 control	Adult	Spain	↓	β-diversity differs
	Zhou et al., 2020^112	22 H. pylori vs. 23 control	Child	China	No differences	No differences in α-diversity and β-diversity; some genera differ

AG, atrophic gastritis; N/A, not available; HpSA, Helicobacter pylori stool antigen

Figure 2. The impact of Helicobacter pylori eradication on the gut microbiome

Significant perturbation of the diversity and composition of gut microbiota develops soon after H. pylori eradication. The microbial diversity recovers during the follow-up, but there is not yet sufficient data to confirm the changes in alpha diversity that occur at the long-term follow-up. There is a reduction in Actinobacteria, relative to baseline, throughout the follow-up. Proteobacteria have a higher relative abundance at the short-term follow-up, which then returns to normal. Only during the long-term follow-up was a reduction in Bacteroidetes and a rise in Firmicutes evident.

Table 4. Summary of studies examining the impact of Helicobacter pylori eradication therapy on the gut microbiota

Authors, year	Number of cases	Regimen used for HP eradication	Sample type	Methods	Short-term changes (2–3 months)	Long-term changes (at least 6 months)
Jakobsson et al., 2010^114	6	PPI, amoxicillin, clarithromycin for 7 days	feces	16S rRNA gene using 454-based pyrosequencing and T-RFLP	N/A	Diversity recovered; some notable changes in genera
Yap et al., 2015^115	17	PPI, amoxicillin, clarithromycin for 7 days	feces	16S rRNA gene sequencing using Illumina MiSeq	N/A	No significant differences in α-diversity and β-diversity; ↓Bacteroidetes; some notable changes at genus levels
Oh et al., 2016^116	23 (non-probiotics: 11; probiotics: 12)	PPI, amoxicillin, clarithromycin, ± probiotics for 7 days	feces	16S rRNA gene sequencing	N/A	N/A
Yanagi et al., 2017^117	20	PPI, amoxicillin, clarithromycin for 7 days	feces, without DNAstabilizer	16S rRNA gene sequencing	No significant differences in α-diversity; ↓F:B ratio	N/A
Hsu et al., 2018^118	11	PPI, bismuth, metronidazole, tetracycline for 14 days	feces, without DNA stabilizer	16S rRNA gene sequencing using Illumina MiSeq	↓α-diversity; the relative abundances of all phyla restored at week 8	No significant differences in α-diversity and β-diversity; some notable changes at genus levels
Chen et al., 2018^101	70 (non-probiotics: 35; probiotics: 35)	PPI, bismuth, furazolidone, amoxicillin, ± probiotics for 14 days	feces	16S rRNA gene sequencing using Illumina MiSeq	α-diversity not completely recovered at week 8; ↓F:B ratio at week 8	N/A
Gotoda et al., 2018^119	8 children	Vonoprazon, amoxicillin, clarithromycin for 7 days	feces	16S rRNA gene sequencing using Illumina MiSeq	No significant differences in α-diversity and β-diversity; two students showed significant changes	N/A
Liou et al., 2019^120	234 (80 triple; 73; concomitant; 77 bismuth quadruple)	PPI-amoxicillin-clarithromycin for 14 days, concomitant for 14 days, bismuth quadruple for 10 days	feces, with DNA stabilizer	16S rRNA gene sequencing using Illumina MiSeq	α-diversity not completely recovered in concomitant and quadruple at week 8	α-diversity not fully recovered in concomitant and quadruple therapy; some notable changes at the genus levels
Martín-Núñez et al., 2019^121	40	PPI, amoxicillin, clarithromycin, for 10 days	feces	16S rRNA gene sequencing using Illumina MiSeq	↓α-diversity; ↓Actinobacteria at week 8	N/A
Hsu et al., 2019^122	12	Reverse hybrid for 14 days	feces	16S rRNA gene sequencing using Illumina MiSeq	α-diversity and β-diversity restored at week 8; relative abundance of all genera restored	No significant differences in α-diversity, β-diversity, or relative abundance of bacteria at genus level
He et al., 2019^54	10	Bismuth quadruple for 14 days	feces	16S rRNA gene sequencing using Illumina MiSeq	No significant difference in phyla at week 4	Significantly higher α-diversity; β-diversity differs; ↑Firmicutes, Actinobacteria; ↓Proteobacteria, Bacteroidetes; notable changes in some genera
Guo et al., 2019^55	34	Bismuth quadruple for 10 days	feces	16S rRNA gene sequencing using Illumina MiSeq	N/A	No significant differences in α-diversity; β-diversity differs; ↑Firmicutes; ↓Bacteroidetes; ↑F:B ratio; notable changes in some genera
Zhou et al., 2020^112	22 children and 23 control	Bismuth quadruple for 10 days	feces	16S rRNA gene sequencing using Illumina MiSeq	↓α-diversity at week 6; β-diversity restored at week 6	No significant differences in α-diversity, β-diversity, and relative abundance of bacteria at genus level

PPI, proton pump inhibitors; F:B ratio, Firmicutes:Bacteroidetes ratio; HP, Helicobacter pylori; N/A, not available; T-RFLP, terminal-restriction fragment length polymorphism

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