OBJECTIVE: Gastric metaplasia may arise as a consequence of chronic inflammation and is associated with an increased risk of gastric cancer development. While Helicobacter pylori (Hp) infection and autoimmune gastritis (AIG) both induce gastric metaplasia, possible distinctions in resulting metaplastic cells and their respective cancer risks requires further investigation.
METHODS: Employing both mouse models and human subjects, we scrutinized the metaplasia originating from Hp infection and AIG. Gastric pathology and metaplasia were examined through histopathologic assessment. Molecular features of metaplastic cells were defined using single-cell transcriptomics in murine models of Hp infection and AIG, as well as in human biopsies from patients with Hp infection and AIG. Expression of a newly defined cancer-related metaplastic biomarker was confirmed through immunofluorescence.
RESULTS: Metaplasia in Hp infection and AIG displayed comparable histopathological and transcriptional features. Diverse metaplastic subtypes were identified across both disease settings, with subtle differences in the prevalence of certain subtypes between inflammatory contexts. Notably, Hp infection did not drive a unique metaplastic cell phenotype. One metaplastic subtype, which resembled incomplete intestinal metaplasia and shared transcriptional features with gastric cancer was identified in both diseases. This cancer-like metaplastic subtype was characterized by expression of the cancer-associated biomarker ANPEP/CD13.
CONCLUSIONS: Both Hp infection and AIG trigger a diverse array of metaplastic cell types. Identification of a cancer-related metaplastic cell uniquely expressing ANPEP/CD13, present in both Hp- and AIG-induced gastritis, indicates the carcinogenic capacity of both diseases. This discovery can guide early detection and risk stratification for patients with chronic gastritis.

METHODS: Gastro-AD (GAD) is a soy flour derived product that undergoes an industrial fermentation with Lactobacillus delbrueckii R0187 and has demonstrated clinical effects in gastroesophageal reflux and peptic ulcer symptom resolution. The aim of this study is to describe and link GAD\'s metabolomic profile to plausible mechanisms that manifest and explain the documented clinical outcomes.
RESULTS: 1H NMR spectroscopy with multivariate statistical analysis is used to characterize the prefermented soy flour and GAD products. The acquired spectra are screened using various resources and the molecular assignments are confirmed using total correlation spectroscopy (TOCSY). Peaks corresponding to different metabolites are integrated and compared between the two products for relative changes. HPLC and GC are used to quantify some specific molecules. NMR analyses demonstrate significant changes in the composition of various assigned bioactive moieties. HPLC and GC analysis demonstrate deglycation of isoflavones after fermentation, resulting in estrogenically active secondary metabolites that have been previously shown to help to reduce inflammation.
CONCLUSIONS: The identification of bioactive molecules, such as genistein and SCFAs, capable of modulating anti-inflammatory signaling cascades in the stomach\'s gastric and neuroendocrine tissues can explain the reported biological effects in GAD and is supported by in vivo data.

The administration of probiotics is an effective approach for treatment of Helicobacter pylori, which is associated with human gastrointestinal diseases and cancers. To explore more effective probiotics for H. pylori infection elimination, bacteria from infant feces were screened in this study. We successfully isolated the Bifidobacterium animalis subsp. lactis strains and evaluated its efficacy to inhibit H. pylori growth in vitro and in vivo. The results showed that a B. animalis strain (named BB18) sustained a high survival rate after incubation in gastric juice. The rapid urease test suggested that B. animalis BB18 reduced pathogen loads in H. pylori-infected Mongolian gerbils. Alleviation of H. pylori infection-induced gastric mucosa damage and decreased levels inflammatory cytokines were observed after the B. animalis BB18 administration. These findings demonstrated that B. animalis BB18 can inhibit H. pylori infection both in vitro and in vivo, suggesting its potential application for the prevention and eradication therapy of H. pylori infection.

The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.

OBJECTIVE: To compare small intestinal inflammation with gastric inflammation in horses with and without equine gastric glandular disease (EGGD), we evaluated endoscopic, macroscopic, and microscopic findings of the glandular stomach and microscopic findings of the small intestine.
METHODS: 36 horses.
METHODS: Horses underwent endoscopy and were scored for EGGD. After euthanasia, stomachs were collected and macroscopically evaluated. Normal pyloric mucosa, glandular lesions, and small intestinal (duodenum, mid-jejunum, and ileum) samples were collected and processed for microscopic examination. Cellular infiltrate was scored. Immunohistochemistry (CD3, CD20, and Iba-1) was performed on the ventral pylorus and small intestine of horses with mild to moderate lymphoplasmacytic infiltrate. A Spearman\'s correlation coefficient was used to evaluate the relationship of EGGD grade with gastric glandular inflammation, and the relationships of cellular infiltrate type and severity among glandular stomach, duodenum, jejunum, and ileum.
RESULTS: Gastrointestinal inflammation was common, with gastric inflammatory infiltrate identified in 92%, duodenal inflammatory infiltrate in 83%, jejunal inflammatory infiltrate in 92%, and ileal inflammatory infiltrate in 92% of horses. Endoscopic evidence of gastric disease (hyperemia or EGGD grade ≥ 2/4) was not associated with the presence or severity of duodenal, jejunal, or ileal inflammation. Gastric lymphoplasmacytic inflammation grade ≥ 2 was associated with duodenal lymphoplasmacytic inflammation grade ≥ 2. This was a convenience sample of horses presenting for euthanasia. Medical history (including deworming history) was unknown.
CONCLUSIONS: Gastric lymphoplasmacytic inflammation is associated with duodenal lymphoplasmacytic inflammation but not more distal small intestinal inflammation. Intestinal inflammation is not associated with endoscopic findings (hyperemia or EGGD grade ≥ 2/4).

Helicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1α) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1α levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1α, H. pylori-infected mice were treated ± dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-κB activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses.

Dietary bioactive compounds from natural sources (e.g., herbal medicines, foods) are known to potentially suppress acute or chronic inflammation and promote the effectiveness of treatment to reduce the harmful effects of gastritis alone or in combination. In this regard, we have characterized four Cameroonian spice extracts, namely Aframomum citratum, Dichrostachys glomerata, Tetrapleura tetraptera, and Xylopia parviflora through reverse phase-high-performance liquid chromatography (RP-HPLC), ultra-performance liquid chromatography-electrospray ionization high-resolution mass spectrometry (UPLC-ESI-HRMS/MS), and Fourier transform infrared spectroscopic (FTIR) analyses and investigated their antioxidant and synergistic anti-inflammatory activities in human gastric adenocarcinoma (AGS) and gastric epithelial (GES-1) cells. The extracts showed a high amount of total phenolic (TPC: 150-290 mg gallic acid equivalents (GAE)/g of extract) and flavonoid content (TFC: 35-115 mg catechin equivalents (CE)/g of extract) with antioxidant properties in a cell-free system (1,1-Diphenyl-2-picryl-hydrazyl (DPPH) half maximal inhibitory concentration (IC50s) ≤ 45 µg/mL; 2,2\'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) half maximal inhibitory concentration (IC50s) ≤ 29 µg/mL. The extracts in combination (MIX) exert a synergistic beneficial effect (combination index (CIs) < 1 and dose reduction index (DRIs) > 1) on inflammatory markers (interleukin (IL)-8 and -6 release, and nuclear factor kappa B (NF-κB) driven transcription) in human gastric epithelial cells, which may result from the presence of phenolic compounds (phenolic acids, flavonoids) or other compounds (protein, lipid, aromatic, and polysaccharide compounds) tentatively identified in the extracts. The general findings of the present study provide supporting evidence on the chemical composition of four Cameroonian dietary plants and their significant synergistic inhibitory activities on inflammatory markers of gastric epithelial cells.

Helicobacter pylori modulates the host inflammatory response, resulting in chronic gastritis, which contributes to gastric cancer pathogenesis. We verified the effect of Cudrania tricuspidata on H. pylori infection by inhibiting H. pylori-induced inflammatory activity. Five-week-old C57BL/6 mice (n = 8) were administered C. tricuspidata leaf extract (10 or 20 mg/kg per day) for 6 weeks. An invasive test (campylobacter-like organism [CLO]) and noninvasive tests (stool antigen test [SAT] and H. pylori antibody enzyme-linked immunosorbent assay) were performed to confirm the eradication of H. pylori. To evaluate the anti-inflammatory effect of C. tricuspidata, pro-inflammatory cytokines levels and inflammation scores were measured in mouse gastric tissue. C. tricuspidata significantly decreased the CLO score and H. pylori immunoglobulin G antibody optical density levels at both 10 and 20 mg/kg per day doses (P < .05). C. tricuspidata decreased the H. pylori antibody levels in a concentration-dependent manner, increased negative responses to SAT by up to 37.5%, and inhibited the pro-inflammatory cytokines interleukin (IL; IL-1β, IL-6, 1L-8, and tumor necrosis factor alpha). C. tricuspidata also relieved gastric erosions and ulcers and significantly reduced the inflammation score (P < .05). We measured rutin in C. tricuspidata extract as a standard for high-performance liquid chromatography. C. tricuspidata leaf extract showed anti-H. pylori activity through the inhibition of inflammation. Our findings suggest that C. tricuspidata leaf extract is potentially an effective functional food material against H. pylori.

Helicobacter pylori neutrophil-activating protein (HP-NAP), a major virulence factor of H. pylori, plays a role in bacterial protection and host inflammation. HP-NAP activates a variety of innate immune cells, including neutrophils, monocytes, and mast cells, to induce their pro-oxidant and pro-inflammatory activities. This protein also induces T-helper type 1 (Th1) immune response and cytotoxic T lymphocyte (CTL) activity, supporting that HP-NAP is able to promote gastric inflammation by activation of adaptive immune responses. Thus, HP-NAP is a potential therapeutic target for the treatment of H. pylori-induced gastric inflammation. The inflammatory responses triggered by HP-NAP are mediated by a PTX-sensitive G protein-coupled receptor and Toll-like receptor 2. Drugs designed to block the interactions between HP-NAP and its receptors could alleviate the inflammation in gastric mucosa caused by H. pylori infection. In addition, HP-NAP acts as a promising therapeutic agent for vaccine development, allergy treatment, and cancer immunotherapy. The high antigenicity of HP-NAP makes this protein a component of vaccines against H. pylori infection. Due to its immunomodulatory activity to stimulate the Th1-inducing ability of dendritic cells, enhance Th1 immune response and CTL activity, and suppress Th2-mediated allergic responses, HP-NAP could also act as an adjuvant in vaccines, a drug candidate against allergic diseases, and an immunotherapeutic agent for cancer. This review highlights the role of HP-NAP in the pathogenesis of H. pylori and the potential for this protein to be a therapeutic target in the treatment of H. pylori infection and therapeutic agents against H. pylori-associated diseases, allergies, and cancer.

Opioids are the standard drug for pain management; however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine-mediated gastric inflammation.
Mice were implanted with 25 mg slow-release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ-free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole.
Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine-mediated gastric pathology was significantly attenuated in germ-free mice, and reconstitution of morphine gastric microbiome in germ-free mice resulted gastric inflammation. In addition, morphine-mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine-induced gastric dysbiosis and preventing inflammation.
This study attributes morphine-induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine-associated pathophysiology.