RESUMEN
Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1ß and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention.
Asunto(s)
Interacciones Microbiota-Huesped/inmunología , Linfocitos Intraepiteliales/inmunología , Neoplasias Pulmonares/inmunología , Animales , Proliferación Celular , Femenino , Interleucina-17/inmunología , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/fisiología , Pulmón/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta , Simbiosis/inmunología , Linfocitos T/inmunologíaRESUMEN
Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (ßOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes ßOHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous ßOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, ßOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through ßOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of ßOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.
Asunto(s)
Dieta Alta en Grasa , Cuerpos Cetónicos/metabolismo , Células Madre/metabolismo , Ácido 3-Hidroxibutírico/sangre , Ácido 3-Hidroxibutírico/farmacología , Anciano de 80 o más Años , Animales , Diferenciación Celular/efectos de los fármacos , Autorrenovación de las Células , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Hidroximetilglutaril-CoA Sintasa/deficiencia , Hidroximetilglutaril-CoA Sintasa/genética , Hidroximetilglutaril-CoA Sintasa/metabolismo , Intestinos/citología , Intestinos/patología , Masculino , Ratones , Ratones Noqueados , Receptores Acoplados a Proteínas G/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/citología , Adulto JovenRESUMEN
BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice. METHODS: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions. RESULTS: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development. CONCLUSIONS: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
Asunto(s)
Adenocarcinoma/patología , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Microbioma Gastrointestinal/fisiología , Interleucina-8/metabolismo , Obesidad/patología , Adenocarcinoma/inmunología , Adulto , Anciano , Animales , Esófago de Barrett/inmunología , Carcinogénesis/inmunología , Carcinogénesis/patología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neoplasias Esofágicas/inmunología , Esófago/inmunología , Esófago/patología , Heces/microbiología , Femenino , Voluntarios Sanos , Humanos , Interleucina-8/genética , Interleucina-8/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Obesidad/sangre , Obesidad/inmunología , Organoides , Suero/inmunología , Suero/metabolismo , Factores de Tiempo , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Aged hamsters naturally infected with novel Helicobacter spp. classified in the H. bilis cluster develop hepatobiliary lesions and typhlocolitis. METHODS: To determine whether enterohepatic H. spp. contribute to disease, Helicobacter-free hamsters were experimentally infected with H. spp. after suppression of intestinal bacteria by tetracycline treatment of dams and pups. After antibiotic withdrawal, weanlings were gavaged with four H. bilis-like Helicobacter spp. isolated from hamsters or H. bilis ATCC 43879 isolated from human feces and compared to controls (n = 7 per group). RESULTS: Helicobacter bilis 43879-dosed hamsters were necropsied at 33 weeks postinfection (WPI) due to the lack of detectable infection by fecal PCR; at necropsy, 5 of 7 were weakly PCR positive but lacked intestinal lesions. The remaining hamsters were maintained for ~95 WPI; chronic H. spp. infection in hamsters (6/7) was confirmed by PCR, bacterial culture, fluorescent in situ hybridization, and ELISA. Hamsters had mild-to-moderate typhlitis, and three of the male H. spp.-infected hamsters developed small intestinal lymphoma, in contrast to one control. Of the three lymphomas in H. spp.-infected hamsters, one was a focal ileal mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, while the other two were multicentric small intestinal large B-cell lymphomas involving both the MALT and extra-MALT mucosal sites with lymphoepithelial lesions. The lymphoma in the control hamster was a diffuse small intestinal lymphoma with a mixed population of T and B cells. CONCLUSIONS: Results suggest persistent H. spp. infection may augment risk for gastrointestinal MALT origin lymphomas. This model is consistent with H. pylori/heilmannii-associated MALT lymphoma in humans and could be further utilized to investigate the mechanisms of intestinal lymphoma development.
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Enfermedades Gastrointestinales/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter/patogenicidad , Linfoma de Células B de la Zona Marginal/microbiología , Factores de Edad , Animales , Antibacterianos/administración & dosificación , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/sangre , Ciego/patología , Colon/patología , Cricetinae , Modelos Animales de Enfermedad , Femenino , Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Humanos , Hibridación Fluorescente in Situ , Hígado/patología , Masculino , Mesocricetus , Organismos Libres de Patógenos EspecíficosRESUMEN
"Black" pigment gallstones form in sterile gallbladder bile in the presence of excess bilirubin conjugates ("hyperbilirubinbilia") from ineffective erythropoiesis, hemolysis, or induced enterohepatic cycling (EHC) of unconjugated bilirubin. Impaired gallbladder motility is a less well-studied risk factor. We evaluated the spontaneous occurrence of gallstones in adult germfree (GF) and conventionally housed specific pathogen-free (SPF) Swiss Webster (SW) mice. GF SW mice were more likely to have gallstones than SPF SW mice, with 75% and 23% prevalence, respectively. In GF SW mice, gallstones were observed predominately in heavier, older females. Gallbladders of GF SW mice were markedly enlarged, contained sterile black gallstones composed of calcium bilirubinate and <1% cholesterol, and had low-grade inflammation, edema, and epithelial hyperplasia. Hemograms were normal, but serum cholesterol was elevated in GF compared with SPF SW mice, and serum glucose levels were positively related to increasing age. Aged GF and SPF SW mice had deficits in gallbladder smooth muscle activity. In response to cholecystokinin (CCK), gallbladders of fasted GF SW mice showed impaired emptying (females: 29%; males: 1% emptying), whereas SPF SW females and males emptied 89% and 53% of volume, respectively. Bilirubin secretion rates of GF SW mice were not greater than SPF SW mice, repudiating an induced EHC. Gallstones likely developed in GF SW mice because of gallbladder hypomotility, enabled by features of GF physiology, including decreased intestinal CCK concentration and delayed intestinal transit, as well as an apparent genetic predisposition of the SW stock. GF SW mice may provide a valuable model to study gallbladder stasis as a cause of black pigment gallstones.
Asunto(s)
Pigmentos Biliares/metabolismo , Colecistoquinina/metabolismo , Vesícula Biliar/metabolismo , Cálculos Biliares/etiología , Contracción Muscular , Músculo Liso/metabolismo , Factores de Edad , Animales , Peso Corporal , Calcio/metabolismo , Femenino , Vesícula Biliar/patología , Vesícula Biliar/fisiopatología , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Cálculos Biliares/patología , Cálculos Biliares/fisiopatología , Predisposición Genética a la Enfermedad , Vida Libre de Gérmenes , Concentración de Iones de Hidrógeno , Modelos Logísticos , Masculino , Ratones , Músculo Liso/patología , Músculo Liso/fisiopatología , Factores de Riesgo , Factores Sexuales , Especificidad de la Especie , Factores de TiempoRESUMEN
OBJECTIVES: Gastric colonisation with intestinal flora (IF) has been shown to promote Helicobacter pylori (Hp)-associated gastric cancer. However, it is unknown if the mechanism involves colonisation with specific or diverse microbiota secondary to gastric atrophy. DESIGN: Gastric colonisation with Altered Schaedler's flora (ASF) and Hp were correlated with pathology, immune responses and mRNA expression for proinflammatory and cancer-related genes in germ-free (GF), Hp monoassociated (mHp), restricted ASF (rASF; 3 species), and specific pathogen-free (complex IF), hypergastrinemic INS-GAS mice 7 months postinfection. RESULTS: Male mice cocolonised with rASFHp or IFHp developed the most severe pathology. IFHp males had the highest inflammatory responses, and 40% developed invasive gastrointestinal intraepithelial neoplasia (GIN). Notably, rASFHp colonisation was highest in males and 23% developed invasive GIN with elevated expression of inflammatory biomarkers. Lesions were less severe in females and none developed GIN. Gastritis in male rASFHp mice was accompanied by decreased Clostridum species ASF356 and Bacteroides species ASF519 colonisation and an overgrowth of Lactobacillus murinus ASF361, supporting that inflammation-driven atrophy alters the gastric niche for GI commensals. Hp colonisation also elevated expression of IL-11 and cancer-related genes, Ptger4 and Tgf-ß, further supporting that Hp infection accelerates gastric cancer development in INS-GAS mice. CONCLUSIONS: rASFHp colonisation was sufficient for GIN development in males, and lower GIN incidence in females was associated with lower inflammatory responses and gastric commensal and Hp colonisation. Colonisation efficiency of commensals appears more important than microbial diversity and lessens the probability that specific gastrointestinal pathogens are contributing to cancer risk.
Asunto(s)
Adenocarcinoma/microbiología , Mucosa Gástrica/microbiología , Gastritis Atrófica/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Neoplasias Gástricas/microbiología , Simbiosis , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Bacteroides , Biomarcadores/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinogénesis , Clostridium , Citocinas/metabolismo , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis Atrófica/complicaciones , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Intestino Grueso/microbiología , Lactobacillus , Masculino , Ratones , Organismos Libres de Patógenos Específicos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Campylobacter is a common bacterial enteropathogen that can be detected in stool by culture, enzyme immunoassay (EIA), or PCR. We compared culture for C. jejuni/C. coli, EIA (ProSpecT), and duplex PCR to distinguish Campylobacter jejuni/C. coli and non-jejuni/coli Campylobacter on 432 diarrheal and matched control stool samples from infants in a multisite longitudinal study of enteric infections in Tanzania, Bangladesh, and Peru. The sensitivity and specificity of culture were 8.5% and 97.6%, respectively, compared with the results of EIA and 8.7% and 98.0%, respectively, compared with the results of PCR for C. jejuni/C. coli. Most (71.6%) EIA-positive samples were positive by PCR for C. jejuni/C. coli, but 27.6% were positive for non-jejuni/coli Campylobacter species. Sequencing of 16S rRNA from 53 of these non-jejuni/coli Campylobacter samples showed that it most closely matched the 16S rRNA of C. hyointestinalis subsp. lawsonii (56%), C. troglodytis (33%), C. upsaliensis (7.7%), and C. jejuni/C. coli (2.6%). Campylobacter-negative stool spiked with each of the above-mentioned Campylobacter species revealed reactivity with EIA. PCR detection of Campylobacter species was strongly associated with diarrhea in Peru (odds ratio [OR] = 3.66, P < 0.001) but not in Tanzania (OR = 1.56, P = 0.24) or Bangladesh (OR = 1.13, P = 0.75). According to PCR, Campylobacter jejuni/C. coli infections represented less than half of all infections with Campylobacter species. In sum, in infants in developing country settings, the ProSpecT EIA and PCR for Campylobacter reveal extremely high rates of positivity. We propose the use of PCR because it retains high sensitivity, can ascertain burden, and can distinguish between Campylobacter infections at the species level.
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Técnicas Bacteriológicas/métodos , Infecciones por Campylobacter/diagnóstico , Campylobacter/clasificación , Campylobacter/aislamiento & purificación , Diarrea/diagnóstico , Heces/microbiología , Reacción en Cadena de la Polimerasa/métodos , Bangladesh , Infecciones por Campylobacter/microbiología , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Países en Desarrollo , Diarrea/microbiología , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Lactante , Masculino , Perú , ARN Ribosómico 16S/genética , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , TanzaníaRESUMEN
BACKGROUND: Helicobacter pylori cholesterol-α-glucosyltransferase (cgt) is essential for survival of H. pylori in mice. Enterohepatic H. hepaticus, the cause of colonic and hepatocellular carcinoma in susceptible mouse strains, contains an ortholog of the H. pylori cgt. However, the role of cgt in the pathogenesis of H. hepaticus has not been investigated. MATERIALS AND METHODS: Two cgt-deficient isogenic mutants of wild-type H. hepaticus (WT) 3B1 were generated and used to inoculate male A/JCr mice. Cecal and hepatic colonization levels of the mutants and WT 3B1 as well as select inflammation-associated cytokines were measured by qPCR at 4 months postinoculation. RESULTS: Both mutants were undetectable in the cecum of any inoculated mice (10 per mutant) but were detected in two livers (one for each mutant); by contrast, 9 and 7 of 10 mice inoculated with WT 3B1 were qPCR positive in the ceca and livers, respectively. The mice inoculated with the mutants developed significantly less severe hepatic inflammation (p < .05) and also produced significantly lower hepatic mRNA levels of proinflammatory cytokines Ifn-γ (p < .01) and Tnf-α (p ≤ .02) as well as anti-inflammatory factors Il10 and Foxp3 compared with the WT 3B1-inoculated mice. Additionally, the WT 3B1-inoculated mice developed significantly higher Th1-associated IgG2a (p < .0001) and Th2-associated IgG1 responses (p < .0001) to H. hepaticus infection than mice dosed with isogenic cgt mutants. CONCLUSION: Our data indicate that the cholesterol-α-glucosyltransferase is required for establishing colonization of the intestine and liver and therefore plays a critical role in the pathogenesis of H. hepaticus.
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Colesterol/metabolismo , Glucosiltransferasas/metabolismo , Infecciones por Helicobacter/microbiología , Helicobacter hepaticus/enzimología , Helicobacter hepaticus/crecimiento & desarrollo , Factores de Virulencia/metabolismo , Animales , Ciego/microbiología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Eliminación de Gen , Glucosiltransferasas/genética , Helicobacter hepaticus/genética , Hígado/microbiología , Masculino , Ratones Endogámicos A , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Virulencia/genéticaRESUMEN
Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1ß transgenic mice, expressing human interleukin (IL)-1ß in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett's esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1ß-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive. We report for the first time that in addition to the previously described Barrett's esophagus-like metaplasia, the L2-IL-1ß mice also develop squamous epithelial dysplasia with progression to squamous cell carcinoma (SCC) in the esophagus and the tongue. L2-IL-1ß showed age-dependent progression of squamous dysplasia to SCC with approximately 40% (n = 49) and 23.5% (n = 17) incidence rates for esophageal and tongue invasive SCC respectively, by 12-15 months of age. Interestingly, SCC development and progression in L2-IL-1ß was similar in both Germ Free (GF) and Specific Pathogen Free (SPF) conditions. Immunohistochemistry revealed a T cell predominant inflammatory profile with enhanced expression of Ki67, Sox2 and the DNA double-strand break marker, γ-H2AX, in the dysplastic squamous epithelia of L2-IL-1ß mice. Pro-inflammatory cytokines, immunomodulatory players, chemoattractants for inflammatory cells (T cells, neutrophils, eosinophils, and macrophages) and oxidative damage marker, iNOS, were significantly increased in the esophageal and tongue tissues of L2-IL-1ß mice. Our recent findings have expanded the translational utility of the IL-1ß mouse model to aid in further characterization of the key pathways of inflammation driven BE and EAC as well as ESCC and Oral SCC.
Asunto(s)
Adenocarcinoma , Esófago de Barrett , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Preescolar , Humanos , Ratones , Adenocarcinoma/patología , Esófago de Barrett/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/complicaciones , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias de Cabeza y Cuello/complicaciones , Inflamación/genética , Inflamación/complicaciones , Metaplasia , Ratones Transgénicos , Neoplasias de la Boca/genética , Neoplasias de la Boca/complicaciones , Carcinoma de Células Escamosas de Cabeza y Cuello/complicacionesRESUMEN
BACKGROUND & AIMS: Transgenic FVB/N insulin-gastrin (INS-GAS) mice have high circulating gastrin levels, and develop spontaneous atrophic gastritis and gastrointestinal intraepithelial neoplasia (GIN) with 80% prevalence 6 months after Helicobacter pylori infection. GIN is associated with gastric atrophy and achlorhydria, predisposing mice to nonhelicobacter microbiota overgrowth. We determined if germfree INS-GAS mice spontaneously develop GIN and if H pylori accelerates GIN in gnotobiotic INS-GAS mice. METHODS: We compared gastric lesions, levels of messenger RNA, serum inflammatory mediators, antibodies, and gastrin among germfree and H pylori-monoinfected INS-GAS mice. Microbiota composition of specific pathogen-free (SPF) INS-GAS mice was quantified by pyrosequencing. RESULTS: Germfree INS-GAS mice had mild hypergastrinemia but did not develop significant gastric lesions until 9 months old and did not develop GIN through 13 months. H pylori monoassociation caused progressive gastritis, epithelial defects, oxyntic atrophy, marked foveolar hyperplasia, dysplasia, and robust serum and tissue proinflammatory immune responses (particularly males) between 5 and 11 months postinfection (P<0.05, compared with germfree controls). Only 2 of 26 female, whereas 8 of 18 male, H pylori-infected INS-GAS mice developed low to high-grade GIN by 11 months postinfection. Stomachs of H pylori-infected SPF male mice had significant reductions in Bacteroidetes and significant increases in Firmicutes. CONCLUSIONS: Gastric lesions take 13 months longer to develop in germfree INS-GAS mice than male SPF INS-GAS mice. H pylori monoassociation accelerated gastritis and GIN but caused less severe gastric lesions and delayed onset of GIN compared with H pylori-infected INS-GAS mice with complex gastric microbiota. Changes in gastric microbiota composition might promote GIN in achlorhydric stomachs of SPF mice.
Asunto(s)
Adenocarcinoma/microbiología , Gastritis/microbiología , Neoplasias Gastrointestinales/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori , Lesiones Precancerosas/microbiología , Adenocarcinoma/patología , Animales , Bacteroidetes/aislamiento & purificación , Femenino , Gastrinas/sangre , Gastrinas/genética , Gastritis/complicaciones , Neoplasias Gastrointestinales/patología , Vida Libre de Gérmenes , Infecciones por Helicobacter/complicaciones , Mediadores de Inflamación/sangre , Insulina/genética , Masculino , Ratones , Ratones Transgénicos , Lesiones Precancerosas/patología , Factores SexualesRESUMEN
BACKGROUND: Helicobacter pylori-infected children from coastal Tumaco, Colombia, have more parasitism, and adults have lower gastric cancer risk compared with high-altitude Pasto/Tuquerres residents. Because helminth and Toxoplasma gondii infections alter helicobacter gastritis in rodent models, we determined whether seropositivity to Ascaris lumbricoides or T. gondii was associated with Th2-IgG1 or Th1-IgG2 responses to H. pylori. METHODS: Sera (240) from the two populations were evaluated for A. lumbricoides and T. gondii seropositivity and results correlated with IgE and IgG isotype responses to H. pylori. RESULTS: Most Tumaco children and adults were seropositive for A. lumbricoides (89%, 66%), T. gondii (59%, 98%), or both (45%, 66%). In contrast, seropositivity among Pasto/Tuquerres children was much lower (9%A. lumbricoides, 11%T. gondii, and 2% dual positive) but increased in adults (58%A. lumbricoides, 82%T. gondii, and 41% dual positive). A. lumbricoides seropositivity correlated with elevated IgE and anti-inflammatory Th2-IgG1 responses to H. pylori, while T. gondiigondii seropositivity was linked to elevated IgE, pro-inflammatory Th1-IgG2, IgG3, and IgG4 responses to H. pylori. Individuals with high T. gondii titers had reduced Th1-IgG2, IgG3, and IgG4 responses to H. pylori. CONCLUSIONS: Results support regional differences for childhood parasitism and indicate A. lumbricoides and T. gondii infections may impact inflammatory responses to H. pylori and partially explain differences in gastric cancer risk in Colombia.
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Ascariasis/inmunología , Ascaris/fisiología , Infecciones por Helicobacter/inmunología , Toxoplasma/fisiología , Toxoplasmosis/inmunología , Adulto , Anciano , Animales , Anticuerpos Antihelmínticos/inmunología , Anticuerpos Antiprotozoarios/inmunología , Ascariasis/complicaciones , Ascariasis/parasitología , Niño , Preescolar , Colombia , Femenino , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Lactante , Masculino , Persona de Mediana Edad , Toxoplasmosis/complicaciones , Toxoplasmosis/parasitologíaRESUMEN
BACKGROUND: The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE: To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS: Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS: No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS: The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.
Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae/psicología , Trastornos de la Memoria/etiología , Estrés Psicológico/psicología , Animales , Ansiedad/microbiología , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Colon/patología , Corticosterona/sangre , Citocinas/biosíntesis , Infecciones por Enterobacteriaceae/metabolismo , Heces/microbiología , Femenino , Vida Libre de Gérmenes , Hipocampo/metabolismo , Hipocampo/fisiopatología , Hiperplasia/microbiología , Hiperplasia/prevención & control , Mediadores de Inflamación/metabolismo , Trastornos de la Memoria/microbiología , Trastornos de la Memoria/prevención & control , Ratones , Ratones Endogámicos C57BL , Probióticos/uso terapéutico , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Psicológico/sangreRESUMEN
In populations with similar prevalence of Helicobacter pylori infection, cancer risk can vary dramatically. Changes in composition or structure of bacterial communities in the stomach, either at the time of exposure or over the course of H. pylori infection, may contribute to gastric pathology. In this study, a population of 37 patients from the low-gastric-cancer-risk (LGCR) region of Tumaco, Colombia, and the high-gastric-cancer-risk (HGCR) region of Túquerres, Colombia, were recruited for gastric endoscopy. Antral biopsy specimens were processed for histology and bacterial isolation. Fifty-nine distinct species among 26 genera were isolated by aerobic, anaerobic, and microaerobic culture and confirmed by 16S rRNA analysis. Urease-positive Staphylococcus epidermidis and Streptococcus salivarius were frequently isolated from gastric biopsy specimens. We asked whether coinfection of H. pylori with urease-positive S. salivarius and/or S. epidermidis had a demonstrable effect on H. pylori-induced gastritis in the germfree (GF) INS-GAS mouse model. Coinfections with S. salivarius and/or S. epidermidis did not affect gastric H. pylori colonization. At 5 months postinfection, GF INS-GAS mice coinfected with H. pylori and S. salivarius had statistically higher pathological scores in the stomachs than mice infected with H. pylori only or H. pylori with S. epidermidis (P < 0.05). S. epidermidis coinfection with H. pylori did not significantly change stomach pathology, but levels of the proinflammatory cytokine genes Il-1ß, Il-17A , and Il-22 were significantly lower than in H. pylori-monoinfected mice. This study demonstrates that non-H. pylori urease-positive bacteria may play a role in the severity of H. pylori-induced gastric cancer in humans. IMPORTANCE Chronic infection with H. pylori is the main cause of gastric cancer, which is a global health problem. In two Colombian populations with high levels of H. pylori prevalence, the regional gastric cancer rates are considerably different. Host genetic background, H. pylori biotype, environmental toxins, and dietary choices are among the known risk factors for stomach cancer. The potential role of non-H. pylori gastric microbiota in gastric carcinogenesis is being increasingly recognized. In this study, we isolated 59 bacterial species from 37 stomach biopsy samples of Colombian patients from both low-gastric-cancer-risk and high-gastric-cancer-risk regions. Urease-positive S. epidermidis and S. salivarius commonly cultured from the stomachs, along with H. pylori, were inoculated into germfree INS-GAS mice. S. salivarius coinfection with H. pylori induced significantly higher gastric pathology than in H. pylori-monoinfected mice, whereas S. epidermidis coinfection caused significantly lower H. pylori-induced proinflammatory cytokine responses than in H. pylori-monoinfected mice. This study reinforces the argument that the non-H. pylori stomach microflora play a role in the severity of H. pylori-induced gastric cancer.
Asunto(s)
Coinfección , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Streptococcus salivarius , Animales , Coinfección/complicaciones , Citocinas , Modelos Animales de Enfermedad , Infecciones por Helicobacter/complicaciones , Humanos , Inmunidad , Ratones , ARN Ribosómico 16S/genética , Staphylococcus epidermidis/genética , Neoplasias Gástricas/etiología , Neoplasias Gástricas/patología , Streptococcus salivarius/genética , UreasaRESUMEN
Helicobacter pylori-associated gastric cancer is male predominant and animal studies suggest that sex hormones influence gastric carcinogenesis. We investigated the effects of 17ß-estradiol (E2) or castration on H.pylori-induced gastritis in male INS-GAS/FVB/N (Tg(Ins1-GAS)1Sbr) mice. Comparisons were made to previously evaluated sham (n = 8) and H.pylori-infected (n = 8), intact male INS-GAS mice which had developed severe corpus gastritis accompanied by atrophy, hyperplasia, intestinal metaplasia and dysplasia of the epithelium within 16 weeks postinfection (all P < 0.01). Castration at 8 weeks of age had no sparing effect on lesions in uninfected (n = 5) or H.pylori-infected mice (n = 7) but all lesion subfeatures were attenuated by E2 in H.pylori-infected mice (n = 7) (P < 0.001). Notably, inflammation was not reduced but glandular atrophy, hyperplasia, intestinal metaplasia and dysplasia were also less severe in uninfected, E2-treated mice (n = 7) (P < 0.01). Attenuation of gastric lesions by E2 was associated with lower messenger RNA (mRNA) expression of interferon (IFN)-γ (P < 0.05) and interleukin (IL)-1ß (P < 0.004), and higher IL-10 (P < 0.02) as well as decreased numbers of Foxp3(+) regulatory T cells when compared with infected intact males. Infected E2-treated mice also developed higher Th2-associated anti-H.pylori IgG1 responses (P < 0.05) and significantly lower Ki-67 indices of epithelial proliferation (P < 0.05). E2 elevated expression of mRNA for Foxp3 (P < 0.0001) and IL-10 (P < 0.01), and decreased IL-1ß (P < 0.01) in uninfected, intact male mice compared with controls. Therefore, estrogen supplementation, but not castration, attenuated gastric lesions in H.pylori-infected male INS-GAS mice and to a lesser extent in uninfected mice, potentially by enhancing IL-10 function, which in turn decreased IFN-γ and IL-1ß responses induced by H.pylori.
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Estradiol/uso terapéutico , Gastritis/prevención & control , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/patogenicidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/prevención & control , Animales , Castración , Ensayo de Inmunoadsorción Enzimática , Estrógenos/uso terapéutico , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Gastritis/etiología , Gastritis/patología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/patología , Técnicas para Inmunoenzimas , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Neoplasias Intestinales/etiología , Neoplasias Intestinales/patología , Neoplasias Intestinales/prevención & control , Masculino , Metaplasia/etiología , Metaplasia/patología , Metaplasia/prevención & control , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estómago/inmunología , Estómago/patología , Neoplasias Gástricas/etiología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/microbiología , Linfocitos T Reguladores/patología , Testosterona/sangreRESUMEN
To investigate how different enterohepatic Helicobacter species (EHS) influence Helicobacter pylori gastric pathology, C57BL/6 mice were infected with Helicobacter hepaticus or Helicobacter muridarum, followed by H. pylori infection 2 weeks later. Compared to H. pylori-infected mice, mice infected with H. muridarum and H. pylori (HmHp mice) developed significantly lower histopathologic activity index (HAI) scores (P < 0.0001) at 6 and 11 months postinoculation (MPI). However, mice infected with H. hepaticus and H. pylori (HhHp mice) developed more severe gastric pathology at 6 MPI (P = 0.01), with a HAI at 11 MPI (P = 0.8) similar to that of H. pylori-infected mice. H. muridarum-mediated attenuation of gastritis in coinfected mice was associated with significant downregulation of proinflammatory Th1 (interlukin-1beta [Il-1ß], gamma interferon [Ifn-γ], and tumor necrosis factor-alpha [Tnf-α]) cytokines at both time points and Th17 (Il-17A) cytokine mRNA levels at 6 MPI in murine stomachs compared to those of H. pylori-infected mice (P < 0.01). Coinfection with H. hepaticus also suppressed H. pylori-induced elevation of gastric Th1 cytokines Ifn-γ and Tnf-α (P < 0.0001) but increased Th17 cytokine mRNA levels (P = 0.028) at 6 MPI. Furthermore, mRNA levels of Il-17A were positively correlated with the severity of helicobacter-induced gastric pathology (HhHp>H. pylori>HmHp) (at 6 MPI, r² = 0.92, P < 0.0001; at 11 MPI, r² = 0.82, P < 0.002). Despite disparate effects on gastritis, colonization levels of gastric H. pylori were increased in HhHp mice (at 6 MPI) and HmHp mice (at both time points) compared to those in mono-H. pylori-infected mice. These data suggest that despite consistent downregulation of Th1 responses, EHS coinfection either attenuated or promoted the severity of H. pylori-induced gastric pathology in C57BL/6 mice. This modulation was related to the variable effects of EHS on gastric interleukin 17 (IL-17) responses to H. pylori infection.
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Gastritis/inmunología , Gastritis/patología , Infecciones por Helicobacter/complicaciones , Helicobacter hepaticus/patogenicidad , Helicobacter pylori/patogenicidad , Helicobacter/patogenicidad , Animales , Citocinas/metabolismo , Regulación hacia Abajo , Femenino , Mucosa Gástrica/patología , Gastritis/complicaciones , Gastritis/microbiología , Helicobacter/clasificación , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Ratones , Ratones Endogámicos C57BL , Índice de Severidad de la Enfermedad , Estómago/patología , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
To model inflammatory bowel disease, we assessed infection with Helicobacter hepaticus 3B1 (ATCC 51449) and a potential probiotic Lactobacillus reuteri (ATCC PTA-6475) in gnotobiotic B6.129P2-IL-10(tm1Cgn) (IL-10(-/-) ) mice. No typhlocolitis developed in germ-free controls (n=21) or in L. reuteri (n=8) or H. hepaticus (n=18) mono-associated mice for 20 weeks post-infection. As positive controls, three specific pathogen-free IL-10(-/-) mice dosed with H. hepaticus developed severe typhlocolitis within 11 weeks. Because L. reuteri PTA-6475 has anti-inflammatory properties in vitro, it was unexpected to observe significant typhlocolitis (P<0·0001) in mice that had been infected with L. reuteri followed in 1 week by H. hepaticus (n=16). The H. hepaticus colonization was not affected through 20 weeks post-infection but L. reuteri colonization was lower in co-infected compared with L. reuteri mono-associated mice at 8-11 weeks post-infection (P<0·05). Typhlocolitis was associated with an increased T helper type 1 serum IgG2c response to H. hepaticus in co-infected mice compared with H. hepaticus mono-associated mice (P<0·005) and similarly, mRNA expression in caecal-colonic tissue was elevated at least twofold for chemokine ligands and pro-inflammatory interleukin-1α (IL-1α), IL-1ß, IL-12 receptor, tumour necrosis factor-α and inducible nitric oxide synthase. Anti-inflammatory transforming growth factor-ß, lactotransferrin, peptidoglycan recognition proteins, Toll-like receptors 4, 6, 8 and particularly 9 gene expression, were also elevated only in co-infected mice (P<0·05). These data support that the development of typhlocolitis in H. hepaticus-infected IL-10(-/-) mice required co-colonization with other microbiota and in this study, required only L. reuteri. Although the effects other microbiota may have on H. hepaticus virulence properties remain speculative, further investigations using this gnotobiotic model are now possible.
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Vida Libre de Gérmenes , Infecciones por Helicobacter/microbiología , Helicobacter hepaticus/patogenicidad , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/microbiología , Interleucina-10/genética , Limosilactobacillus reuteri/fisiología , Inmunidad Adaptativa , Animales , Linfocitos B/inmunología , Ensayo de Inmunoadsorción Enzimática , Inmunidad Innata , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunohistoquímica , Enfermedades Inflamatorias del Intestino/inmunología , Ratones , Ratones Noqueados , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany. METHODS: Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine. RESULTS: The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine. CONCLUSIONS: Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.
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Anafilaxia/inducido químicamente , Sulfatos de Condroitina/análisis , Sulfatos de Condroitina/farmacología , Activación de Complemento/efectos de los fármacos , Contaminación de Medicamentos , Heparina/química , Calicreínas/efectos de los fármacos , Animales , China , Sulfatos de Condroitina/efectos adversos , Complemento C3a/biosíntesis , Complemento C3a/efectos de los fármacos , Complemento C5a/biosíntesis , Complemento C5a/efectos de los fármacos , Industria Farmacéutica , Femenino , Alemania , Heparina/efectos adversos , Humanos , Hipotensión/inducido químicamente , Calicreínas/metabolismo , Persona de Mediana Edad , Sus scrofa , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND & AIMS: The nuclear factor kappaB (NF-kappaB)/IkappaB-kinase-beta (IKKbeta) pathway has been shown to represent a key link between inflammation and cancer, inducing pro-inflammatory cytokines in myeloid cells and anti-apoptotic pathways in epithelial cells. However, the role of NF-kappaB pathway in gastric carcinogenesis and injury has not been well-defined. We derived mice with a conditional knockout of IKKbeta in gastric epithelial cells (GECs) and myeloid cells, and examined responses to ionizing radiation (IR) and Helicobacter felis infection. METHODS: Ikkbeta(Deltastom) mice were generated by crossing Foxa3-Cre mice to Ikkbeta(F/F) mice. Cellular stress was induced with IR and H felis in Ikkbeta(Deltastom), Ikkbeta(F/F), and cis-NF-kappaB-enhanced green fluorescent protein (GFP) reporter mice. Gastric histopathology, apoptosis, proliferation, necrosis, reactive oxygen species, and expression of cytokines, chemokines, and anti-apoptotic genes were assessed. The role of myeloid IKKbeta in these models was studied by crosses with LysM-Cre mice. RESULTS: NF-kappaB activity was upregulated in myeloid cells with acute H felis infection, but in GECs by IR or long-term H felis infection during progression to dysplasia. Deletion of IKKbeta in GECs led to increased apoptosis, reactive oxygen species, and cellular necrosis, and resulted in up-regulation of interleukin-1alpha and down-regulation of anti-apoptotic genes. Loss of IKKbeta in GECs resulted in worse inflammation and more rapid progression to gastric preneoplasia, while loss of IKKbeta in myeloid cells inhibited development of gastric atrophy. CONCLUSIONS: The loss of IKKbeta/NF-kappaB signaling in GECs results in increased apoptosis and necrosis in response to cellular stress, and accelerated development of dysplasia by Helicobacter infection.
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Apoptosis , Proliferación Celular , Mucosa Gástrica/enzimología , Infecciones por Helicobacter/enzimología , Helicobacter felis/patogenicidad , Quinasa I-kappa B/deficiencia , Lesiones Precancerosas/enzimología , Neoplasias Gástricas/enzimología , Animales , Apoptosis/efectos de la radiación , Proteínas Reguladoras de la Apoptosis/metabolismo , Atrofia , Proliferación Celular/efectos de la radiación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Mucosa Gástrica/efectos de la radiación , Genes Reporteros , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Factor Nuclear 3-gamma del Hepatocito/genética , Quinasa I-kappa B/genética , Mediadores de Inflamación/metabolismo , Integrasas/genética , Interleucina-1alfa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/enzimología , Células Mieloides/microbiología , Células Mieloides/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Necrosis , Estrés Oxidativo , Lesiones Precancerosas/genética , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Factores de TiempoRESUMEN
Helicobacter infection is the primary risk factor for gastric cancer, with the cytokine environment within the gastric mucosa the strongest predictor of disease risk. Elevated TNF-alpha, IL-1beta, and low IL-10 are associated with the highest risk. In this study, we used C57BL/6 mice to identify T-bet as a central regulator of the cytokine environment during Helicobacter felis infection. We infected male and female C57BL/6 and C57BL/6-T-bet knockout (KO) litter mates with H. felis and examined the bacterial colonization, immune response, and mucosal damage at varying time points. T-bet KO mice maintained infection for 15 mo at similar levels to wild-type mice. Infection and immune response did not differ between male and female mice. Despite sustained infection, T-bet KO mice respond with a blunted Th1 response associated with preservation of parietal and chief cells and protection from the development of gastric cancer. Unexpectedly, T-bet KO mice develop a gastric environment that would not be expected based on the phenotype of T-bet KO CD4 cells alone. T-bet KO mice respond to H. felis infection with a markedly blunted IL-1beta and TNF-alpha and elevated IL-10 levels. Activity of this one master regulator modulates the expression of the key gastric mucosal cytokines associated with gastric cancer and may be a target for therapy to restore immune balance clinically in patients at risk for gastric cancer.
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Adenocarcinoma/microbiología , Adenocarcinoma/prevención & control , Infecciones por Helicobacter/prevención & control , Helicobacter felis/inmunología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/prevención & control , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Adenocarcinoma/inmunología , Animales , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/patología , Interleucina-1beta/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Gástricas/inmunología , Proteínas de Dominio T Box/fisiología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Introduction. Helicobacter suis (Helicobacter heilmannii type 1) commonly infects nonhuman primates but its clinical importance is in question.Aim. To characterize H. suis infection in a colony of rhesus macaques (Macaca mulatta) used in cognitive neuroscience research.Hypothesis/Gap Statement. Inquiries into the nature of Helicobacter suis in nonhuman primates are required to further define the organism's virulence and the experimental animal's gastric microbiome.Methodology. Animals with and without clinical signs of vomiting and abdominal pain (n=5 and n=16, respectively) were evaluated by histology, culture, PCR amplification and sequencing, fluorescent in situ hybridization (FISH) and serology. Three of the five animals with clinical signs, an index case and two others, were evaluated before and after antimicrobial therapy.Results. The index animal had endoscopically visible ulcers and multifocal, moderate, chronic lymphoplasmacytic gastritis with intraglandular and luminal spiral bacteria. Antimicrobial therapy in the index animal achieved histologic improvement, elimination of endoscopically visible ulcers, and evident eradication but clinical signs persisted. In the other treated animals, gastritis scores were not consistently altered, gastric bacteria persisted, but vomiting and abdominal discomfort abated.Nineteen of 21 animals were PCR positive for H. suis and five animals were also PCR positive for H. pylori. Organisms were detected by FISH in 17 of 21 animals: 16S rRNA sequences of two of these were shown to be H. suis. Mild to moderate lymphoplasmacytic gastritis was seen in antrum, body and cardia, with antral gastritis more likely to be moderate than that of the body.Conclusion. No clear association between the bacterial numbers of Helicobacter spp. and the degree of inflammation was observed. H. suis is prevalent in this colony of Macaca mulatta but its clinical importance remains unclear. This study corroborates many of the findings in earlier studies of H. suis infection in macaques but also identifies at least one animal in which gastritis and endoscopically visible gastric ulcers were strongly associated with H. suis infection. In this study, serology was an inadequate biomarker for endoscopic evaluation in diagnosis of H. suis infection.