Helicobacter pylori is a gram-negative, microaerophilic, spiral-shaped bacterium that colonizes the gastric mucosa of 43% of the world’s population (Malfertheiner et al., 2023). Infection rates depend on the geographical location, with high variation among regions reflecting urbanization, sanitation, access to clean water, and socioeconomic status (Hooi et al., 2017). It is suggested that H. pylori infection is acquired during early childhood through oral-oral or fecal-oral transmission routes and usually persists lifelong. Spontaneous clearance without encountering antibiotics is seldom (Yokota et al., 2015; Kayali et al., 2018). H. pylori was first cultivated from the stomach and characterized in 1984 by Barry Marshall and Robin Warren, who linked the bacterium to chronic gastritis and gastric and duodenal ulcers (Marshall and Warren, 1984). For this discovery, which reversed the assumption that the stomach is a sterile organ because of its high acidity, Marshall and Warren were awarded the Nobel Prize in 2005 (Pincock, 2005). The milestone discovery also led to the cure of gastric pathologies by H. pylori eradication treatment, whose efficacy was first demonstrated in 1990 (Rauws and Tytgat, 1990). Further studies confirmed H. pylori as the underlying cause of gastritis (Morris and Nicholson, 1987; Graham et al., 1988). Notably, H. pylori infection was also identified as the strongest known risk factor for gastric cancer, as up to 90% of gastric cancer cases could be attributable to the infection. Chronic gastritis can result in gastric carcinogenesis, most often through the Correa cascade of atrophic gastritis, intestinal metaplasia, and dysplasia (Moss, 2017). In addition, the infection can lead to the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma (Pereira and Medeiros, 2014). For this reason, the International Agency for Research on Cancer classified H. pylori in 1994 as a class I carcinogen for gastric cancer and MALT lymphoma (Møller et al., 1995). Although 80% of infected individuals remain asymptomatic and are unaware of the presence of H. pylori in their stomachs, the infection always leads to chronic gastric inflammation. For some individuals, the infection can have severe consequences, leading to high morbidity and mortality (Suerbaum and Michetti, 2002). As a consequence, it is recommended that all H. pylori-infected patients should be treated with eradication therapy (Malfertheiner et al., 2022). Still, the susceptibility to developing severe illness depends on H. pylori strains and their virulence factors, environmental factors, and host genetics, such as inadequate T-cell responses (Robinson et al., 2008).

H. pylori has evolved several mechanisms, mainly exerted by specific virulence factors, for successful colonization of the human stomach, manipulation of the host immune system, and signaling pathways by simultaneously avoiding clearance and maintaining a chronic inflammatory infection ( Figure 1 ). First, after entering the unique hostile environment of the stomach, H. pylori uses its helical shape and motility driven by a bundle of flagella to reach the viscous gastric mucosa and for initial colonization (Ottemann and Lowenthal, 2002) (Martínez et al., 2016). Secondly, H. pylori possesses the enzyme urease to neutralize the acidic gastric environment (pH 2) by converting urea to ammonium and carbonic acid (Weeks et al., 2000). After reaching the gastric mucus layer, H. pylori adheres to gastric epithelial cells using adhesins such as the blood group antigen binding adhesin (BabA) and the sialic acid binding adhesin (SabA). Those adhesins mediate binding interactions with fucosylated Lewis b histo-blood group antigens and sialyl-Lewis x antigens, respectively (Mahdavi et al., 2002; Rad et al., 2002). Upon chronic inflammation, carcinoembryonic antigen-related cell adhesion molecules (CEACAM) receptors are expressed in the stomach mucosa and support further adhesion by interacting with Helicobacter outer membrane protein (Hop) Q. The HopQ-CEACAM interaction also enables the translocation of the virulence factor cytotoxin-associated gene A (CagA) into host cells (Javaheri et al., 2016; Königer et al., 2016). CagA is one of the most critical factors of H. pylori. CagA is injected into host gastric epithelial cells by a type IV secretion system (T4SS) encoded by the 40-kb cag pathogenicity island (CagPAI) (Xiang et al., 1995; Censini et al., 1996; Odenbreit et al., 2000). Upon translocation, differential phosphorylation of CagA by c-Src and c-Abl kinases activates its effector properties, including perturbation of multiple cell signaling pathways, thereby promoting tumorigenesis of gastric cancer (Mueller et al., 2012; Yong et al., 2015). Numerous studies showed that, in particular, CagA-positive H. pylori strains induce pro-inflammatory and pro-carcinogenic effects on gastric epithelial cells, resulting in peptic ulcer, premalignant lesions, and gastric adenocarcinoma (Blaser et al., 1995; Parsonnet et al., 1997; Huang et al., 2003). Thus, CagA is also designated as an oncoprotein of H. pylori. Other important virulence factors secreted by H. pylori are the pore-forming Vacuolating cytotoxin A (VacA) and the γ-glutamyl transpeptidase (γGT). VacA can induce cell apoptosis and subsequently inhibit T-cell activation (Boncristiano et al., 2003; Palframan et al., 2012). Lastly, γGT is an enzyme found in nearly all H. pylori strains and participates in glutamate metabolism. γGT damages gastric epithelial cells and further contributes to immune tolerance (Schmees et al., 2007; Shibayama et al., 2007; Käbisch et al., 2016). Altogether, those virulence factors are critical for the colonization and persistence of H. pylori in the human host.

Although H. pylori chronically persists in a unique niche, the human stomach, where it it maintains an intrincate host-pathogen relationship, the infection has also been associated with systemic effects and a variety of extragastric diseases in the past years (Banić et al., 2012). Mainly, epidemiologic studies demonstrated that H. pylori infection negatively affects several diseases, such as neurological and coronary heart disorders, but also exerts protective effects on the host, for example, by reducing the risk for asthma and inflammatory bowel disease (IBD) (Kyburz and Müller, 2017).

Besides being the main risk factor for gastric cancer, the infection was associated with an increased risk for other digestive cancers, such as colon cancer, pancreatic cancer, and hepatocellular carcinoma (Xiao et al., 2013; Butt and Epplein, 2019; Madala et al., 2021). Outside of the gastrointestinal (GI) tract, H. pylori is reported to affect neurological, hematologic, and metabolic diseases. The association is less clear for dermatological, ocular, cardiovascular, and allergic diseases (Franceschi et al., 2014; Gravina et al., 2018; He et al., 2022). In contrast, H. pylori infection was also shown to protect from chronic inflammatory diseases, such as IBD. One mechanism described in IBD protection involves the manipulation of dendritic cells (DC) by H. pylori. DCs are major antigen-presenting cells and essential for activating naïve T lymphocytes (Th0) to differentiate into different T-cell subsets (Hilligan and Ronchese, 2020). It was shown that H. pylori impairs the maturation of DCs and induces a tolerogenic phenotype resulting in high numbers of regulatory T-cells (Treg cells). Mechanistically, CagA activates the signal transducer and activator of transcription 3 (STAT3) signaling in human DCs, inducing tolerization of DCs and subsequently favoring a tolerogenic immune response in the infected host (Kaebisch et al., 2014). Besides CagA, γGT was also demonstrated to promote a regulatory immune response in H. pylori-infected gastric tissue by provoking a semimature state of DCs, which was dependent on glutamate produced as result of γGT activity (Oertli et al., 2013; Käbisch et al., 2016). It is believed that H. pylori-induced Treg cells secreting anti-inflammatory interleukin (IL)-10 and transforming growth factor ß (TFGß) can migrate to other sites of the human body and exert immunoregulatory effects, thereby reducing the risk for inflammatory conditions and IBD. In addition, H. pylori stimulates a systemic immunosuppressive T helper 2 (Th2)/macrophage M2 response and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome, followed by IL-1ß and IL-18 cytokine secretion, which, together with a Treg-skewed response, protects from the development of IBD (Engler et al., 2015; Feilstrecker Balani et al., 2023). The protective effect on IBD with convincing experimental evidence suggests a pivotal role of H. pylori infection on systemic immune responses.

However, the association between H. pylori infection and extragastric diseases is mainly based on epidemiological studies, and underlying mechanisms for most extragastric diseases are still unclear and currently under investigation. One possibility could be that the bacterium exerts direct effects, which would imply that the bacterium can colonize organs other than the stomach. Due to the unique adaption of H. pylori to the gastric mucosa, different habitats in the human body seem unlikely. Studies investigating other sites of H. pylori colonization than the stomach are sparse. Regarding the colon, only a few studies could detect H. pylori genetic sequences by qPCR or sequencing in human colon biopsies (Grahn et al., 2005; Monstein et al., 2005; Keenan et al., 2010), and this is most likely due to the transit of non-viable but not of resident bacteria. Kienesberger et al. could not detect H. pylori in murine feces by qPCR or by high-throughput sequencing of fecal, ileal, and cecal samples after six months of infection (Kienesberger et al., 2016). In humans, Vasapolli et al. analyzed the transcriptionally active microbiota of the whole GI tract in H. pylori positive and negative patients. However, they could not detect 16S rRNA of H. pylori in the lower GI tract or feces, suggesting that H. pylori is not an active member of the microbiota in the small and large intestine (Vasapolli et al., 2019). Therefore, it seems plausible that H. pylori infection affects other organs, particularly the colon, through systemic immunomodulation, and alteration of microbial composition and function (He et al., 2022). Those mechanisms will be discussed in more detail in the following sections.

Nevertheless, studies focusing on the effects of H. pylori in extragastric diseases present conflicting and heterogeneous results, which may be due to differences in age and ethnicity of the study population or due to different methods for H. pylori detection. For example, if H. pylori positivity is only defined by serological screening, H. pylori-eradicated patients might be counted as currently infected, which leads to a bias in the analyses.

The impact of H. pylori infection on increased CRC risk has been studied for years. Already in 1997, a small case-control study reported that in patients with colon polyps, H. pylori prevalence, measured by IgG antibody responses, was significantly higher than in matched controls (49% in controls vs. 71.4% in patients with colon polyps, OR=2.6). However, in patients with colon cancer, H. pylori incidences (69.2%, p=0.18) did not significantly differ from those of control patients, which might be due to antibiotic treatment of CRC patients before surgery and, thus, unintentional H. pylori eradication (Meucci et al., 1997). Later, a study from Korea reported that patients with colorectal neoplasms had a significantly higher H. pylori prevalence than control patients, resulting in an OR of 1.90 (Nam et al., 2013). When analyzing Chinese patients undergoing both colonoscopy and esophagus-gastro-duodenoscopy, it was found that H. pylori infection and H. pylori-associated gastric diseases doubled the risk for colorectal neoplasia, but the severity of gastric conditions was only mildly correlated with the level of CRC risk (Qing et al., 2016). Kim et al. could also confirm a positive association between H. pylori and CRC risk. In a large-scale study involving around 9000 healthy male subjects undergoing screening colonoscopy and testing for H. pylori IgG antibody response, the odds for advanced colorectal neoplasm in H. pylori-positive participants was 1.90 (Kim et al., 2017). In a Chinese cohort with almost 4000 H. pylori-positive individuals, Liu et al. reported a significantly higher risk of developing CRC (hazard ratio (HR)=1.87) as well, the risk of CRC was associated with the frequency of H. pylori-related clinical visits. Of note, H. pylori-infected participants also displayed a much higher number of other comorbidities, such as hypertension, diabetes mellitus, hypercholesterolemia, and coronary artery disease (Liu et al., 2019). In 2022, a meta-analysis of seventeen observational studies summarized that H. pylori infection is an independent risk factor for overall colorectal polyps with an OR of 1.67. In particular, the infection is associated with adenomatous polyps (OR=1.71), advanced adenomatous polyps (OR=2.06), and hyperplastic polyps (OR=1.54) but not with sessile serrated polyps (OR=1.00) (Lu et al., 2022). Another systematic review and meta-analysis came to similar results. Wu et al. found a positive association between H. pylori and the risk for colorectal adenoma (OR=1.66), as well as for CRC (OR=1.39) (Wu et al., 2013). A summary OR for the relationship between H. pylori infection and CRC risk of 1.4 was found by a smaller and earlier meta-analysis. The lower OR from this meta-analysis could be due to the very small and heterogeneous studies available in those early years (Zumkeller et al., 2006). Finally, the up-to-date greatest retrospective population-based study from the USA reported an independent positive association between the history of H. pylori infection status and CRC development with an OR of 1.89. However, as the H. pylori status was determined based on serological testing, the authors could not differentiate between active or past infection and thus explore the effects of eradication therapy on CRC risk (Boustany et al., 2023).

Certain virulence factors of H. pylori are associated with more severe gastric malignancies, predisposing some H. pylori carriers to a high risk for serious clinical outcomes. Whether this also accounts for the H. pylori-associated CRC risk is currently a subject of research. Butt et al. investigated, in a consortium of ten different US cohorts representing diverse populations, whether H. pylori-specific antigen responses were associated with CRC risk. The authors concluded that VacA seropositivity slightly increased the odds of CRC in a dose-response relationship (OR=1.11), which was especially strong for African Americans (OR=1.45) (Butt et al., 2019). Similarly, in a European study cohort, H. pylori positivity increased the risk for CRC with an overall OR of 1.36. Here again, antibody responses towards 13 H. pylori virulence factors were measured, and it appeared that the increased cancer risk was mainly driven by VacA (OR=1.34) and cysteine-rich protein C (HcpC) seropositivity (OR=1.66) (Butt et al., 2020). Other studies investigated the association between infection with H. pylori CagA-positive strains and CRC risk, as it is known that CagA-positive strains highly increase the risk for gastric cancer, as mentioned before. Indeed, Shmuely et al. found, in a relatively small Israelian cohort, CagA seropositivity to be strongly associated with an increased risk for not only gastric cancer (OR=88.1), as expected but also for CRC (OR=10.6) (Shmuely et al., 2001). Those findings were confirmed in another cohort with around 1000 CRC patients in China. CRC patients had higher H. pylori infection rates compared to control patients, and importantly, serum gastrin levels and expression of the proliferation marker Ki67 in colonic tumor tissues were significantly higher in patients infected with CagA-positive strains compared to CagA-negative strains (Zhang et al., 2020). These studies were the first to suggest that the effects of specific virulence factors, especially CagA and VacA, might not be limited to the stomach but influence inflammatory and carcinogenic processes in the gut. However, further studies are needed to confirm the molecular role of these virulence factors in CRC development to elucidate if those could be used as biomarkers. Overall, considering the large number of cohort studies and meta-analyses performed in the last decades, H. pylori infection can be regarded as a relevant risk factor for CRC by increasing the odds by almost a factor two. Nevertheless, those studies did not clarify causal and functional mechanisms.

H. pylori infection of the stomach elicits a pro-inflammatory response by recruiting multiple innate and adaptive immune cell populations into the gastric mucosa, which is critical for developing H. pylori-induced pathologies. At the same time, the virulence factors mentioned above allow the bacterium to evade innate immune mechanisms and manipulate antigen presentation and T-cell responses to maintain a chronic infection. Noteworthy, H. pylori infection also induces systemically inflammatory immune responses in the host (Jackson et al., 2009). The increasing evidence linking H. pylori infection to CRC development suggests a complex immune crosstalk between the upper and lower digestive tract. Hence, it can be assumed that the infection provokes a pro-inflammatory condition in the gut by manipulating CD4⁺ and CD8⁺ T-cell responses that may increase CRC risk.

In 2020, a global consensus meeting was held in Taipei to discuss current evidence and therapeutic guidelines for H. pylori screening and eradication to prevent gastric cancer. The consensus report suggested offering all H. pylori-infected individuals eradication treatment. Different antibiotic regimens are available and should be chosen according to antibiotic resistance profiles, efficacy, adverse effects, and costs in the specific region (Liou et al., 2020). In general, standard treatment regimens comprise standard triple therapy (proton-pump inhibitor (PPI), most often omeprazole, clarithromycin, and amoxicillin), non-bismuth quadruple therapy (PPI, clarithromycin, amoxicillin, and metronidazole), or bismuth-containing quadruple therapy (PPI, bismuth, tetracycline, and metronidazole). In case of failure, fluoroquinolone-containing therapy (PPI, levofloxacin, amoxicillin, and, in case of quadruple therapy, bismuth) or PPI-amoxicillin high-dose dual therapy (PPI twice daily and amoxicillin) should be used (Malfertheiner et al., 2022). H. pylori eradication is an effective measure to reduce the risk of gastric cancer. A prospective, randomized controlled trial in a high-risk area in southern China found that H. pylori eradication treatment is associated with long-term protection against gastric cancer development (Yan et al., 2022). Furthermore, a systematic review and meta-analysis of twenty-four studies concluded that H. pylori eradication effectively reduces the risk for gastric cancer. In addition, the protective effect of eradication increased with increasing baseline gastric cancer incidences, arguing against a “point-of-no-return” in H. pylori-driven gastric carcinogenesis (Lee et al., 2016). Such “point-of-no-return” describes the fact that in some studies, H. pylori-positive patients presenting already with gastric intestinal metaplasia could not benefit from eradication, compared to patients with gastritis (Chen et al., 2016). The stage of intestinal metaplasia was therefore classified as “point-of-no-return”, suggesting imprinted immune and microbiome signatures in the stomach upon H. pylori infection. As some other studies drew different conclusions, a “point-of-no-return” in H. pylori-driven diseases is under debate.

Based on these studies, it might be speculated that H. pylori-positive patients could similarly benefit from antibiotic eradication regarding CRC development. In a retrospective study cohort of 615 adults in Taiwan, persistent H. pylori-infected patients had higher colorectal adenoma incidences than subjects without infection or those who underwent eradication therapy (60.11% vs. 20-24%). Therefore, H. pylori infection was associated with a significantly increased risk of colorectal adenoma compared to the eradication group (HR = 3.04), suggesting that antibiotic therapy may prevent CRC (Hu et al., 2019). Recently, Guo et al. conducted a large retrospective cohort study with almost 97.000 patients who had received a clarithromycin-containing triple therapy between 2003-2015 in Hong Kong. The authors compared the observed incidences of CRC in the eradication group with the expected incidences in the age- and sex-matched general population. While in the first five years after eradication, higher CRC incidences were observed (standardized incidence ratio (SIR) = 1.47), in the long-term follow-up after 11 years, eradicated study participants showed lower CRC incidences compared to the general population (SIR = 0.85), especially for rectal cancer (SIR = 0.90) (Guo et al., 2023). In conclusion, H. pylori eradication may confer protective effects and reduce the risk for CRC development in the long-term, at least as was shown in Asian populations. In this context, a new population-based cohort study, called “Nordic Helicobacter pylori Eradication Project”, with more than 670.000 patients in up to twenty-three years follow-up period will help to determine the impact of antibiotic therapy on gastrointestinal cancer risk in Scandinavian countries (Pettersson et al., 2023).

A protective effect of H. pylori eradication on CRC would imply that H. pylori-induced changes in intestinal immune and microbiome signatures are reversible. Studies that address the intestinal immune response after H. pylori eradication therapy are lacking. In the up-to-date only experimental study available, Ralser et al. showed in Apc-mutant and wild-type mice that antibiotic eradication with a triple therapy regimen consisting of clarithromycin, metronidazole, and omeprazole after short-term H. pylori-infection, reduces tumor formation in the small intestine and colon to the level of non-infected controls, and prevents the H. pylori-induced phenotype of intestinal inflammation and barrier impairment. The analysis of colon tissue samples of 154 patients showed a declined phenotype in immune and epithelial signatures in H. pylori-eradicated patients. Moreover, eradicated patients showed a similar bacterial composition in their stool as non-infected patients, whereas the microbiota from actively infected patients clustered more distantly. This study further supports eradication therapy as a CRC prevention measure ( Figure 4 ) (Ralser et al., 2023). However, Velin et al. administered antibiotics to H. pylori-infected mice one month before they were engrafted with B16-PVA melanoma cells and vaccinated to explore whether eradication improves the efficacy of anti-cancer vaccination. Eradication was found not to substantially revert the H. pylori-induced hyporesponsiveness to cancer immunity in mice (Oster et al., 2022). A similar imprinting of H. pylori-induced T-cell responses was observed when neonatal mice were either directly infected with H. pylori or treated with H. pylori immunomodulatory components and subsequently challenged in an allergy model (Kyburz and Müller, 2017). Although these findings were obtained in other experimental models than CRC, they suggest that H. pylori-imprinted changes in the immune system might not be reversible upon eradication, which significantly limits therapy options for the host ( Figure 3 ). Therefore, if H. pylori-induced immune and microbiome changes in the small and large intestines after long-term infection are also imprinted or reversible upon antibiotic eradication must be further investigated to decipher optimal treatment options.

The scientific community’s attention to the effects of antibiotics on the gut microbiome has increased considerably. In general, antibiotics are more and more seen as potentially harmful because of their detrimental impact on the intestinal microbiota and related disorders, such as IBD (Ianiro et al., 2016) (Fishbein et al., 2023). High levels of antibiotic usage were also associated with an increased risk for colorectal neoplasia (Aneke-Nash et al., 2021). In addition, resistance rates of H. pylori to antibiotics have dramatically increased worldwide, but antibiotics are currently the only option to prevent H. pylori-related malignancies (Malfertheiner et al., 2022). However, one study provided evidence that the gut microbiota of young, healthy individuals is resilient towards a short-term broad-spectrum antibiotic therapy and could recover one and a half months after antibiotic treatment (Palleja et al., 2018). Ng et al. reported a remarkably high resilience and recovery capacity of the human microbiome after antibiotic treatment, where only short-term transient changes of some taxa were detected (Ng et al., 2019). Hence, elucidating alterations of the intestinal microbiota following antibiotic eradication is crucial to decipher and weight the risks and benefits of H. pylori eradication therapy on the host.

Several studies analyzing the intestinal microbiota after H. pylori eradication reported only short-term changes in alpha- or beta-diversity. After bismuth quadruple therapy, which is recommended first-line instead of triple therapy in high areas of clarithromycin resistance, temporary changes in the gut microbiota have been reported in adult patients with H. pylori-related gastritis. Antibiotics reduced the alpha-diversity and relative abundances of Bacteroidetes and Actinobacteria but increased that of Proteobacteria. However, already eight weeks post antibiotics, bacterial richness was restored to the levels at baseline, and at week 48, relative abundances of all phyla did not differ significantly from those before therapy. Here, patients reporting adverse effects during treatment also had higher abundances of Proteobacteria (Hsu et al., 2018). Another study, including sixty-three children from China, investigated short- and long-term changes in the intestinal microbiota after different H. pylori eradication regimens. Although short-term dysbiosis with reduced richness was observable after all antibiotic therapies (standard triple therapy including omeprazole, clarithromycin, and amoxicillin for fourteen days; sequential therapy including omeprazole plus amoxicillin for the first week, omeprazole plus clarithromycin and metronidazole for the second week; bismuth-based quadruple therapy including omeprazole and amoxicillin, metronidazole and bismuth for fourteen days, and concomitant therapy including omeprazole plus amoxicillin, clarithromycin, and metronidazole for fourteen days), one year after the antibiotic administration, richness, and composition recovered to baseline levels independently of the chosen antibiotics (Zhou et al., 2021). He et al. reported recovery of the gut microbiota already twenty-six weeks after bismuth quadruple therapy in ten young asymptomatic infected adults. No dysbiosis was seen in the long term. Instead, the beneficial taxa Blautia and Lachnoclostridium levels increased, the relative abundance of detrimental Alistipes decreased, and the overall composition approached that of healthy controls. As the intestinal microbiota after eradication differed from the H. pylori-associated microbiota before treatment, one could conclude that eradication treatment does not restore but rather abrogates H. pylori-induced microbial dysbiosis and thus could prevent H. pylori-associated diseases (He et al., 2019). Beneficial effects of antibiotic therapy in H. pylori-positive individuals were also observed in a prospective study from China analyzing stool samples from fifty-three H. pylori positive individuals by 16S rRNA sequencing. Successful H. pylori eradication enriched a probiotic Bifidobacterium-related taxa and did not substantially alter microbial diversity before and six months after receiving quadruple therapy (omeprazole, tetracycline, metronidazole and bismuth citrate for ten days) (Guo et al., 2020). Finally, in a multicentric, randomized trial including 1620 patients, only minimal adverse changes in fecal microbial diversity and composition were detected in the one-year follow-up after antibiotic treatment. H. pylori eradication also significantly improved metabolic parameters, for example, insulin resistance, triglycerides, and LDL levels (Liou et al., 2019).

However, some human studies also observed long-lasting and potentially harmful effects. A study with seventeen H. pylori-infected young adults aged eighteen to thirty years investigated the fecal microbiome before and after antibiotic eradication by 16S rRNA analysis. Whereas the overall richness and evenness of the intestinal microbiota did not differ much between before and after eradication, changes at the phylum level were found. In particular, the relative abundance of Bacteroidetes decreased, whereas Firmicutes increased until 12 months post-eradication, leading to a shift in the Bacteroidetes/Firmicutes ratio, which is associated with obesity. In addition, a significant increase in SCFA-producing bacteria was noticed, leading to an increased risk for metabolic disorders (Yap et al., 2016). A systemic review including 24 studies with three different follow-up periods reported inconsistent effects of H. pylori eradication on the intestinal microbiota. Alpha-diversity of fecal samples decreased in the short term, but no reliable conclusion could be drawn regarding the long-term observation of patients. While the authors found most phyla to recover to baseline levels at the long term, Actinobacteria levels, for example, decreased six months post-eradication compared to pre-eradication status. Together, these results suggest that antibiotic therapy for H. pylori eradication may affect microbial populations and richness beyond the stomach. These changes depend highly on race and eradication regimens (Ye et al., 2020). Long-term decreased relative abundances of Actinobacteria in the fecal microbiome of individuals receiving H. pylori triple therapy were similarly identified by Jakobsson et al. Still, alpha-diversity of the microbiota recovered to pre-treatment levels. However, in some individuals, a disrupted gut microbiome remained until up to four years post-treatment, indicating long-lasting consequences of H. pylori eradication on the intestinal microbiome (Jakobsson et al., 2010).

In conclusion, studies reported adverse effects of antibiotic therapy, with changes in the gut bacterial community lasting longer than a year. In many other studies, H. pylori eradication regimens appear safe, as no long-term consequences in alpha- or beta-diversity of the intestinal microbiota were identified ( Figure 4 ). However, if we assume, based on current evidence, that H. pylori infection has a detrimental impact on the gut microbiota and that this dysbiosis may cause or contribute to inflammation and promote colorectal carcinogenesis, a “recovery” of the intestinal microbiota after H. pylori eradication treatment to the state before, is not favorable. Instead, the bacterial composition after eradication should convert to the composition of non-infected healthy subjects, as seen by (He et al., 2019). Recovery of the intestinal community to pre-eradication status would suggest that H. pylori infection of the stomach promotes changes in the intestinal microbiome, which get imprinted and persist even without an active infection. Hence, further studies are needed to address this question and its consequences.