Helicobacter pylori and oral–gut microbiome: clinical implications

More than half of the world’s population are colonized with H. pylori; however, the prevalence varies geographically with the highest incidence in Africa. H. pylori is probably a commensal organism that has been associated with the development of gastritis, ulcers, and gastric cancer. H. pylori alone is most probably not enough for the development of gastric carcinoma, but evidence for its association with the disease is high and has, therefore, been classified by the International Agency for Research on Cancer as a Class 1 carcinogen. Bacteroidetes and Fusobacteria positively coexisted during H. pylori infection along the oral–gut axis. The eradication therapy required to treat H. pylori infection can also have detrimental consequences for the gut microbiota, leading to a decreased alpha diversity. Therefore, therapy regimens integrated with probiotics may abolish the negative effects of antibiotic therapy on the gut microbiota. These eradication therapies combined with probiotics have also higher rates of eradication, when compared to standard treatments, and are associated with reduced side effects, improving the patient’s compliance. The eradication therapy not only affects gut microbiome but also affects the oral microbiome with robust predominance of harmful bacteria. However, there have been reports of a protective role of H. pylori in Barrett’s esophagus, esophageal adenocarcinoma, eosinophilic esophagitis, IBD, asthma, and even multiple sclerosis. Therefore, eradication therapy should be carefully considered, and test to treat policy should be tailored to specific communities especially in highly endemic areas. Supplementation of probiotics, prebiotics, herbals, and microbial metabolites to reduce the negative effects of eradication therapy should be considered. After failure of many eradication attempts, the benefits of H. pylori eradication should be carefully balanced against the risk of adverse effects especially in the elderly, persons with frailty, and intolerance to antibiotics.


Background
H. pylori is a commensal organism associated with the development of gastritis, ulcers, and gastric cancer.The organism as well as eradication remedies can modulate gut microbiota in humans.Other non-H.pylori microbial species may colonize the same milieu, but H. pylori are regarded as a human pathogen [1].Interactions between H. pylori and other members of the microbiome, the host, and the environment influence the clinical consequence and may lead to either disease or possible protective effects.Considering the beneficial effects on the host by regulating gastrointestinal microbiota, eradication of H. pylori can produce various adverse effects and alter the gastrointestinal microbiota.Gastrointestinal microbiota are defined as the entire community of microorganisms dwelling in the gastrointestinal tract, and it is dominated substantially by bacteria [2].Gut microbiota composition varies between ethnic groups due to the different dietary, hygienic, and genetic factors in addition to the use of antibiotics.Its homeostasis plays a critical role in maintaining host health.Dysbiosis of the gut microbiome may produce multiple diseases and bacterial infections in addition to compromising human alimentation [3].This review aims to discuss the relationships between H. pylori alone and in combination with oral and gut microbiota in the development of GI disease.

General characteristics of H. pylori
H. pylori colonization affects more than half of the population worldwide [4] with the highest incidence in Africa (79.1%) [5].Despite this high prevalence, the majority of the infected population are asymptomatic.Acquisition of H. pylori occurs in early childhood (30%-50%), while during early adolescence, it reaches over 90% in developing countries [6].The consequence of infection varies either from no clinical symptoms or continuing throughout his life with superficial chronic gastritis [7,8] or developing peptic ulcers, 25% even experience ulcer complications, and 1% will advance to gastric cancers (GC) [9].
The main transmission route of H. pylori is not known.However, the intrafamilial transmission of the pathogen is the most significant route.This may be facilitated by close personal contacts, the unified socioeconomic status of the family members, and the genetic predisposition to H. pylori persistence [10,11].
Children < 5 years of age have high infection rates, after which infection declines at school age when less time is spent at home.In Egypt, 33% of children < 6 years are infected [12].The disease development is influenced by several factors such as host genetics, environmental factors related to diets, lifestyle habits, and pathogens [13].
Once entering the stomach, H. pylori produces urease to convert urea to ammonia which neutralizes hydrochloric acid, then after, uses mobile flagella to spread over the surface of the gastric epithelium forming microbial biofilms.Gastric persistence is determined mainly by bacterial adhesion [14].The adhesion of H. pylori is facilitated by the gastric epithelium α1,2-Fucosylated glycans [15].Both virulence factors; cytotoxic-associated gene, (CagA) and vacuolating cytotoxin A (vacA), have direct damaging impact on the gastric mucosal epithelium [16,17].The initial host Th1 cell immune response intended to eradicate the microorganisms is opposed by H. pylori vacA immunosuppressive effect [18].A Th2 cellular pathway facilitates H. pylori colonization in infancy and leads to the development of immune tolerance resulting in a symbiotic relationship between the microbe and the host [19].H. pylori influence host immune responses and the microbiota of both the stomach and distal organs [20].

Helicobacter pylori and oral microbiota
H. pylori detected in both the mouth and gut.The oral-gut axis microbiota has a dominant effect in H. pylori's colonization, infection, and pathogenicity [52].The number of H. pylori in the mouth is lower than in the stomach.It constitutes 42%-97% of the total gastric bacterial community [53].The oral and gastric milieus are affected by saliva and digested food.The oral microbiome is the dominant source of gastric microbes, so, it is accused for the infection and transmission of H. pylori [54,55].
The interplay between H. pylori and oral microbiome may take one or further of three main forms: co-aggregation, symbiotic biofilm formation, and endosymbiosis [56].Fusobacterium nucleatum and Porphyromonas gingivalis are crucial bacteria in periodontal infection.The aggregation with H. pylori promotes oral to gastric colonization by oral bacteria [57].Biofilms are surface bacterial communities embedded within an extracellular matrix.They contribute to an infection becoming chronic or recurrent, promote inflammation, and can make bacterial colonies resistant to antibiotics and the immune system [58].
The major cariogenic bacterium, Streptococcus mutans, forms a symbiotic biofilm with H. pylori prolonged its survival in the unsuitable atmosphere of the mouth [59].H. pylori can anchor on the surface and/or enter C. albicans to form a mixed biofilm in the oral cavity and vagina [60,61].
The interaction between and H. pylori members of the oral microbial community yields different results according to oral or gastrointestinal complaints in H. pylori-positive people.P. gingivalis has been established as a pathogenic agent of periodontitis and positively associated with H. pylori, indicating that H. pylori infection may promote periodontal disease [62].The inter-transmission between oral and gut microorganisms can affect the ecosystem in both territories and hence regulate the pathogenesis of different diseases [63].

Gastric bacterial microbiome profile
The gastric core microbiome is mainly formed from five major phyla, including Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, and Proteobacteria [64,65].Numerous oral bacteria such as Neisseria, Veillonella, Fusobacterium, Streptococcus, and Hemophilus, are enriched in the lower digestive tract and can be significantly found in gastric biopsy too [66].A healthy gut microbiome is characterized by high gut microbial diversity [67].The co-occurrence interactions were stronger in intestinal metaplasia (IM) than superficial gastritis (SG) [68] and among genera in IM which then decreased in intraepithelial neoplasia (IN) of gastric biopsies with gastritis progression suggesting that the bacteria tend to co-occur to form a specific micro ecology before the occurrence of neoplasia [69].Several factors can affect the gastric microbiome such as diet, aging, geographic area of residence, and medications like PPI and antibiotics [70,71].A reduced number of Bacteroidetes and elevated numbers of Firmicutes and Proteobacteria were observed in patients with gastritis as compared with healthy individuals [72] (Fig. 1).

Gut microbiota and Helicobacter pylori infection
H. pylori infection disturbs commensal bacterium equilibrium in the gastric mucosa in addition to the disturbance of microbial changes in the human gut [73][74][75][76].H. pylori mainly influences the microbial composition and diversity in gastric mucosa rather than both gastric juice and stool [69] H. pylori infection results concerning bacterial diversity have been controversial as has been found with other specific groups of gut bacteria [77,78].Lactobacillus species abundance was higher in H. pylori-infected patients than in non-infected persons [79] , protecting the human gut from bacterial colonization through gut barrier preservation [80].Iino et al. in 2018 [79] found that H. pylori-positive patients displayed reduced amounts of L. acidophilus and an increased proportion of L. salivarius in comparison with non-infected subjects due to the suppression of gastric acid secretion by H. pylori infection.He reported a higher abundance of Lactobacillus in H. pylori-positive patients with severe atrophic gastritis compared to infected patients with mild atrophic gastritis or without gastritis denoting affection of gastric microbiota according to symptom severity.On the other hand, gut bacteria might also influence the bacterial colonization of other gastrointestinal regions, including H. pylori in the stomach.Nitrospirae phylum can be seen only in H. pylori-negative personnel with minimal values in patients with duodenal ulcer and H. pylori infection as nitrite has a bactericidal effect against H. pylori [80,81].H. pylori infection alters the gut microbiota in asymptomatic patients by increasing Proteobacteria, Clostridium, Firmicutes, and Prevotella in a pediatric population [78] and members belonging to Succinivibrio, Coriobacteriaceae, Enterococcaceae, and Rikenellaceae in adults [75] compared to noninfected subjects.Gao et al. in 2018 [72] reported a disturbance of fecal microbiota, mainly the phyla Bacteroidetes, Firmicutes, and Proteobacteria in H. pylori-induced gastric diseases.The relationship between H. pylori and gastric microbiota could be mediated through multiple mechanisms, such as virulence factors, the modification of gastric acidity, host immune responses, and competition [82] (Fig. 2).
H. pylori-resistant strains showed a higher trend of diversity and evenness than the sensitive samples.The abundance of resistant strains decreased with increasing cohabitation of pathogenic bacteria.There is an increase in the α-diversity index among the MDR.The resistance status of H. pylori was correlated with the enriched diversity of the gastric microbiome composition, where the abundance of nonpylori pathogens increased, especially in triple-resistant strains [83].

Gut microbiota and Helicobacter pylori eradication therapy
Antibiotic administration decreases bacterial diversity [84,85].Bacterial diversity was restored in the short and the long term after treatment conclusion [86][87][88][89].Still, not all studies reported enhancement in bacterial diversity after treatment conclusion [90,91].Generally, gut microbiota composition is restored in most cases at 2 months post-treatment.Proteobacteria phylum is proposed to be partially responsible for the development of adverse effects during eradication therapy [92].Probiotic supplementation and the antibiotic impose a beneficial gut microbiota profile after eradication therapy [93].Niu et al. in 2021 [94] reported a success rate of H. pylori eradication 95.5% using the quadruple remedy.The majority of phyla in the two groups were the same and included Proteobacteria, Bacteroides, Firmicutes, Actinomycetes, and Fusobacteria.The microbial diversity in the failure group had a lowering fashion and the species abundance became extensively reduced compared with the success group.The presence of Rhodococcus, Lactobacillus, and Sphingomonas was associated with high rate of H. pylori eradication in the successful group.Veronococcus and Cilium were enriched in the mucosa of chronic atrophic gastritis cases compared to chronic superficial gastritis cases.In both study groups, H. pylori were negatively identified with other bacterial groups.They concluded that gastric microbiota is the corner stone in the effect of quadruple H. pylori eradication therapy.Tawfik et al. in 2023 [95] found oral microbiomes more diverse than the gut microbiomes.The eradication of H. pylori was associated with a significant reduction in the bacterial diversity along the orointestinal axis.H. pylori positive patients showed positive correlation between Proteobacteria and Fusobacteria.After eradication Fig. 2 Main mechanisms mediating the relationship between H. pylori and gastric microbiota.Created with BioRender.comtherapy, Fusobacterium, Veillonella, Catenibacterium, Neisseria and Prevotella enriched significantly.They stress the importance of eradication therapy on certain genera especially, in the oral microbiota.

Gastritis and ulcer disease
Only 10% of the population develop clinical manifestations latterly in their lives when getting elderly [96].Seventy percent of people who are established to have the bacterium are healthy bacterial carriers, and 5%-10% of those infected develop symptoms of gastritis or PUD [97][98][99][100][101].Absence of H. pylori-gastritis had been reported [102,103] , and indeed in severe cases and premalignant conditions, a low abundance of H. pylori had been reported [104].H. pylorinegative gastritis was found to be 21% in the United States [105] and 27% of all cases of gastritis in Indonesia [103].Araújo et al. in 2014 [106] reported that the discovery rate of H. pylori infection in cases diagnosed with PUD is the same as in the general population and 20-50% of PUD patients had idiopathic etiology.The high prevalence rate and low incidence of pathological diseases indicate that H. pylori are more likely to be an opportunistic or latent pathogen rather than a truly pathogenic bacterium.The development of PUD is multifactorial and depends on endogenous and exogenous factors, which means that the presence of H. pylori infection may be only one of many factors involved in the genesis of ulcerative disorders.The genotype of H. pylori is a determinant factor in producing ulcer disease.Cases with a verified diagnosis of PUD had vacA-positive and CagApositive genotypes [107,108].Our group [109] reported a low prevalence of CagA (26.5%).Western type CagA is the fundamental kind (62.5%) while the East Asian type was not detected and others (37.5%) remain uncharacterized.Western-genotype CagA was found in 80% of patients with peptic ulcer disease and 40% of patients with gastritis.The primary genotype mixture in the studied Egyptian sufferers were; vacAs2m2/iceA1, vacAs1m1/cagA, mostly related to gastritis, and vacAs1/cagA/icA, mainly in PUD.The much less virulent (s2, s2m2) H. pylori genotypes were found in cases over the age of 43 years [110].Lately, there has been a progressive increase in the idiopathic forms of PUD with a drop in the global frequencies of H. pylori infection.A further study demonstrated a significant correlation between the isolation of Streptococci and peptic ulcer disease [111].Iijima and his associates [112] reported that 45.9% of cases of peptic ulcers of the stomach and 29.6% of those of the duodenum were idiopathic.H. pylori-positive ulcer had better convalescence rates, better course, more positive prognosis, less hospital stay, less 30 days readmission, and fewer recurrence rates [113,114].

Gastric carcinoma
Gastric carcinoma (GC) develops in H. pylori-infected people 1.4-4.2times more often than within the general population [115][116][117].Even so, only 1-2% of cases develop GC in 50% or more of H. pylori-infected patients [118].In spite of the superiority of H. pylori in Africa and India than in the West, the incidence of GC is less frequent than in the West [119], which is known as an epidemiologic paradox [120].This decreasing trend of bacterial richness going from the normal tissue to peritumoral and tumoral tissues indicated that as the microenvironment of a tumor is altered, it becomes unsuitable for colonization with specific bacteria.The low microbial diversity of the upper digestive tract was associated with a low serum pepsinogen I/pepsinogen II ratio, which has also been associated with gastric carcinogenesis [121].H. pylori virulence factors have not been reported to be essential for cancer development [1].In an Egyptian study of the prevalence of H. pylori CagA among patients with gastric carcinoma, a total of 34 (56.67%)patients have been CagA + ve and 26 (43.33%) patients were CagA − ve, with no statistically significant difference regarding sex or age [122].It is well known that the persistence of H. pylori infection is linked to the development of only noncardiac carcinoma, while it had a protective effect against cancer development in the cardiac area and lower esophagus [48].The decrease in H. pylori infections in Japan is believed to have contributed to a decline in gastric cancer cases [123].However, the cause of an increase in gastric cancer in the young population in the USA (notably, young Hispanic men), where overall the incidence of H. pylori infection is also waning, is unexplained [124].Thus, unknown factors likely unrelated to H. pylori infection may be contributing to a rise in gastric cancer in specific populations.
Recently, it is accepted that cancer pathogenesis is precipitated by confounding factors such as high-salt diets and other carcinogenic substances that promote the carcinogenic pathway in addition to bacterial agents [125].The multistep processes involved in the development of GC are initiated by the transition of the mucosa into chronic non-atrophic gastritis, which is primarily triggered by infection with H. pylori.This gastritis then progresses into atrophic gastritis and intestinal metaplasia, and then to dysplasia, and following Correa's cascade, to adenocarcinoma [119].
During the transition from gastritis to GC, a significant difference in the gastric microbial community was observed.There is an increase in the abundance of non-H.pylori proteobacteria [126] (Fig. 3).
An analysis of gastric microbial communities from different stages of gastric cancer development revealed the significance of Peptostreptococcus stomatis, S. anginosus, Parvimonas micra, Slackia exigua, and Dialister pneumosintes in the progression of gastric cancer, as they were found in the precancerous stage [68].Gastric cancer prevalence varies among different regions of the stomach, with cancers arising in the corpus potentially caused by mechanisms distinct from the other regions [127].Alternatively, physiological factors that vary along the length of the stomach and pylorus such as differences in oxygen concentration, pH, mucus, and nutrient availability could play a part in determining regional cancer susceptibility [128].
Ralser and his colleagues in 2023 identified a unique H. pylori-driven immune alteration signature characterized by a reduction in regulatory T cells in addition to H. pylori induction of pro-carcinogenic STAT3 signaling and a loss of goblet cells in colonic epithelium, changes that have been shown to contribute; in combination with pro-inflammatory and mucus degrading microbial signatures, to tumor development in the intestinal and colonic epithelium [129].
Metabolites and their interactions with microbiota may be involved in Helicobacter pylori-associated gastric lesion development.Negative correlations between Helicobacter and glycerophospholipids, glycosylceramide, and triacylglycerol, which were altered by eradication.The characteristic negative correlations between glycosylceramides and Fusobacterium, Streptococcus, and Gemella in H. pylori-positive baseline biopsy specimens were further noticed in active gastritis and intestinal metaplasia.This helps discriminate high-risk for progression from mild lesions to advanced precancerous lesions in short-term and long-term follow-up [130].
Antibiotic treatment in H. pylori-infected patients can reduce GC progression even if H. pylori is not eradicated, suggesting that suppression of other bacteria may serve a protective function [131].Niikura and his colleagues in 2023 [132] identified potential pathogens; abnormally colonized gastric bacteria, particularly Fusobacterium and Neisseria spp., play an additional fundamental role in the later stages of gastric carcinogenesis.Testing for Fusobacterium and Neisseria spp. in gastric mucosal samples as a surrogate for gastric dysbiosis could be a next-generation approach for screening high-risk patients for GC.In addition, eradication of these oncogenic bacteria and/or inhibition of carcinogenic bacteria-derived molecules may be a future strategy for preventing GC development, particularly in patients with severe atrophic gastritis and intestinal metaplasia.

Clinical implications
H. pylori infection is frequent in developing countries and represents an annoying health problem.Eradication remedies had been recommended by all societies for fear of malignancy.Eradication remedies are complicated by the requirement for several agents such as the use of 2 antibiotics and a PPI.These strategies can be complicated by antibiotic resistance, high cost on the national level, PPIrelated complications, and not the least microbiota dysbiosis.Despite the high frequency of H. pylori infection, there is a low prevalence of gastric malignancy.H. pylori alone is most probably not enough for the development of GC.Considering the protective role of H. pylori against numerous conditions such as IBD, asthma, multiple sclerosis, Barrett's esophagus, esophageal adenocarcinoma, and eosinophilic esophagitis, H. pylori is now considered one of the bacteria in the healthy microbiome for the majority of the human population.Therefore, not every case should be treated for eradication.A personalized approach according to the H. pylori indigenous region, the presence of gastrointestinal malignancies among relatives, or the Fig. 3 Association of Helicobacter pylori abundance with the different stages of gastric conditions.The presence of H. pylori was dominant in the superficial gastritis condition; thus, this domination reduced microbial diversity.In atrophic gastritis and intestinal metaplasia, the relative abundance of H. pylori began to decrease with the introduction of other bacteria, including the incremental of Prevotella sp. and Neisseria sp.In the gastric cancer condition, H. pylori started to deteriorate with a significantly increased amount other bacteria, including oral cavity microbiota, intestinal microbiota, and lactic acid bacteria.Published in Gut Pathogens (2022) 14:19 with permission impossibility of banning non-modifiable threat factors is needed.It should include relatives with high familial risk or living in high-risk areas/populations where eradication effectively reduces the threat of gastric carcinoma as in South East Asia and cases with cancer who are on therapy with immune checkpoint inhibitors or vaccine-grounded immunotherapy [133].
The supplementation of probiotics, prebiotics, and microbial metabolites to reduce the negative effects of eradication should be considered.
Probiotics reduce H. pylori-induced gastric pathology in mice, with reduced inflammatory infiltration and precancerous lesion incidence [134], enhance H. pylori eradication rates, and reduce side effects in humans [135].
Autoprobiotics refer to indigenous bifidobacteria, lactobacilli, or enterococci isolated from a specific individual, intended to restore microbiota and improve health.The advantages of autoprobiotics include its safety, high survival rate, its unique individual composition and, extended duration in the gut [136].Both the quadruple therapy group and the H. pylori-negative subjects after probiotic-supplemented eradication treatment had nearly the same microbial diversity [137].The most effective types belong to the Firmicutes (Enterococcus and Lactobacillus) and Actinobacteria (Bifidobacterium genus) phyla and Saccharomyces boulardii [138,139].However, Yang and his colleagues in 2021 [140] reported failure to improve the eradication rate of H. pylori after supplementation with lactobacillus, but it helped build up a beneficial microbial profile and reduced the frequencies of abdominal distention and diarrhea.
The potential mechanisms of probiotic action against H. pylori include correction of the gut microbiota, immunological effects such as enhancement of humoral and cellular immunity, and reduction of oxidative stress, direct antagonistic effects against H. pylori such as colonization resistance and bacteriocin synthesis, and stimulation of local immunological protection such as strengthening of the mucous protective barrier and reduction of gastric mucosa inflammation [141].As a double-edged sword, the use of probiotic-induced adverse effects include higher risk of systemic neonates infections throughout their life span [142], long-term gut dysbiosis [143], and risk to develop Parkinson's disease mostly due to Desulfovibrio bacteria [144,145].The oral administration of multi-strain probiotics and paraprobiotics were more than single-strain probiotics, reducing the incidence of developing metabolic disorders [146].
Washing microflora transfer (WMT) is a modified FMT method that uses washed preparations.Ye et al. in 2020 [147] reported that WMT has an overall H. pylori eradication of 40.6%.No H. pylori transmission was recorded from healthy, asymptomatic donors to recipients by oral capsulebased FMT [148].
H. pylori living in both oral cavity and gut looks to be a commensal, occasionally pathogenic.It is not surprising for a case to have more than an eradication course.This is harmful to both oral and gut microbiota and may lead to different diseases.After multiple failed eradication attempts, the implicit benefits of H. pylori eradication should be weighed against the liability of adverse effects with repeated highdose acid suppression and antibiotic exposure, particularly among individuals who are not at an identifiably advanced threat of complications from persistent H. pylori infection such as, GC or peptic ulcer disease.Similarly, a careful decision-making approach should be seriously considered, especially in the senior, those with frailty, and those with intolerance to antibiotics [149] (Best Practice Advice #9).

Fig. 1
Fig. 1 Gastric micro ecological imbalance and gastric diseases.Despite the differences among individuals, there are five dominant bacterial phyla in the healthy stomach, and their common dominant bacterial genera are summarized (green).The gastric microbiota is dynamically balanced and affected by many factors, such as Helicobacter pylori infection, probiotics, gut microbiota, drugs, diet, and