Dincolo de Helicobacter pylori: o recenzie critică a Helicobacter heilmannii, un agent patogen gastric zoonotic emergent

Introduction

To date, there are more than 50 Helicobacter species described in the literature, as Helicobacter is a fast-growing genus that can persistently colonize a wide range of animals and people. However, a small number of species (e.g., Helicobacter felis, Helicobacter fennelliae, Helicobacter cinaedi and Helicobacter heilmannii) are known to cause gastritis in humans. Among the Helicobacter spp. that are proven human pathogens, H. heilmannii (previously Gastrospirillum hominis) is the most frequent⁽¹⁾.

The bacterial species identified as H. heilmannii sensu lato are distinguished, among other characteristics, by their resemblance to Helicobacter pylori, especially concerning their connection with diverse upper gastrointestinal disorders like gastritis, gastric and duodenal ulcers, along with certain types of lymphomatous gastric cancer. All H. heilmannii s.l. species are Gram-negative, spiral (with 4-6 helical turns and measuring 2.3-10 µm in length), motile (having bipolar flagella, except for H. felis, which has periplasmic fibrils), microaerophilic, positive for catalase and positive for urease⁽²⁾.

The significance and frequency of H. heilmannii infection are poorly understood, as indicated by various studies⁽²⁾. Due to the infrequency of H. heilmannii infection in people and the lack of clinical and epidemiological data, there is a need for up-to-date, summarized information about H. heilmannii. In this context, the current paper aims to identify, summarize and critically discuss the available literature about H. heilmannii.

Methodology

A narrative review was conducted to identify relevant studies on H. heilmannii that fit the scope of the review. The used database was PubMed. The selected studies had to meet the following inclusion criteria: original research articles, written in English and available in full-text format, published in the last ten years. 

Exclusion criteria included: review articles, both narrative and systematic, articles written in languages other than English, and articles that were not available or accessible in full text.

The selection process was performed manually. Snowballing the references was also used.

Epidemiology and transmission

The incidence of H. heilmannii s.l. in human ­stomach biopsies is typically below 1% in both adults and children in Western nations and Japan. Reports from China and Thailand show that the infection prevalence may reach 2% and 6%, respectively⁽³⁾.

A study conducted in Venezuela found non-H. pylori Helicobacter DNA in gastric biopsies from rural dyspeptic patients, while no such infections were detected in urban patients, suggesting zoonotic exposure in rural environments⁽⁴⁾. In Western Europe, the prevalence of H. heilmannii is generally under 1% among patients undergoing gastric biopsy^(5,6).

H. heilmannii s.l. has been found colonizing the stomachs of various companion and domestic animals (e.g., dogs, cats, pigs), and also in wild animals (e.g., cheetah, lynx, fox, non-human primates). Notably, five species – H. suis, H. felis, H. bizzozeronii, H. salomonis and H. heilmannii – have also been isolated from the human stomach, underscoring their zoonotic potential^(3,5).

The transmission is generally fecal-oral, particularly through the consumption of animal-derived foods, such as milk and milk products. Oral-oral pathways, facilitated by intimate contact between dogs and their humans, including activities such as licking, sharing living spaces, or inadequate hygiene practices^(7,8). The definitive mechanisms of transmission are unknown due to insufficient evidence and are still under investigation. A 2022 study investigating the presence of H. heilmannii in the feces of companion dogs identified only a potential association, based on bacterial detection in fecal samples, without providing evidence for the routes of infection in either human or animal hosts⁽⁷⁾. 

Pathology (associated diseases)

Recently, Helicobacter heilmannii has been recognized as a possible pathogen responsible for gastritis in humans. Its frequency is far smaller than that of H. pylori, and its pathogenic significance is poorly understood compared with H. pylori^(2,9). From an endoscopic perspective, H. heilmannii infection typically exhibits features that differ from those of H. pylori, such as the preservation of the gastric body mucosa without signs of atrophy, and the presence of a distinctive cobblestone pattern or fissuring of the antral mucosa⁽¹⁰⁾.

During the eradication therapy of H. pylori, gastric colonization by H. heilmannii was observed, indicating that non-H. pylori (NHP) species may contribute to the production of gastric polyps. Consequently, further screening for NHP may be required, particularly for those in immediate contact with dogs, to prevent unexpected post-treatment complications⁽¹¹⁾.

To investigate the pathogenic mechanisms of H. heilmannii, researchers conducted in 2015 an experimental infection of BALB/c mice with H. heilmannii. The findings indicated a reduction in genes associated with stomach acid production and an elevation in Muc4, Tff2, Dmbt1 and pIgR, indicating the beginning of metaplasia in the gastric fundus. Histopathological examination revealed lesions with mucosal metaplasia and MALT lymphoma-like characteristics⁽⁷⁾. Such pathological modifications were documented in H. pylori infection where long-term colonization can result in the development of gastric MALT lymphoma and metaplasia⁽¹²⁾. The results indicate that H. heilmannii may influence the host’s immune system by modifying the expression of genes related to inflammation and stomach metaplasia⁽¹³⁾.

Although the processes connecting H. heilmannii to gastrointestinal cancer remain incompletely elucidated, cobblestone-like gastritis has been proposed as a possible risk factor, especially for undifferentiated carcinomas⁽¹⁰⁾. A substantial association has been shown between H. heilmannii s.l. infection and stomach mucosa-associated lymphoid tissue (MALT) lymphoma. Identifying these connections is crucial, since several disorders have shown positive responses to antibiotic treatments aimed at the underlying bacterial infection⁽³⁾.

Table 1 presents a comparison of the transmission routes and pathological features of H. heilmannii and H. pylori.

Pathogenesis

The pathogenic potential of H. heilmannii is closely linked to its capacity to adhere to gastric epithelial cells, a process mediated by various adhesins, which are specialized proteins that recognize and bind to specific host cell receptors. The initial attachment enables the bacterium to interfere with host cell signaling pathways, triggering structural and functional alterations that promote its persistence and replication. In addition to adhesion, H. heilmannii utilizes a range of virulence factors to modulate the host immune response. These include enzymes and toxins capable of disrupting the gastric mucus barrier, thereby facilitating deeper colonization of the gastric mucosa. Moreover, the bacterium contributes to mucosal damage by inducing oxidative stress, characterized by the generation of reactive oxygen species and free radicals, which further drive tissue injury and the development of gastric lesions^(18,19).

The attachment of bacteria to the gastric mucosa is facilitated by the recognition of specific glycan receptors displayed on the surface of host epithelial cells. Glycans are ubiquitously expressed on all cell membranes and play essential roles in various biological processes, including protein folding, cell signaling, cellular recognition and mediating interactions between host and pathogen⁽¹⁹⁾.

Molecular mechanisms of virulence

To be able to cause diseases, H. heilmannii relies on various virulence factors. Virulence factors are bacteria-associated molecules that facilitate host colonization at the cellular level⁽²⁰⁾. H. heilmannii lacks the low-virulence strains as the main known adhesins associated with stomach colonization in humans^(19,21). It only presents high virulence factors, like urease enzymes, flagella and adhesins to attach to the gastric epithelium⁽²⁰⁾.

Highly virulent strains from Helicobacter heilmannii sensu stricto ASB1 were isolated using Genomic-tips in combination with the Genomic DNA Buffer Set⁽²²⁾. The genome comprises 1918 protein-coding genes, with an average coding sequence length of 933 base pairs, along with 41 tRNA genes and 9 rRNA genes. Comparative genomic analysis with fully sequenced H. pylori strains revealed that H. heilmannii sensu stricto possesses numerous genes encoding homologues of known H. pylori virulence determinants, including gamma-glutamyl transpeptidase (GGT), neutrophil-activating protein (NapA), flavodoxin (FldA), plasminogen-binding proteins (PgbA and PgbB), collagenase (PrtC), the carcinogenic factor Tipα, proline oxidase (PutA), and the secreted serine protease HtrA⁽²³⁾.

Details of these gens can be found in Table 2.

H. heilmannii possesses homologues of genes that encode various outer membrane proteins found in H. pylori; however, it lacks homologues for the BabA and SabAadhesins. This bacterium lacks homologous sequences to the H. pylori cag pathogenicity island, such as the gene for CagA, and to the vacuolating cytotoxin VacA. The differences in the genomes of H. heilmannii s.l. species compared to the H. pylori genome, particularly the absence of homologues to recognized H. pylori virulence factors linked to disease, may partially clarify the variations in pathology associated with H. pylori and H. heilmannii s.l.⁽³⁾(Table 3).

Resistance to antibiotics

Eradication therapy for H. heilmannii s.l. is recommended for individuals exhibiting significant pathology and clinical symptoms linked to the infection⁽³⁾.

The antimicrobial management of gastric infections caused by NHPspecies in humans largely relies on clinical experience, as standardized treatment protocols are lacking. In most cases, therapeutic regimens designed for H. pylori eradication are employed. These typically involve a combination of two to three antibiotics (such as clarithromycin, amoxicillin, metronidazole, tetracycline, or levofloxacin) administered alongside an acid suppressive agent, including either a proton pump inhibitor (PPI) or an H2-receptor antagonist⁽⁴⁷⁾. NHP species, like H. heilmannii (but, also, H. suis and H. ailurogastricus), present challenges for standard antimicrobial susceptibility assays due to their fastidious nature and the difficulties associated with their cultivation, which translates into a low number of isolates⁽⁴⁷⁾.

Clarithromycin resistance is a significant issue, since it is an essential element of first-line treatment for H. pylori. The incidence of clarithromycin resistance exhibits significant regional variation, with elevated rates seen in some Asian nations and reduced rates in Europe and North America⁽⁴⁸⁾.

Resistance to metronidazole remains high globally, with reported rates ranging between 40% and 70%. In contrast, resistance to tetracycline is relatively uncommon; however, its clinical use is often limited due to potential adverse effects. Levofloxacin has demonstrated efficacy against H. pylori, though its utility is increasingly constrained by rising resistance. Amoxicillin continues to show low resistance rates and remains a reliable component of H. pylori eradication therapy⁽⁴⁹⁾.

Laboratory diagnostic

The diagnosis of H. heilmannii infection poses a significant challenge due to the limited sensitivity of conventional diagnostic methods⁽¹⁰⁾, especially when compared to the well-established tools available for detecting H. pylori.

The detection of H. heilmannii sensu lato has predominantly relied on histopathological identification in gastric tissue samples⁽³⁾, a diagnostic method that involves specialized silver staining to visualize the spirals and, when available, PCR and gene sequencing to confirm species identity.  A recent study showed that H. heilmannii activates several important genes when it sticks to gastric cells, including genes for urease (ureB, ureE, ggt), flagella (fliW), and proteins⁽¹⁸⁾.

H. heilmannii exhibits unique characteristics endoscopically and histologically when compared to H. pylori, such as a cobblestone-like appearance in the gastric antrum and a predominance of lymphocyte infiltration with reduced neutrophilic activity⁽¹⁰⁾.

The histopathological diagnostic of bacteria presents a series of limitations. For example, it often requires special silver stains and, in some cases, may fail to detect infections, especially if patients took proton pump inhibitors or antibiotics. Also, it cannot reliably distinguish between H. pylori and non-H. pylori species⁽⁵⁰⁾. In a large study conducted by Kiss et al., over 9000 gastric biopsies were histopathologically negative, but H. heilmannii DNA was detected by PCR in 2.1% of cases⁽⁵¹⁾.

H. heilmannii-like organisms isolated from infected individuals closely resemble H. bizzozeronii, H. salomonis or H. felis, but can be distinguished from true H. heilmannii using sequence analysis and fluorescence in situ hybridization (FISH). FISH enables the direct visualization of H. heilmannii types and their distribution within the stomach⁽⁵²⁾.

Nowadays, there are no dedicated antibodies for the immunohistochemical detection of H. heilmannii s.l., and the most precise approach for species identification is PCR, followed by the sequencing of target genes. The genes include urease A and B (ureA, ureB), heat shock protein 60 (hsp60), and gyrase subunit B (gyrB)⁽³⁾.

A significant use of PCR-based assays is in the identification of antibiotic resistance and virulence factors. A significant use of PCR-based approaches is for identifying the frequency of H. pylori infection and antibiotic resistance in pediatric populations⁽⁵³⁾. PCR-based methods, based on their high sensitivity, may effectively identify H. pylori infection in patients with peptic ulcer hemorrhage, gastric cancer or gastric MALT lymphoma, when diagnosis using nonmolecular means is challenging but crucial. Sensitivity and specificity for PCR are close to 100%. Usually, in traditional PCR, several genes are amplified, such as vacA, cagA, ureA, glmM, hsp60, 16S rRNA, ureC and flaA, using specialized primers. Amplification of the 23S rRNA gene has superior efficacy in detecting H. pylori infection.  Compared to conventional PCR, RT-PCR is more sensitive and specific, and it targets small segments of 16S rRNA genes, urease, and 23S rRNA genes⁽⁴³⁾.

The current understanding of H. heilmannii pathophysiology is supported by controlled experimental studies and molecular analyses, which provide strong evidence of its association with gastric MALT lymphoma and mucosal metaplasia. The use of PCR for the direct identification of the organism in stomach biopsies enhances diagnostic precision^(3,10).

Coinfections with both species are prevalent, and H. heilmannii demonstrates a favorable response to standard H. pylori eradication therapies, underscoring the necessity for specialized detection technologies.

The review highlights the absence of large-scale, controlled human research, the lack of noninvasive diagnostic techniques, and the challenges associated with culturing the bacteria in vitro^(3,47).

Conclusions

H. heilmannii, although less common than H. pylori, has been associated with various gastrointestinal disorders, such as mild chronic gastritis and, in certain instances, with an elevated risk of gastric MALT lymphoma. A significant portion of the current knowledge regarding H. heilmannii, encompassing its pathogenic mechanisms and treatment strategies, has been derived from H. pylori research. This is primarily attributable to the scarcity of studies concentrating specifically on H. heilmannii species. H. heilmannii is not as often linked to peptic ulcer disease; instead, it usually shows up with milder forms of gastritis, ­which suggests that it has a different pathogenic profile. Antibiotic resistance remains a major challenge in the management of H. pylori.

Research data suggest that a high carbohydrate diet and gastric colonization by Helicobacter-like bacteria facilitate the development of clinically significant gastroesophageal ulcers. Dietitians and nutritionist need to be updated about the risk profile of their patients.

Future studies should aim to improve species-specific diagnostic tests, to better detect H. heilmannii infections, and to clarify the exact role of various virulence factors in the development and progression of human disease and risk management.

Autor corespondent: Cristina-Nicoleta Ciurea E-mail: cristina.ciurea@umfst.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.