Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10 ^−/− Mice

Abstract

A urease-negative, fusiform, novel bacterium named Helicobacter saguini was isolated from the intestines and feces of cottontop tamarins (CTTs) with chronic colitis. Helicobacter sp. was detected in 69% of feces or intestinal samples from 116 CTTs. The draft genome sequence, obtained by Illumina MiSeq sequencing, for H. saguini isolate MIT 97-6194-5, consisting of ϳ2.9 Mb with a G؉C content of 35% and 2,704 genes, was annotated using the NCBI Prokaryotic Genomes Automatic Annotation Pipeline. H. saguini contains homologous genes of known virulence factors found in other enterohepatic helicobacter species (EHS) and H. pylori. These include flagellin, ␥-glutamyl transpeptidase (ggt), collagenase, the secreted serine protease htrA, and components of a type VI secretion system, but the genome does not harbor genes for cytolethal distending toxin (cdt). H. saguini MIT 97-6194-5 induced significant levels of interleukin-8 (IL-8) in HT-29 cell culture supernatants by 4 h, which increased through 24 h. mRNAs for the proinflammatory cytokines IL-1␤, tumor necrosis factor alpha (TNF-␣), IL-10, and IL-6 and the chemokine CXCL1 were upregulated in cocultured HT-29 cells at 4 h compared to levels in control cells. At 3 months postinfection, all H. saguini-monoassociated gnotobiotic C57BL/129 IL-10 ؊/؊ mice were colonized and had seroconverted to H. saguini antigen with a significant Th1-associated increase in IgG2c (P < 0.0001). H. saguini induced a significant typhlocolitis, associated epithelial defects, mucosa-associated lymphoid tissue (MALT) hyperplasia, and dysplasia. Inflammatory cytokines IL-22, IL-17a, IL-1␤, gamma interferon (IFN-␥), and TNF-␣, as well as inducible nitric oxide synthase (iNOS) were significantly upregulated in the cecal tissues of infected mice. The expression of the DNA damage response molecule ␥-H2AX was significantly higher in the ceca of H. saguini-infected gnotobiotic mice than in the controls. This model using a nonhuman primate Helicobacter sp. can be used to study the pathogenic potential of EHS isolated from primates with naturally occurring inflammatory bowel disease (IBD) and colon cancer. C otton-top tamarins (CTTs) are New World primates indigenous to the rain forests of Colombia and were imported into the United States for biomedical research beginning in the 1960s, until their classification as endangered species in 1976 (1). Approximately 50% of colony-maintained tamarins develop idiopathic chronic colitis, with 20 to 40% of cases evolving into colonic adenocarcinomas (2). The clinical and histopathological manifestations of colitis in CTTs resemble human inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), making the CTT an attractive animal model of naturally occurring IBD. The etiology of colitis in CTTs remains unknown but has been speculated to be caused by genetic predispositions and/or conditions related to captivity, such as husbandry, the environment (temperature, humidity, and sanitation), abnormal diet, stress, and infectious agents (Escherichia coli, C...

Gamma-glutamyltranspeptidase expression byHelicobacter saguini, an enterohepaticHelicobacterspecies isolated from cotton top tamarins with chronic colitis

“…Recently, we demonstrated that H. saguini infection in a gnotobiotic IL‐10 −/− mouse model elicits inflammatory and dysplastic changes to the large intestine, suggesting an etiological role of H. saguini infection in the pathogenesis of IBD in captive CTTs (Shen et al, ). Although EHS infection is strongly associated with gastrointestinal inflammation and cancer progression, the mechanisms by which H. saguini and other EHS colonise their host and cause disease are only elucidated in part and require further studies (Shen et al, ; Whary & Fox, ; Young et al, ).…”

“…Of these, GGT appears to be important because its activity has been shown to promote hose colonisation, proinflammatory responses, and intestinal pathology. Furthermore, biochemical characterisation of H. saguini detected GGT activity (Shen et al, ). Therefore, the aim of this study was to determine if H. saguini expresses an enzymatically active GGT gene with virulence properties.…”

“…The clinical and histopathological manifestations of large bowel inflammation in CTTs strongly resemble those of human ulcerative colitis, making these animals the ideal model to study etiopathogenesis of this disease. Although the protected status of CTTs has prevented establishing a direct etiological relationship between Helicobacter infection and IBD, we recently demonstrated that monoassociated infection of gnotobiotic C57BL/6 IL‐10 −/− mice with H. saguini induces IBD and procarcinogenic changes in the large intestine (Shen et al, ). These data suggest that H. saguini infection may influence the onset and progression of chronic colitis and colon cancer in CTTs.…”

Bacterial Diseases

“…In addition to the inflammatory lesions found at necropsy, the colony from which H. jaachi was isolated was noted to have clinical gastrointestinal disease as evidenced by sporadic cases of diarrhea and chronic weight loss [63]. The finding of IBD, sometimes in conjunction with colon adenocarcinoma or hepatobiliary inflammatory changes, is reminiscent of findings reported in other nonhuman primates (NHPs) infected with Helicobacter spp [64e68].…”

Helicobacter pylori infection and extragastric diseases in 2017

“…The influence of H. pylori on CD activity merits further investigation; there are protective effects of this gastric infection for IBD, which may be linked to the cag A‐positive status of the strain . A model using the non‐human primate Helicobacter, Helicobacter saguini, seems to be useful to study the pathogenic potential of EHS isolated from primates with naturally occurring IBD …”