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Autoimmune gastritis is characterized by atrophy of acid secreting parietal cells resulting in achlorhydria. Upper gastrointestinal symptoms are common in autoimmune gastritis and frequently result in prescriptions for acid suppressant medications despite the inability of the stomach to secrete acid. Evidence-based recommendations for management of gastrointestinal symptoms in autoimmune gastritis are lacking.The most common symptoms in patients with autoimmune gastritis are dyspepsia, heartburn, and regurgitation. Gastroesophageal reflux should be confirmed by pH-impedance testing and is typically weakly acid or alkaline. Therapy for reflux focuses on mechanical prevention of reflux (i.e., elevation of the head of the bed and alginates) or when severe, antireflux surgery. The etiology of dyspepsia in autoimmune gastritis is unclear and largely unstudied. In the first half of the 20th century, oral administration of acid to "aid digestion" was widely used with reported success. However, randomized, placebo-controlled trials are lacking. Here, we provide suggestions for attempting gastric acidification therapy.Upper GI symptoms are common in autoimmune gastritis. Their pathogenesis and therapy remain incompletely understood. Acid suppressant medications are useless and should be discontinued. A trial of acid replacement therapy is recommended especially in the form of placebo-controlled trials.

ObjectiveAutoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently testedH. pylori-negative (naïveH. pylori-negative subjects).DesignTwo-hundred eleven naïveH. pylori-negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; pResultsOver the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was ConclusionsOxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/currentH. pyloricomorbidity.

Background: Human noroviruses are a leading cause of acute and sporadic gastroenteritis worldwide. The evolution of human noroviruses in immunocompromised persons has been evaluated in many studies. Much less is known about the evolutionary dynamics of human norovirus in healthy adults. Methods: We used sequential samples collected from a controlled human infection study with GI.1/Norwalk/US/68 virus to evaluate intra- and inter-host evolution of a human norovirus in healthy adults. Up to 12 samples from day 1 to day 56 post-challenge were sequenced using a norovirus-specific capture probe method. Results: Complete genomes were assembled, even in samples that were below the limit of detection of standard RT-qPCR assays, up to 28 days post-challenge. Analysis of 123 complete genomes showed changes in the GI.1 genome in all persons, but there were no conserved changes across all persons. Single nucleotide variants resulting in non-synonymous amino acid changes were observed in all proteins, with the capsid VP1 and nonstructural protein NS3 having the largest numbers of changes. Conclusions: These data highlight the potential of a new capture-based sequencing approach to assemble human norovirus genomes with high sensitivity and demonstrate limited conserved immune pressure-driven evolution of GI.1 virus in healthy adults.

SUMMARYThe majority of the world population carry the gastric pathogenHelicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism whereH. pyloriattachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority ofH. pyloricarriers. These antibodies block binding of theH. pyloriattachment protein BabA by mimicking BabA’s binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.

Helicobacter pylori infection and elevated expression of tissue matrix metalloproteinase 1 (MMP-1) are both associated with gastric cancer. We investigated the regulation of MMP-1 expression during H. pylori infection. Real-time reverse transcription-PCR was used to examine mucosal MMP-1 mRNA levels in 55 patients with gastric cancers and 61 control patients. Increased MMP-1 mRNA levels in the gastric mucosa and epithelial cells were observed in H. pylori infections in which both the cag pathogenicity island (PAI) and outer inflammatory protein A (OipA) were expressed. The combined induction of c-fos, c-jun, and polyoma enhancing activator-3 (pea-3) by H. pylori caused maximal increase in MMP-1 expression. Activation of the MMP-1 promoter by H. pylori involved occupation of the activator protein 1 (AP-1) sites at −72 and −181 and, surprisingly, vacancy of the −88 PEA-3 site. Electrophoretic mobility shift, supershift, and chromatin immunoprecipitation assays showed increased binding of c-Fos and c-Jun to the −72 and −181 AP-1 sites during H. pylori infection. Importantly, during wild-type H. pylori infection, we detected increased PEA-3 binding to the −72AP-1 site and decreased PEA-3 binding to the −88 PEA-3 site. However, during infection with the cag PAI and oipA mutants, PEA-3 binding to the −88 site was detected. MMP-1 and pea-3 activities are increased in gastric cancers. Maximal activation of MMP-1 transcription requires the cag PAI and OipA, which regulate AP-1 and PEA-3 binding. Thus, cag PAI and OipA provide a possible link between bacterial virulence factors and important host factors related to disease pathogenesis. (Cancer Res 2006; 66(10): 5111-20)

Supplementary Table 1S from Balance between Polyoma Enhancing Activator 3 and Activator Protein 1 Regulates Helicobacter pylori–Stimulated Matrix Metalloproteinase 1 Expression

The best strategy to manage direct-acting oral anticoagulants (DOACs) for patients undergoing cold snare polypectomy remains unclear. This study compared the effect of continuing versus stopping DOACs only on the day of the procedure on bleeding after cold snare polypectomy.This prospective, observational, single-center cohort study enrolled consecutive patients receiving antithrombotic agents and undergoing cold snare polypectomy of colorectal polyps ≤10 mm in diameter. During period 1 (2017 and 2018) antithrombotic agents including DOACs were not discontinued (DOAC continued group). In period 2 (2019 and 2020) DOACs were withheld only on the day of the procedure (DOAC withheld group) and restarted the next day after the procedure. The primary outcome was delayed bleeding requiring endoscopic treatment occurring within 2 weeks after cold snare polypectomy. Secondary outcomes were immediate bleeding and the number of hemostatic clips used.For the 2 groups, 204 (DOAC continued group; 34% women; mean age, 75 years) and 264 (DOAC withheld group; 36% women; mean age, 74 years) patients were enrolled. Clinical features were similar between the 2 groups. Delayed bleeding after cold snare polypectomy occurred in 4 of 47 patients (8.5%) in the DOAC continued group versus 0 of 66 (0%) in the DOAC withheld group (P .001). Immediate postpolypectomy bleeding occurred in 12 of 47 patients (25.5%) in the DOAC continued group versus 4 of 66 (6.1%) in the DOAC withheld group (P .008).Cold snare polypectomy may be safely preformed if DOACs are withheld only on the day of the procedure. (Clinical trial registration number: NCT02594813.).

The last 5 years have seen major shifts in defining whom to test and how to treat Helicobacter pylori infection. Peptic ulcer has changed from a chronic disease to a one-off condition, and countries with a high incidence of gastric cancer have begun implementing population-wide screening and treatment. A proactive approach to testing and treatment of H. pylori is now recommended, including outreach to family members of individuals diagnosed with active infection as well as high-risk local populations such as immigrants from high-risk countries. Increasing antimicrobial resistance has resulted in an overall decline in treatment success, causing a rethinking of the approach to development of treatment guidelines as well as the need to adopt the principles of antibiotic usage and antimicrobial stewardship. Required changes include abandoning empiric use of clarithromycin, metronidazole, and levofloxacin triple therapies. Here, we discuss these transformations and give guidance regarding testing and use of therapies that are effective when given empirically.

Recent guidelines dictate that all Helicobacter pylori (H. pylori) infected subjects should receive curative therapy. The efficacy of empirical regimens for H. pylori eradication might decline with bacterial, drug, and host factors. The necessity of a tailored therapy still remains controversial. Here we provide a meta-analysis of the current status of susceptibility-based (tailored) therapy in which susceptibility-based therapies were compared to the currently accepted choice of empiric therapy. In this rapidly closing era, neither the susceptibility nor empiric therapies were routinely optimized, such that we report the outcome of comparisons on the efficacy of unoptimized tailored vs. locally preferred empiric treatments.PubMed, Medline, and Embase databases were searched using suitable keywords. Individual and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed- or random-effects model as appropriate. Heterogeneity was calculated employing the Cochrane Q test and IThirty-four studies were included with a total of 9613 patients. Tailored therapy proved superior to empiric treatment [OR 2.07 (95% CI 1.53-2.79)]. However, tailored therapy achieved eradication rates90% in only 15 (44%) studies and95% in only 6 (17.6%).Although tailored therapy performed better than empiric treatment, the lack of optimization of therapies failed to reliably achieve high cure rates (90%). These results emphasize that H. pylori infection, like other infectious diseases, should utilize the principles of antimicrobial stewardship in relation to treatment guidance.

Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray–Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.

Guidelines recommend that proton pump inhibitor-based triple regimens with clarithromycin not be used for Helicobacter pylori infection in areas where clarithromycin resistance is ≥15%, or in patients with prior macrolide use. Up-to-date information on local resistance patterns is limited, especially in the US. Here, we report resistance rates to antibiotics commonly used to treat H. pylori from a large study conducted in the US and Europe (pHalcon-HP).Gastric mucosal biopsies were collected from adult participants with H. pylori infection during screening. Minimum inhibitory concentrations were determined via agar dilution for clarithromycin, amoxicillin, and metronidazole, with breakpoints ≥1 μg/mL,0.125 μg/mL, and8 μg/mL, respectively. Resistance rates were obtained for the US and Europe, and also for US subregions and participating European countries.Resistance rates were established in isolates from 907 participants. Overall, 22.2% were resistant to clarithromycin, 1.2% to amoxicillin, and 69.2% to metronidazole. Resistance in the US and Europe was similar; metronidazole resistance was the most prevalent (50%-79%) and amoxicillin the least (≤5%). In all subregions, ≥15% of isolates were resistant to clarithromycin, except the UK (0/8 isolates). Among clarithromycin-resistant isolates, 75% were also metronidazole-resistant. Two US isolates were resistant to clarithromycin and amoxicillin; one of these was also metronidazole-resistant.The resistance rates observed in this study argue against the continued empiric use of proton pump inhibitor-based triple therapy containing clarithromycin, per treatment guidelines, and highlight the need for antibiotic resistance surveillance and novel treatment strategies for H. pylori infection in the US and Europe.

ObjectiveScreening and eradication ofHelicobacter pylorihelp reduce disparities in the incidence of gastric cancer. We aimed to evaluate its acceptability and feasibility in the indigenous communities and develop a family index-case method to roll out this programme.DesignWe enrolled residents aged 20–60 years from Taiwanese indigenous communities to receive a course of test, treat, retest and re-treat initial treatment failures with the13C-urea breath tests and four-drug antibiotic treatments. We also invited the family members of a participant (constituting an index case) to join the programme and evaluated whether the infection rate would be higher in the positive index cases.ResultsBetween 24 September 2018 and 31 December 2021, 15 057 participants (8852 indigenous and 6205 non-indigenous) were enrolled, with a participation rate of 80.0% (15 057 of 18 821 invitees). The positivity rate was 44.1% (95% CI 43.3% to 44.9%). In the proof-of-concept study with 72 indigenous families (258 participants), family members of a positive index case had 1.98 times (95% CI 1.03 to 3.80) higher prevalence ofH. pylorithan those of a negative index case. The results were replicated in the mass screening setting (1.95 times, 95% CI 1.61 to 2.36) when 1115 indigenous and 555 non-indigenous families were included (4157 participants). Of the 6643 testing positive, 5493 (82.6%) received treatment. According to intention-to-treat and per-protocol analyses, the eradication rates were 91.7% (89.1% to 94.3%) and 92.1% (89.2% to 95.0%), respectively, after one to two courses of treatment. The rate of adverse effects leading to treatment discontinuation was low at 1.2% (0.9% to 1.5%).ConclusionA high participation rate, a high eradication rate ofH. pyloriand an efficient rollout method indicate that a primary prevention strategy is acceptable and feasible in indigenous communities.Trial registration numberNCT03900910.

Duodenal eosinophilia may play a role in functional dyspepsia (FD), but existing study results are conflicted. We investigated the association between duodenal eosinophils (count and degranulation) and FD symptoms, accounting for atopic conditions, medications, and seasonal variations. In a cross-sectional study conducted in the Michael E. DeBakey VA Medical Center in Houston, Texas, we analyzed duodenal histopathology of 436 patient samples from a prospective cohort with a validated symptom survey data and chart reviews. FD was defined using Rome II symptom criteria. Eosinophil count was number per 5 high-power fields (HPF), and eosinophil degranulation was eosinophilic granules in the stroma both determined by two independent investigators. The study cohort was predominantly male (87.4%) with a mean age of 59.3 (standard deviation (SD) ± 9.8). Mean and median eosinophil counts were 75.5 (± 47.8) and 63 (IQR: 43, 101) per five HPF, respectively. Duodenal eosinophilia (defined as ≥ 63 per 5 HPF) and eosinophil degranulation were present in 50.5% and 23.1% of patient samples, respectively. FD was observed in 178 patients (41.7%), but neither the mean eosinophil count nor duodenal eosinophilia was associated with FD. Eosinophil degranulation was independently associated with FD overall (OR 1.74; 95% CI 1.08, 2.78; p = 0.02) and early satiety (OR 2.04; 95% CI 1.26, 3.30; p = 0.004). In this large, ethnically diverse cohort of adult patients, we found no significant association between duodenal eosinophilia and FD. However, the presence of duodenal eosinophilic degranulation, an activated eosinophil marker, was significantly associated with FD, especially early satiety.

Alcohol misuse is a risk factor for many adverse health outcomes. Alcohol misuse has been associated with an imbalance of gut microbiota in preclinical models and alcoholic diseases. We hypothesized that daily alcohol use would change the community composition and structure of the human colonic gut microbiota. Thirty-four polyp-free individuals donated 97 snap-frozen colonic biopsies. Microbial DNA was sequenced for the 16S ribosomal RNA gene hypervariable region 4. The SILVA database was used for operational taxonomic unit classification. Alcohol use was assessed using a food frequency questionnaire. We compared the biodiversity and relative abundance of the taxa among never drinkers (ND, n = 9), former drinkers (FD, n = 10), current light drinkers (LD,2 drinks daily, n = 9), and current heavy drinkers (HD, ≥2 drinks daily, n = 6). False discovery rate-adjusted P values (q values) .05 indicated statistical significance. HD had the lowest α diversity (Shannon index q value0.001), and HD's microbial composition differed the most from the other groups (P value = .002). LD had the highest relative abundance of Akkermansia (q values0.001). HD had the lowest relative abundance of Subdoligranulum, Roseburia, and Lachnospiraceaeunc91005 but the highest relative abundance of Lachnospiraceaeunc8895 (all q values0.05). The multivariable negative binomial regression model supported these observations. ND and FD had a similar microbial profile. Heavy alcohol use was associated with impaired gut microbiota that may partially mediate its effect on health outcomes.

Amoxicillin and proton pump inhibitor dual Helicobacter pylori therapy has proved not to be reliably highly effective primarily because of traditional proton pump inhibitors' inability to maintain a high intragastric pH. Clarithromycin and proton pump inhibitor H. pylori dual therapy failed in part because clarithromycin resistance emerged during therapy causing treatment failures. The combination of amoxicillin, clarithromycin, and proton pump inhibitor was subsequently undermined by increasing clarithromycin resistance. Although vonoprazan appeared to restore the effectiveness of triple therapy, the improvement was almost entirely to improved effectiveness of amoxicillin dual therapy component and resulted in the majority (>85% currently in Japan) of those receiving vonoprazan-amoxicillin plus a second antibiotic (e.g. clarithromycin, metronidazole, fluoroquinolone, or rifabutin) receiving no benefit from the second antibiotic. The results in somewhere between 2800 and 5600 kg of unnecessary clarithromycin per one million H. pylori treatment courses per year in Japan. The only contribution of the second antibiotic is to increase global antimicrobial resistance. There are now sufficient data to prove that optimized vonoprazan-amoxicillin dual therapy can reliably achieve cure rates ≥95%. This manuscript discusses use of the principles of antimicrobial stewardship to develop potassium-competitive acid blocker-containing H. pylori therapies that will reliably achieve high H. pylori cure rates with minimal or no use of excess antibiotics. Such therapies are urgently needed so that use of vonoprazan triple therapies can be curtailed while also improving overall H. pylori cure rates.

ObjectiveAlthough mass eradication ofHelicobacter pylorihas been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear.DesignMass eradication ofH. pyloriinfection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalentH. pyloriinfection. Test positives for the13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively.ResultsAfter six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates ofH. pylorifell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, pH. pylori.ConclusionPopulation-based eradication ofH. pylorihas significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period.Trial registration numberNCT00155389

Background and aim The reliable method to stratify the gastric cancer risk after Helicobacter pylori eradication remains an elusive goal. Methods Mass eradication of H. pylori began in 2004 in a high-risk population. After eradication, a screening program involving first-stage serological tests (pepsinogen-I, pepsinogen-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018. Index lesions included gastric cancer or extensive premalignant lesions. We evaluated the performance of the serological tests to "rule in" and "rule out" the risk based on positive and negative likelihood ratios, respectively. The methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage. Results Among 6512 invited subjects, 3895 (59.6%) participated. Both gastrin-17 and pepsinogen tests were normal in 3560 (91.4%) subjects; 206 (5.3%) gastrin-17 and 129 (3.3%) pepsinogen tests were abnormal. Years after eradication, the severity of gastritis had fallen greatly, and extensive premalignant lesions or gastric cancer frequently occurred in newly non-atrophic-appearing mucosa. Pepsinogen testing could moderately predict atrophic gastritis (positive likelihood ratio: 4.11 [95% confidence interval: 2.92-5.77]; negative likelihood ratio: 0.14 [0.10-0.19]). Gastrin-17 was not useful (0.66 and 1.20, respectively). However, pepsinogen testing poorly predicted the index lesions (2.04 [1.21-3.42] and 0.57 [0.34-0.95]). DNA methylation levels in the post-eradication mucosa were more discriminative for predicting index lesions (3.89 [2.32-6.54] and 0.25 [0.15-0.42]). Conclusions After eradication, pepsinogen false-negative results become more frequent because histology is improved but genetic damage may persist. Direct testing for genetic damage offers better discrimination.

All patients with Helicobacter pylori infection should be offered eradication therapy. However, antimicrobial resistance has undermined the success rate of most current eradication therapies. This ...

Production of lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria promotes the survival of cancer cells. Systemic level of LPS is considered a biomarker for microbial translocation. The association between LPS and the risk of colorectal tumors is not well known. The goal of this study was to examine the association between LPS serum levels and risk of advanced colorectal adenoma (ACA).

The late 1800s Louis Pasteur and Robert Koch introduced and popularized the germ theory of disease. At that time, gastric cancer was the most common cause of cancer deaths in most countries making the stomach an early site of microbial research with a focus on gastric luminal and mucosal bacteria and the role of Boas-Oppler bacillus (Lactobacillus) in the diagnosis of gastric cancer. In the 1970s, the research focus evolved to studies of the gastric microbiome in the production of nitrosamines and included development of the Correa cascade. Interest in nitrosamine production peaked in the late 1980s and was replaced by studies of the newly described Helicobacter pylori and studies of its role in gastritis, gastric atrophy, and gastric cancer. The last decade has witnessed a rebirth in interest in the gastric microbiota as part of worldwide interest in the human microbiome. Although fungi were prominent in the studies of gastric microbiology in the nineteenth century, their potential role in disease pathogenesis has yet to be addressed using modern techniques. Overall, current studies of the gastric bacterial microbiome do not provide convincing evidence to expand the role of the gastric microbiome in cancer pathogenesis beyond what is directly attributable to the oncogenic potential of H. pylori and its role in persisting acute-on-chronic inflammation.