Candida-Associated Gastric Ulcer Revisited

Review Article

J Bacteriol Mycol. 2021; 8(2): 1165.

Candida-Associated Gastric Ulcer Revisited

Sasaki K*

Department of Internal Medicine, Midtown Medicare Clinic, Japan

*Corresponding author: Sasaki K, Department of Internal Medicine, Midtown Medicare Clinic, 76-1, Nakada, Kanetani, Matsuyama, Ohsaki, Miyagi, 987- 1303, Japan; Tel: +81-80-1817-8414; Fax: +81-229-55- 4673; Email: kydosarnymai@aria.ocn.ne.jp

Received: January 29, 2021; Accepted: February 19, 2021 Published: February 26, 2021

Abstract

Candida-associated gastric ulcer occurs not only in debilitated but healthy individuals. Though had been reported to demonstrate nothing but nonspecific endoscopic features, it occasionally exhibits a typical finding I designated a candidarium. The natural history of the disease had not been clarified and the recurrence had not been described. However, I demonstrated that the ulcer not only occurs but also recurs in a different site with a different shape in a non-diabetic, H. pylori-negative patient, who has not taken NSAIDs, antibiotics, antineoplastic agents, or systemic corticosteroids, advocating that, contrary to the prevailing opinion, Candida is no innocuous bystander but an etiologic perpetrator. It has recently been shown to secrete a cytolytic PFT, candidalysin, into a pocket in the epithelium after penetrating into it to activate MAPK/MKP1/ c-Fos pathway, triggering release of damage as well as immune cytokines in OPC and VVC. While candidalysin, exerting an effect even on the adjacent oropharyngeal cells, directly injures the tissue with damage cytokines, immune counterparts activate PMNs to eventually terminate inflammation. Though the epithelial response to the fungus is different from organ to organ, it invades into and induces necrotic cellular damage to the IECs through the toxin to translocate: the action of candidalysin is proven not only on the squamous but on the columnar epithelium. Since, by analogy with intestinal candidiasis, it is never difficult to speculate that the PFT inflicts such damage to the gastric mucosa, a theoretically strong possibility has come up that Candida-associated gastric ulcer is actually Candida-induced.

Keywords: Candidarium; Candida-Associated Gastric Ulcer; Candida- Induced Gastric Ulcer; Candidalysin; H. Pylori-Negative Gastric Ulcer; Recurrent Gastric Ulcer

Abbreviations

H. pylori: Helicobacter Pylori; NSAID: Non-Steroidal Anti- Inflammatory Drug; C: Candida; PFT: Pore-Forming Toxin; MAPK: Mitogen-Activated Protein Kinase; MKP1: MAPK Phosphatase 1; VVC: Vulvovaginal Candidiasis; GI: Gastrointestinal; SMT: Submucosal Tumor; PPI: Proton Pump Inhibitor; RHOE: Reconstituted Human Oral Epithelium; Sap: Secreted Aspartyl Proteinase; JNK: c-Jun N-Terminal Kinase; ERK: Extracellular Signal- Regulated Protein Kinase; NF-κB: Nuclear Factor Kappa-Light- Chain-Enhancer of Activated B Cells; PMN: Polymorphonuclear Leukocyte; EGFR: Epidermal Growth Factor Receptor; MMP: Matrix Metalloproteinase; PAMP: Pathogen-Associated Molecular Pattern; DAMP: Danger-Associated Molecular Pattern; OPC: Oropharyngeal Candidiasis; IEC: Intestinal Epithelial Cell; PRR: Pattern Recognition Receptor; TLR: Toll-Like Receptor; NKT: Natural Killer T Cell; ILC3: Type 3 Innate Lymphoid Cell; nTh 17: TCRβ+ “natural” Th 17 Cell

Introduction

Though a commensal colonizer ubiquitously detected in the normal human oropharynx to GI tract throughout [1], Candida causes infections in the tract under certain conditions, which are more widespread than previously recognized [2,3]. The stomach is the second most frequently involved organ following the esophagus [2]. Gastric candidiasis is classified into thrush, nodular, and ulcerated type [4]. Though usually seen in immunocompromized hosts [2,3], the third type, Candida-associated gastric ulcer, also occurs in apparently healthy individuals [5,9] with very widely different frequency contingent on the researchers [8-12]. The natural history of the disease had not been clarified and the clinical significance of the fungus remains to be elucidated [2] so that the treatment has not yet been established. It had been reported to be no longer detected once the ulcers were healed and no recurrence of the disease had been described [9,11]. I [13], however, reported a case of the disease relapsing in a different site with a different shape in an H. pylorinegative, non-diabetic patient with no antecedent peptic ulcers or history of the lesions, who had not taken NSAIDs, antibiotics, antineoplastic agents, or systemic corticosteroids, speculating that it plays an etiologic role.

Given the recently clarified mechanism of pathogenicity of candidiasis in the oropharyngeal, vulvovaginal, and intestinal fields, I have drastically updated my former review of Candida-associated gastric ulcer to evaluate the validity of the speculation in the light of the recent microbiological, molecular biological and immunological findings.

Candida Infection of the GI Tract

Candida is totally lacking a lifestyle outside the human body and establishes a colony in the human oropharynx and in the GI and vaginal tracts. Langenbeck [14] is credited with having discovered it in the cadaveric intestine in 1839 and now C. albicans is proven to be the most frequent symbiont fungus in the oropharynx to the GI tract of the normal human adults [1]. It increases both in frequency and concentration directed toward the anus: it was detected in 27% of the oropharynx samples obtained by swabbing, 43% of the jejunal and 50% of the ileal aspirates, and 59% of the fecal specimens [1].

No fungal growth, whether it is Candida or not, was detected in the gastric juice with pH value lower than 4.0 and the positive rate of fungal recovery was significantly increased with the elevation of the acidity of the juice [15]. Colonization of Candida in the stomach was observed more frequently in older patients [11] and in patients with hypoacidity [16]. It is also demonstrated to be the most common fungus causing significant, histologically proven GI infection in the debilitated patients: the infection was detected in 13% of the patients with myeloproliferative diseases and in 1.5% of those with solid tumors, respectively [2]. It involved all segments of the GI tract but the most frequently afflicted organ was the esophagus followed by the stomach [2].

Candida infection is more widespread than previously recognized [2,3], shown to occur not only in debilitated but also apparently healthy individuals [3]. Gastric candidiasis is shown to affect 0.96% of all patients undergoing endoscopy and to be more common in men and the elderly [4]. Minoli et al. [4] endoscopically classified the disease into 3 forms: thrush, nodular, and ulcerated, each accounting for 42%, 31%, and 27%, respectively. The first type presents itself as a white or green-white, readily removable membrane of variable extension spreading over the inflamed mucosa in various locations. The second is described as nodular projections of a few milliliters in diameter overlaid by the remarkably inflamed mucosa, mainly located in the antrum. The third has no particular endoscopic features distinct from other peptic ulcers.

Candida-Associated Gastric Ulcer Until Yesterday

Candida-associated gastric ulcer is regarded as the above mentioned ulcerated-typed gastric candidiasis, the diagnostic criterion of which is demonstration of infiltration of the tissue or ulcer slough by the hyphae [5,8,10]. It is also seen in apparently healthy individuals [5-9] with quite widely different frequency according to the researchers [8-12] ranging from 0.12% to 36% of gastric ulcer. The species in the genus reported to be associated with gastric ulcer are albicans, tropicalis, parapsilosis, krusei, and pseudotropicalis in decreasing order of frequency [10]. The natural history of the disease had remained to be clarified [2] and the disease has been reported to engender no specific symptoms [8]. As Minoli et al. [4] described, the endoscopic features of the disease had been asserted to be nonspecific [9,11].

Whereas some cases of the ulcer have been reported to have spontaneously healed [12], it has been reported to have low healing rate [6,11]. The rate of decrease in ulcer diameter, an indication of lesion healing, was slower in patients whose stomachs were significantly colonized by the fungus as compared with patients who were not [17]. Brozozowski et al. [18] demonstrated that persistent colonization with it in the stomach of rats suffering from ulcer induced by acetic acid, which were inoculated with the fungus, was achieved in those treated with antisecretory agents or NSAIDS and that such candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in the gastric blood flow in the ulcerated area and enhanced expression and release of IL-1β and TNFa. Reviewing Crohn’s disease, ulcerative colitis, and gastric and duodenal ulcers, Kumamoto [19] points out that significant colonization with it is associated with more severe disease and the colonization delays healing of inflammatory lesions and inflammation promotes colonization, producing a vicious circle.

The fungus had been reported to be no longer detected once the ulcers were healed even without antifungal treatment and no recurrence had been described [9,11]. Though the clinical significance of it has not yet been elucidated, ---- so that the appellation of the disease is modified by an ambiguous adjectival past participle “associated”---- it was not regarded as directly etiologic in development of ulcer but was considered to possibly aggravate or perpetuate ulceration [5,6,8].

I designate such a state of the recognition of the disease Candidaassociated gastric ulcer until yesterday after one of Dr Jared Diamond’s masterpieces. The proofs that it exacerbates gastric ulcer or delays its healing are considered to be the proofs that it has the ability to damage the gastric tissues but they by no means deny that it initiates peptic ulcers. No direct evidences, however, have been obtained so far that it is ulcerogenic.

Candida-Associated Gastric Ulcer Today

I [13], however, presented a then unreported case of Candidaassociated gastric ulcer relapsing in a different site with a different appearance in a non-diabetic, H. pylori-negative patient with no antecedent peptic ulcers or history of the lesions who had not taken NSAIDs, antibiotics, antineoplastic agents or systemic corticosteroids. The first ulcer was detected in an 87-year-old, Japanese housewife complaining of anorexia as a medium-sized, SMT-like elevation overlaid with the erythematous mucosa with an oval, deep, central ulceration covered with thick, whitish exudate I designated a candidarium [20] (vide infra) on the greater curvature of the upper gastric body (Figure 1). No signs of candidiasis were detected in the oropharynx through esophagus or in the duodenal bulb through descending part of the duodenum. She had endoscopically been shown to have no such lesions or scars in the upper or no signs of candidiasis in the lower GI tract 2 months before. She had no past history of peptic ulcers. Biopsy showed no malignancy or H. pylori but countless hyphae in the ulcer slough (Figure 2), which were proven to be C. tropicalis by culture. She, though diagnosed as having Candida-associated gastric ulcer, refused to be treated.