Beyond fecal-oral routes - Candida as a reservoir for vertical transmission of Helicobacter pylori: Insights from a murine model

Abstract

In this editorial, we comment on the article published in the World Journal of Gastroenterology by Xu et al. This article experimentally investigated the route of Helicobacter pylori (H. pylori) transmission of Candida harboring H. pylori from mothers to offspring using murine vaginal and gastric infection models. The study showed serological evidence of H. pylori infection and molecular detection of H. pylori genes in multiple tissues in the infected maternal mice, accompanied by marked gastric inflammation, indicating the release of viable, pathogenic H. pylori from Candida. In addition, it also reported that the offspring mice exhibited H. pylori-specific antibodies and molecular evidence of infection, regardless of the delivery mode, strongly supporting maternal–neonatal transmission. The authors concluded that H. pylori infection in newborns may be acquired through vertical transmission during childbirth, possibly originating from maternal Candida that has been internalized by H. pylori. This editorial focuses specifically on the possibility that H. pylori can reside within the cells of Candida yeasts that colonize the maternal vagina, addressing the risk of its transmission to offspring. A comprehensive understanding of the transmission routes of H. pylori will help guide the implementation of effective infection prevention and control measures.

Key Words: Candida; Helicobacter pylori; Polymicrobial interaction; Neonates; Vertical transmission

Core Tip: This editorial comments on the article published in the World Journal of Gastroenterology by Xu et al. Helicobacter pylori (H. pylori) represents a significant global pathogen with poorly understood transmission dynamics. The editorial highlights the novel hypothesis of Candida-mediated vertical transmission of H. pylori in a murine model. This model challenges traditional H. pylori transmission routes, urging clinical validation in human cohorts. A comprehensive understanding of the transmission routes of H. pylori will help pave the way for implementing effective infection prevention and control measures.

This editorial refers to “Candida-mediated vertical transmission of Helicobacter pylori in C57BL/6J mice” by Xu et al, 2025; https://dx.doi.org/10.3748/wjg.v32.i7.115143.

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INTRODUCTION

Helicobacter pylori (H. pylori) is a spiral-shaped Gram-negative bacterium that is characterized by its flagella, large genome, complex antibiotic resistance, and microaerophilic nature. This bacterium requires a complex enriched growth medium for cultivation and can escape both innate and adaptive immune responses[1,2]. The first-time identification of this bacterium was in 1983, by Warren and Marshall, who detected it in gastritis biopsy specimens and established its pathogenic role in the gastric and duodenal mucosa. For their pioneering work, Warren and Marshall were awarded the Nobel Prize in 2005[1,3].

H. pylori is a transmissible bacterium that inhabits the human stomach and affects nearly half of the global population[4,5]. Among family members, mother-to-child transmission is considered the main route of H. pylori transmission. However, the exact mechanisms by which it can pass from mother to child are still unclear[6]. Several studies performed in different countries reported a high prevalence of H. pylori in newborns based on the detection of H. pylori antigen in stool samples; A recent study in China reported that 33.7% of assessed mothers and 40.4% of their newborns tested positive for H. pylori using H. pylori stool antigen (HpSA)[6], while a Spanish study showed that H. pylori Ag was positive in 71.6% (48/67) of pregnant mothers at the term of their pregnancy and 8.96% (6/67) of their newborns showed H. pylori colonization/persistent infection[7]. In Chile, about one-third of children (33%) from birth to 3 years tested positive for H. pylori using stool enzyme-linked immunosorbent assay tests[8]; however, it was shown that children less than 6 years tend to have high false positive rates for noninvasive H. Pylori diagnostic tests like urea breath test and HpSA[9]. Meanwhile, genetic studies have investigated H. pylori infection in mothers and their offspring using multi-locus sequence typing and random amplified polymorphic DNA fingerprinting techniques and have provided further evidence supporting that early childhood infections may arise primarily from maternal transmission[10,11].

Candida is well known as an eukaryotic opportunistic yeast that causes infection in immunocompromised individuals or those with altered health status[12]. Candida species (Candida spp.) are inhabitants of many parts of the body, including skin, vagina, and gastrointestinal system, and can be transmitted vertically from mothers to offspring[6,13,14]. Over 200 species of Candida are present, of which only five species, including Candida albicans, Candida parapsilosis, Candida glabrata, Candida krusei, and Candida tropicalis, are collectively responsible for over 90% of the worldwide candidiasis[15,16]. The World Health Organization 2022 fungal priority pathogens list included 19 fungal species. Candida albicans and Candida auris are classified within the critical priority group, while Candida glabrata, Candida tropicalis, and Candida parapsilosis are included in the high priority group. These species are of clinical concern due to their prevalence, virulence, and emerging antifungal resistance[17]. Candida spp. can withstand a wide range of host-mediated stressors, including extreme pH conditions present in the gastric and vaginal niches, nutrient limitation, thermal stress associated with fever, osmotic and mechanical stresses present at mucosal surfaces, and hypoxic conditions within tissues and biofilms. The ability of Candida spp. to overcome these diverse stressors explains their adaptability, long-term colonization, and success as opportunistic pathogens[18].

Several experimental data collected from works performed in vitro on murine models suggest that Candida spp. can act as intracellular reservoirs for H. pylori, possibly facilitating early neonatal acquisition from their mothers. While these results do not establish Candida as a natural transmission vector in humans, they highlight a previously neglected polymicrobial interaction that may facilitate bacterial persistence and complicate efforts to eradicate the infection. Given that Candida can internalize H. pylori, this editorial comments on the article published in World Journal of Gastroenterology by Xu et al[19]. It will address current research on two important issues: First, the hypothesis that H. pylori can be internalized within Candida cells; and second, the risk of vertical maternal-neonatal transmission of H. pylori.

H. PYLORI INTERNALIZATION WITHIN CANDIDA CELLS

The endosymbiosis phenomenon helps to understand how one organism (the endosymbiont) internalizes and persists within another (host) for a prolonged period. The interaction may be mutualistic (beneficial), commensal, or parasitic (harmful), and can be either obligate (essential for survival) or facultative (conditional or temporary). A wide range of microbes, ranging from Rickettsia to eukaryotic cells, live within other cells of higher organisms, where host cells provide nutrients and protection[20,21].

Yeasts are eukaryotic microorganisms with a significant capacity for change, which can adapt to environmental stress and establish symbiotic relationships with certain organisms[22,23]. Candida cells are well known to internalize bacteria like Staphylococci and H. pylori, protecting them from the immune system and antibiotics, contributing to persistent and more severe mixed infections[24]. Within the human gastrointestinal tract, H. pylori and Candida spp. occupy the same anatomical niches, particularly the oral cavity and stomach, where both can tolerate the highly acidic environment[25]. The first interaction between Candida and H. pylori was suggested in 1998, following the detection of yeast colonies as contaminants of gastric biopsies cultured on blood agar plates[26]. Optical microscopy and fluorescently labeled H. pylori were observed as rapidly moving, viable, bacterium-like bodies within the vacuoles of gastric, oral, vaginal, and foodborne Candida yeasts[26,27]. Because the bacterium-like bodies were non-culturable after yeast disruption, polymerase chain reaction (PCR) was used to confirm the presence of H. pylori -specific DNA within the yeast cells[26]. Subsequently, several studies confirmed and supported the idea that Candida might act as a reservoir of H. pylori outside the human stomach[6,28-31].

It has been suggested that H. pylori internalization within the Candida spp. occurs as a protective mechanism when exposed to environmental stress[26]. Alterations in pH (especially ≤ 4), nutrient limitation, temperature fluctuations, antibiotics like amoxicillin, and anaerobic conditions promote entry and favor the growth of H. pylori within Candida cells[32-34]. Several unique biological characteristics of the Candida cells facilitate the internalization and intracellular persistence of bacteria; Candida cells exhibit morphological plasticity, stress-induced cell wall remodeling, active endocytosis-like machinery, and a dynamic vacuolar system[35,36]. Growing evidence showed that H. pylori internalization into Candida spp. occurs through a stress-induced, active uptake process mediated by the yeast cell, as demonstrated by bacterial localization within intracellular vacuoles, supporting a phagocytosis-like mechanism involving cytoskeletal rearrangement, cell wall remodeling, and vacuolar trafficking rather than passive penetration or surface adhesins[36,37]. Despite these insights, the precise molecular signaling pathways, the specific yeast receptors involved, and the full sequence of events leading to bacterial internalization remain incompletely understood and need further investigation.

Importantly, internalized H. pylori retain viability and metabolic activity within Candida cells, as evidenced by sustained urease activity, detection of ureA/ureB genes, its persistence through multiple Candida passages, and intracellular motility. Antifungal agents such as amphotericin B can disrupt fungal membranes and trigger bacterial ejection, with experimental data suggesting that bacterial viability is preserved following release[24,30]. Evidently, the current manuscript showed that culturing H. pylori in vitro after exit from fungal cells was unsuccessful, suggesting that the bacteria may persist in a viable but non-culturable state, or may depend on highly specific, currently unknown conditions for recovery and multiplication.

TRANSMISSION OF INTERNALIZED H.PYLORI FROM MOTHERS TO OFFSPRING

Among family members, mother-to-child transmission is considered the main route of H. pylori transmission. However, the exact mechanisms remain incompletely defined[6]. The two possible routes of mother-to-child transmission are postnatal horizontal (oral-oral route) and perinatal vertical (through Candida)[38]. H. pylori present in maternal oral secretions could directly infect infants through pre-chewed food or mouth-to-mouth contact[35]. Several experimental, clinical, and molecular studies have increasingly supported transmission of H. pylori from mothers to offspring through Candida spp. H. pylori can survive intracellularly within Candida spp., where it will be protected from adverse environmental conditions such as acidity, oxygen stress, nutrient deprivation, and antibiotic exposure. Maternal colonization of the vagina, oral cavity, or gastrointestinal tract with Candida harboring H. pylori creates a potential vertical transmission pathway, especially during vaginal delivery or early postnatal contact. The transferred yeast cells to the neonate can persist in the digestive system and subsequently release viable H. pylori, enabling gastric colonization. In addition, several genetic studies have reported close genetic relatedness between H. pylori detected within maternal vaginal yeasts and those within neonatal fecal or oral yeasts, supporting Candida-mediated mother-to-child transmission pathway[6,19,26,30-34,39,40]. Figure 1 shows a chronological timeline of H. pylori-Candida research from internalization to vertical transmission.

Figure 1 Chronological timeline of development in Helicobacter pylori-Candida research: From internalization to vertical transmission[6,19,26,30,32-34,36,37]. Helicobacter pylori (H. pylori) was initially detected as bacterium-like bodies within Candida vacuoles, and its specific genes and proteins were subsequently identified inside the yeast. Experimental co-culture studies demonstrated that environmental stress influences its internalization, while genetic analyses revealed a relationship between H. pylori in neonates’ fecal yeasts and their mothers’ vaginal yeasts. Once internalized, H. pylori retained viability and urease activity, ultimately enabling Candida-mediated vertical transmission in an animal model, highlighting Candida’s role as a reservoir and vehicle for maternal–neonatal transmission. H. pylori: Helicobacter pylori.

DISCUSSION

H. pylori represents a significant global pathogen with poorly understood transmission dynamics. H. pylori acquisition by neonates early after delivery challenges the classical fecal-oral route, as exposure to this pathway is very minimal during early life. A comprehensive understanding of the transmission routes of H. pylori is critical for implementing effective infection prevention and control measures. This editorial illustrates the pros and cons that help to validate the hypothesis of the Xu et al[19] published article, where murine vaginal and gastric infection models with Candida harboring H. pylori were established to investigate the role of maternal Candida in transmitting potentially infectious H. pylori to neonates. The successfully infected female mice were then mated with normal male mice until conception. The infection status of H. pylori in mothers and offspring was evaluated using an enzyme-linked immunosorbent assay for quantitative detection of H. pylori immunoglobulin G in serum and qualitative detection of H. pylori immunoglobulin M in the serum of the offspring. Meanwhile, nested PCR amplification targeting the H. pylori 16S rDNA and the ureA genes was used to detect H. pylori DNA. Candida isolation and histopathological examination were also investigated. The study showed serological evidence of H. pylori infection and molecular detection of H. pylori genes in multiple tissues in the infected maternal mice, accompanied by marked gastric inflammation, indicating the release of viable pathogenic H. pylori from Candida. In addition, the study reported that the offspring mice exhibited H. pylori-specific antibodies and molecular evidence of infection, regardless of the delivery mode, which strongly supports maternal-neonatal transmission. In this study, the authors attempted to culture and isolate H. pylori from mouse tissues, but they experienced difficulties, which were explained by the unsuitability of traditional cultivation conditions to isolate H. pylori within Candida, the presence of low amounts of H. pylori in Candida cells, or the persistence of H. pylori in a viable but non-culturable state.

The potential role of Candida as an H. pylori shelter could explain various outstanding aspects regarding H. pylori epidemiology, including persistent infection, treatment failure, reinfection after successful eradication, and transmission pathways that cannot be fully explained by traditional fecal-oral or oral-oral routes. However, H. pylori diagnostic challenges are an issue of concern, where HpSA was reported to have high false-positive rates in children less than 6 years[9].

The potential role of Candida in transmitting H. pylori may have important public health implications, particularly in resource-limited settings such as Ethiopia and Uganda, where maternal candidiasis prevalence is high[41,42], highlighting the urgent need for locally specific research. In such contexts, vertical transmission of H. pylori via Candida could contribute to early-life colonization and persistence, highlighting the need for awareness, early detection, and targeted management strategies to reduce potential neonatal infection. Preventive measures like maternal Candida screening or antifungal treatment trials may be beneficial, especially in low-income settings. However, the current evidences have some limitations, including the inability to isolate and culture internalized H. pylori within Candida cells, the detection of infection in offspring that were delivered by cesarean sections and had no contact with vaginal Candida, and the absence of direct endoscopic evidence confirming gastric colonization with H. pylori in neonates. Moreover, because the bacteria were non-culturable, molecular detection results should be interpreted cautiously, as they may reflect potential contamination or PCR artifacts. These limitations prevent causality from being conclusively inferred and necessitate a cautious interpretation.

CONCLUSION

It is essential to state that current evidence is indirect, since the conclusions are based on genomic analyses of H. pylori residing within Candida isolates rather than on successful isolation of the bacterium from the gastric mucosa of neonates or young infants. To date, direct proof of gastric colonization in this age group remains lacking, and experimental validation of this hypothesis is currently confined mainly to animal models. Further well-designed experimental and clinical studies are required to confirm this interaction and to clarify its implications for diagnosis, treatment strategies, and infection prevention and control measures. If validated, this mechanism could represent a paradigm shift in our understanding of H. pylori persistence and transmission.