Dysbiosis by Eradication of Helicobacter pylori Infection Associated with Follicular Gastropathy and Pangastropathy

1. Introduction

Gastropathy is a condition that affects the gastric mucosa [1]. It is characterized by the prevalence of mononuclear infiltrates, the formation of lymphoid follicles with germinal centres in the lamina propria, and subsequent tissue inflammation and regeneration. Histological injury is frequently located in the gastric antrum; however, it sometimes extends to the gastric corpus [2]. Gastropathies are classified according to their aetiologies. Follicular gastropathy (also known as reactive or chemical gastropathy) is mainly attributed to irritants, and their recurrent abuse, including alcohol and nonsteroidal anti-inflammatory drugs (NSAIDs) [1], which play an important role in the development of bacterial infections in the mucosa, particularly those induced by Helicobacter pylori [3]. Approximately 50% of the worldwide population is colonized with H. pylori, representing up to 90% of the gastric microbiota of healthy subjects [4]. However, only 1–2% of this population develops several degrees of chronic mucosal inflammation with clinical manifestations and severe complications [5]. The Mexican consensus on the diagnosis, prevention, and treatment of NSAID-induced gastropathy and enteropathy [6] has determined that the consumption of NSAIDs in subjects with H. pylori infection is a risk factor (relative risk = 20.8) for the development of gastroduodenopathies [7].

H. pylori is classified as a high-priority pathogen because of its resistance to multiple antibiotics [8]. Its association with several infectious diseases has led us to seriously consider the most accurate diagnoses for the optimal selection of treatment therapies. Several non-invasive diagnostic techniques, such as the urea breath test, blood and stool tests, and upper gastrointestinal series [9], have been widely developed for the detection of this bacterium. However, endoscopic studies, which are considered invasive methods for clinical diagnosis, remain helpful because they facilitate the early identification of the aetiological agent [10].

H. pylori eradication has been suggested in patients with gastropathy, who are undergoing NSAIDs therapy, to avoid subsequent complications (i.e., development of ulcerations) [6]. International guidelines for the treatment of H. pylori infections suggest the use of the standard triple therapy (STT), which is considered the first therapeutic alternative for effective eradication [11]. This therapy consists of two antibiotics and a proton pump inhibitor (PPI), usually composed of clarithromycin (CLR), amoxicillin (AMX), and omeprazole [12]. However, clinical guides for the eradication of H. pylori in Mexico and several European countries have replaced the use of CLR by considering metronidazole (MTZ) as a first-line drug for treating this infection [13,14].

Antibiotics have improved the outcomes of treatment therapies for bacterial infectious diseases. They are considered one of the major contributors to the rise in life expectancy by exponentially diminishing morbidity and mortality rates. Unfortunately, the sometimes-unjustified employment and abuse of drugs for the relief of gastric symptomatology or self-treatment of several infectious diseases have contributed to the global crisis of resistance to multiple antibiotics. Although antibiotics are widely employed for the treatment of specific bacterial infections [15], they can cause several states of dysbiosis.

Dysbiosis, defined as the induction of several alterations in the native microbiota of the host, can be observed as a significant reduction or permanent loss of commensal species in the affected microbial communities and/or the establishment, colonization, or overgrowth of gastrointestinal pathobionts (native commensal microbiota that presents pathogen behaviours under dysbiotic conditions) [16]. Although H. pylori induces dysbiosis in infected patients by colonizing up to 90% of the total gastric microenvironment for its establishment, recent studies have highlighted the possible association of non-H. pylori bacteria with the initiation and development of not only follicular gastropathy and pangastropathy but also several gastric infectious diseases [17] by correlating bacterial overgrowth under non-favourable microenvironmental conditions [18], such as the pathobiont Cutibacterium acnes.

The species of the genus Cutibacterium reside as dominant commensal bacteria in the human skin [19]. Although most Cutibacterium species are adapted to inhabit the human skin [20,21], C. acnes is mainly associated with the maintenance of skin homeostasis due to its multiple benefits in this organ. This species was first reported in healthy gastric mucosa [22,23,24]; however, its functions in the gastric microenvironment have not been fully elucidated. C. acnes has recently been classified as a possible trigger of gastric clinical outcomes, such as corpus-dominant lymphocytic gastritis [25], and has been considered a high-risk factor for the initiation and development of gastric cancer [26].

This study aimed to characterize the gastric microbiota of patients with follicular gastropathy and pangastropathy, evaluate the effects of STT on the gastric environment, and correlate the presence of pathobiont C. acnes with the development of gastric infectious diseases.

2. Materials and Methods

2.1. Characterization of the Gastric Microenvironment

2.2. Correlation of the Presence of C. acnes and H. pylori with Gastric Diseases

3. Results

3.1. Characterization of the Gastric Microenvironment

3.2. Correlation of C. acnes in Gastric Diseases

Forty FFPE gastric biopsy samples from patients with non-significant histologic alterations, gastritis, gastropathies, and intestinal metaplasia were evaluated using qRT-PCR. Figure 7 shows the correlation between the presence of C. acnes and H. pylori in the FFPE samples obtained from patients with gastric infectious diseases. Seventeen patients revealed C. acnes transcripts, whereas H. pylori was determined as absent. Five patients with non-significant alterations were exclusively colonized with C. acnes. However, when evaluating gastropathies, six samples were presented with both bacteria. The number of C. acnes transcripts was significantly higher than that of H. pylori transcripts. Finally, when evaluating the samples from patients diagnosed with intestinal metaplasia, only one patient presented with C. acnes transcripts. The remaining patients did not present C. acnes or H. pylori transcripts .

Figure 7. Presence of C. acnes and H. pylori in patients with gastric diseases. Evaluation of the presence of C. acnes and H. pylori in FFPE gastric biopsies via the determination of the log of the number of transcripts of both bacteria in the gastric biopsy samples.

As observed in , the number of C. acnes transcripts was determined as statistically significant compared with the number of H. pylori transcripts, with the non-parametric Mann–Whitney U-Test.

The number of C. acnes transcripts was determined significantly higher than the number of H. pylori transcripts .

Additionally, the significance of the number of C. acnes transcripts by pathology was determined using the Kruskal–Wallis test . As observed, the number of C. acnes transcripts was higher in gastritis (maximum = 573,263,008.44), whereas it was lower in gastropathies (maximum = 48,151,777.41).

4. Discussion

The health status of the host can be significantly altered by the induction of dysbiosis in the human gastrointestinal microbiome, which increases the susceptibility to gastric disorders [16], and difficulting both clinical diagnosis and treatment of infections.

The diagnosis for the identification of H. pylori infection is not easy [36]. Therefore, different methodologies are necessary for clinical diagnosis. Nevertheless, each technique presents variable sensitivity and specificity. Histopathological evaluation revealed that patients 3B and 4B tested positive for H. pylori. However, microbiological and molecular analyses only confirmed patients 1B, 5B, and 6B as H. pylori positive. Metagenomics revealed H. pylori representative sequences in patients 3B (interpreted as an occult infection event), 5B, and 6B, but not in patient 1B. Although this may be interpreted as a false-negative result, we attribute this result to the sampling site. Conflicting reports regarding the best sampling site for the detection of H. pylori continue because of the migration mechanisms of this bacterium in the stomach [37,38]. Advanced stages of histological injury have been also implied in the diminishment of H. pylori populations, reducing its detection rates [39] and hindering its identification using molecular methods, including metagenomics.

Coccoid structures were detected in patient 5A via histopathological evaluation. Although H. pylori can modify its native morphology under dysbiotic microenvironmental conditions (i.e., antibiotic and antisecretory therapies, and accumulation of toxigenic metabolic products (reactive O₂ species, pyrimidine nucleotides)) as an adaptative mechanism [40,41], it was impossible to conclude its presence. Therefore, we attribute this finding to the muco-microbiotic layer, which is described from a morphofunctional and histological point of view, as the first line of defense under hostile conditions. This structure is the product of the union of the mucus layer and microorganisms. Although in most routine histologic evaluations the muco-microbiotic layer is unfortunately not visible due to the processing of the sample, the detection of microbial morphologies in H. pylori-negative subjects, as observed in our study, can elucidate a possible key role of these bacteria in the gastrointestinal physiology and pathophysiology [42].

Patients 1B, 6B, and 4B presented with urealytic activity. Although the urea breath test is one of the fastest and most employed tests for clinical diagnosis [43], studies have reported false-positive rates of up to 16.9% [44,45], supporting other reports that have also observed native commensal bacteria with urealytic activity in the stomach, e.g., Staphylococcus epidermidis, Streptococcus salivarius, and Staphylococcus capitis urealiticum [46].

Although these results strongly suggest a lack of trustworthy in the different tests for clinical diagnosis, this study attempts to highlight the importance of the integration of all diagnostic tools for the identification of H. pylori. We suggest not treating all results as mutually excluding but as complementary data.

Although the international guidelines for the treatment of H. pylori infection usually suggest the use of the STT composed of CLR, AMX, and omeprazole [8,9], this therapy has lost its effectiveness due to the increasing resistance rates to antibiotics [47], lengthened periods of treatment up to 2 weeks, and the intention to reduce treatment periods to less than 1 week [48]. To date, STT with CLR is considered one of the least effective treatments since its eradication rates stand < 73% [49], forcing the clinical practice to reconsider other broad-spectrum antibiotics, such as MTZ, which has shown an improvement in the symptomatology and eradication rates > 94.3% when combined with AMX and omeprazole [48].

The lack of objectivity in selecting an optimal therapy according to the phenotypic and genotypic characteristics of H. pylori remains a major challenge, particularly with regard to the increasing rates of antimicrobial resistance, which in consequence hamper the treatment of the bacterial infection, and rapidly increases the gastroduodenal morbidity rates [50]. Three primary cultures isolated from the pretreatment patients presented with specific susceptibility profiles to the four antibiotics. However, when testing the subcultures, discrepancies were observed in their susceptibility profiles. Although the emergence of multidrug-resistant strains has been recognized as a growing problem for the treatment of these infections, heteroresistance, a non-widely discussed issue, must be examined [50].

Heteroresistance, which is defined as the different susceptibility profiles to specific antibiotics in H. pylori subpopulations [51], has been poorly detected mainly due to the lack of standardized methods for its characterization. However, our findings justify the need for new methods for the optimal detection and genotyping of these subpopulations prior to a multiple-antibiotic therapy prescription [50].

Clinical outcomes are attributed to strain-specific virulence factors [52]. Although cagA+ increases the risk of mucosal inflammation [53,54], highly diverse vacA s1m1/s2m2 variants were correlated with more severe histological lesions and clinical outcomes [55,56]. Demirturk et al. [57] reported severe atrophy in diverse cagA and vacA genotypes, revealing a higher risk of progression of precancerous lesions than each virulence factor considered separately. Urtiz-Estrada et al. [58] identified that the cagA+vacAs1+m1 genotype is the most prevalent genotype in Mexican patients and is correlated with various gastric diseases. In our study, it was the most observed genotype; however, some studies widely suggest the possible association of non-H. pylori microbiota with the induction of histological injuries in H. pylori-negative patients [25].

Patient 2A revealed H. pylori representative sequences after the administration of STT. Buffie et al. [59] reported that dysbiotic events can facilitate the establishment of infections as recent acquisition events during the recolonization period, which was determined after the administration of STT. Although some studies reported de novo infections via the inadequate sterilization of surgical materials [60,61], other factors must be considered for these types of events, such as the habits of the host during the infection treatment process, including age, sex, diet, fomites, lipid metabolism, smoking, alcohol consumption, and physical activity [62].

Although dysbiosis is mainly attributed to STT administration, the broad-spectrum activity of the antibiotics prevented the development of infections by not allowing exogenous bacteria to infiltrate the mucosal tissue during therapy, in addition to the competition mechanisms for the inhibition of colonization resistance, pressure selection, and regulation of overgrowth by the survivor gastric microbiota (production of bacteriocins, alterations in gastric pH, consumption of limited resources for competition, and promotion of the epithelial barrier by antimicrobial peptides) [63,64].

Bacterial communities that were altered during dysbiosis (Figure 7) have been reported to be involved in the maintenance of gastrointestinal homeostasis, e.g., signalling for the release of gastric acids [65]; regulation of pathobiont overgrowth [66]; synthesis of precursors in the synthesis of short-chain fatty acids [67]; metabolism of processed foods and production of histamine under halophilic conditions [68]; immunomodulation [69,70,71,72]; and lipid digestion processes [73]. Some of these bacteria have also been shown to be associated with secondary infections in immunocompromised patients [74,75,76,77,78,79,80].

Diversity and richness index values after the recolonization period varied between individuals. The overgrowth and dominance of pathobiont bacteria of clinical interest were observed; however, both metrics after the administration of STT slightly increased, suggesting recolonization which we attribute to the lifestyle [16]. Recolonization by pathobionts was observed. Palleja et al. [81] observed recolonization of the intestinal microbiota after the administration of a multiple-antibiotic therapy. Most species recovered their almost native relative abundances 42 days after treatment, suggesting the modulation of recovery patterns by antibiotics resistance genes (ARGs). In our study, recolonization was observed to be predominantly performed by non-dominant facultative bacteria on day 30. Birg, Ritz, and Lin. [64] reported that eradication treatments generate organ-specific dysbiosis by inducing oxygenation of the gastric tissue via severe inflammation processes, favouring the growth of facultative anaerobic pathogens with antibiotic resistance genes (ARGs).

Recolonization by pathobiont bacteria is an actual concern due to their ability to infect patients with an increased risk of infection. Our study revealed the dominance of Pseudomonas after dysbiosis over time [82]. Although this genus colonizes healthy subjects, it can overgrow on almost any surface due to its non-restrictive metabolic requirements. Pseudomonas aeruginosa and Pseudomonas fluorescens are considered to be of clinical interest because of their role as opportunist pathogens in healthcare-associated infections (HAIs) [83,84], in addition to the risk of establishment of carbapenem-resistant P. aeruginosa [82].

Microbial communities with specific functions (the inhibition of H. pylori growth and its conversion to coccoid structures via the modulation of uremic toxins [18]; acquisition and competition of nutrients to prevent the establishment of Escherichia coli pathotypes [85,86,87,88]; bioeradication and recovery from infectious diseases [89,90]; and generation of energy [91,92]) increased their relative abundances in the gastric microenvironment of the study subjects. However, these bacteria have been also associated with immunocompromised patients and those with gastric diseases [85,86,87,88,91,92,93,94,95].

According to the results of our study, we strongly suggest that dysbiotic events, such as bacterial eradication by the administration of a multiple-antibiotic treatment, and its consequences, e.g., survival and overgrowth of adapted microbial communities, indicate a true ecological opportunity for these pathobionts to persist in the microenvironment by benefitting of the alterations induced in the native microbiota, e.g., eradication of non-resistant native microbiota, whose principal functions might include the regulation of the establishment or overgrowth of specific pathobionts or exogenous microbiota, both of clinical interest.

All pre-treatment patients were initially diagnosed with H. pylori infection. Histological injury was observed as well. However, only three patients showed relative abundances < 9% and <1% of this bacterium. Both presence and bacterial overgrowth are widely correlated with the pathogenesis of infectious diseases, which were not observed for H. pylori in this study. Through metagenomics, C. acnes was observed to be dominant in almost all pre-treatment patients, regardless of the presence–absence of histological injury (i.e., patient 2), strongly suggesting the role of non-H. pylori microbiota in not only development but also the initiation of gastric infectious diseases [96].

To support our findings, FFPE gastric biopsy samples were evaluated. H. pylori was exclusively present in samples from patients with gastropathies. This bacterium is the most frequent cause of gastroduodenal diseases due to its evident dominant relative abundances in subjects with these conditions [97]. However, H. pylori has coevolved within humans through time as a pathobiont by inducing multiple benefits within the host [98]. Additionally, studies have reported the incidence of gastric alterations in the absence of this bacterium in worldwide populations, in which the aetiology of the cases could not be determined [99,100], suggesting a possible role of specific gastric bacteria under dysbiosis.

Research on the microbiome and its significant findings regarding the dysbiosis of several clinical outcomes opens the opportunity to study other bacterial agents possibly involved in the initiation and development of infectious diseases [101]. Studies have reported an overgrowth of Paludibacter sp. and Dialister sp. in patients with gastritis [102], whereas other authors have observed the role of an overabundance of Streptococcus spp., Haemophilus parainfluenzae, and Treponema spp. in the development and progression of dysbiosis in patients with non-H. pylori gastritis [103], suggesting new potential associations between the absence of this pathobiont and the development of infectious diseases [101]. Native commensal bacteria (i.e., Lactobacillus spp., Prevotella melaninogenica, Streptococcus anginosus) have also been shown to be associated with the development of peptic ulcer and gastric cancer [17,18]. The skin pathobiont Cutibacterium acnes was present in almost all FFPE samples.

Neither H. pylori nor C. acnes transcripts were identified in intestinal metaplasia gastric biopsy samples, except in one patient. Studies have determined significant differences in gastric microbial diversity, which is gradually reduced while progressing from non-atrophic gastritis to gastric cancer [104] due to an increase in the production of proinflammatory cytokines and subsequent progressive inflammation [105]. Although these conditions result in an inhospitable microenvironment for most native bacteria, studies have reported dysregulation of the bacterial overgrowth of lactic acid bacteria, which can also promote the development of neoplasia [101,105]. Patient 30 was colonized with C. acnes, which has shown overabundance in gastric tumoral tissues because of its ability to induce inflammation via the production of interleukin-15 [105].

5. Conclusions

NGS tools enable us to determine alterations in the microbiota under specific health-disease conditions. The dysbiotic events of specific pathobionts were highlighted by the dominance of C. acnes in the gastric microenvironment, suggesting the possible role of this bacterium in the initiation or development of diseases. However, some limitations could not allow us to conclude its possible role in the stomach. To support our findings, the presence of C. acnes was evaluated, allowing us to highlight its dominance in different gastric alterations. Therefore, gastroduodenal disorders should no longer be considered as self-limiting diseases. Studies regarding the characterization of C. acnes must be conducted to evaluate the functions of this bacterium in the gastric microenvironment and determine its role in the pathogenesis of infectious diseases. This study takes part in the list of studies that have characterized dysbiotic events, in addition to the recent emergence of pathobiont bacterial species, which under a disequilibrium state can induce severe injury to the host, instead of generating multiple benefits to a specific organ.

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