7 research outputs found
Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue
BACKGROUND & AIMS: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domaincontaining 5 (NLRC5), in patients and mice with Helicobacter infection. METHODS: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5(memptysetKO)) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5(-/-) THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed. RESULTS: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection ( P <.01), and correlated with gastritis severity (P<.05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5(-/-) THP-1 macrophages than by control THP- 1 cells (P<.05). After 3 months of infection with H felis, Nlrc5(memptyset-KO) mice developed gastric hyperplasia (P<.0001), splenomegaly (P <.0001), and increased serum antibody titers (P<.01), whereas control mice did not. Nlrc5(memptyset-KO) mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P<.0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5(memptyset-KO) mice. CONCLUSIONS: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection
Review article: the future of microbiome-based therapeutics
Published online 24 May 2022Background: From consumption of fermented foods and probiotics to emerging applications of faecal microbiota transplantation, the health benefit of manipulating the human microbiota has been exploited for millennia. Despite this history, recent technological advances are unlocking the capacity for targeted microbial manipulation as a novel therapeutic.Aim: This review summarises the current developments in microbiome- based medicines and provides insight into the next steps required for therapeutic development.Methods: Here we review current and emerging approaches and assess the capabilities and weaknesses of these technologies to provide safe and effective clinical inter-ventions. Key literature was identified through Pubmed searches with the following key words, âmicrobiomeâ, âmicrobiome biomarkersâ, âprobioticsâ, âprebioticsâ, âsynbioticsâ, âfaecal microbiota transplantâ, âlive biotherapeuticsâ, âmicrobiome mimeticsâ and âpostbioticsâ.Results: Improved understanding of the human microbiome and recent technological advances provide an opportunity to develop a new generation of therapies. These therapies will range from dietary interventions, prebiotic supplementations, single probiotic bacterial strains, human donor-derived faecal microbiota transplants, ra-tionally selected combinations of bacterial strains as live biotherapeutics, and the beneficial products or effects produced by bacterial strains, termed microbiome mimetics.Conclusions: Although methods to identify and refine these therapeutics are continually advancing, the rapid emergence of these new approaches necessitates accepted technological and ethical frameworks for measurement, testing, laboratory practices and clinical translation.Emily L. Gulliver, Remy B. Young, Michelle Chonwerawong, Gemma L. D'Adamo, Tamblyn Thomason, James T. Widdop, Emily L. Rutten, Vanessa Rossetto Marcelino, Robert V. Bryant, Samuel P. Costello, Claire L. O'Brien, Georgina L. Hold, Edward M. Giles, Samuel C. Forste
The innate immune molecule NLRC5 protects against gastric b cell lymphoid formation in response to chronic helicobacter infection
The regulation of miR-320a/XBP1 axis through LINC00963 for endoplasmic reticulum stress and autophagy in diffuse large B-cell lymphoma
Uncovering Hegemony in Higher Education: A Critical Appraisal of the Use of âInstitutional Habitusâ in Empirical Scholarship
Interferon-Îł promotes gastric lymphoid follicle formation but not gastritis in Helicobacter-infected BALB/c mice
BACKGROUND: Mouse infection studies have shown that interferon-Îł (IFN-Îł), a T helper 1 (Th1) cytokine, is required for the development of severe pathology induced by chronic Helicobacter infection. This finding is largely based on studies performed using mice that have polarised Th1 responses i.e. C57BL/6 animals. The current work aims to investigate the role of IFN-Îł in Helicobacter-induced inflammation in BALB/c mice which have Th2-polarised immune responses. RESULTS: At 7Â months post-infection with Helicobacter felis, IFN-Îł deficiency in BALB/c mice had no significant effect on H. felis colonisation levels in the gastric mucosa, nor on humoral responses, or gastritis severity. Ifng (â/â) animals with chronic H. felis infection did, however, develop significantly fewer lymphoid follicle lesions, as well as increased IL-4 splenocyte responses, when compared with infected Ifng (+/+) mice (PÂ =Â 0.015 and PÂ =Â 0.0004, respectively). CONCLUSIONS: The work shows that in mice on a BALB/c background, IFN-Îł is not required for bacterial clearance, antibody responses, nor gastric inflammation. Conversely, IFN-Îł appears to play a role in the development of gastric lymphoid follicles, which are precursor lesions to mucosa-associated lymphoid tissue (MALT) lymphoma. This study highlights the importance of mouse host background on the susceptibility to Helicobacter-induced pathologies