Aidan Filley

Introduction: Ulcerative colitis (UC), a disease characterized by intestinal inflammation with complex etiology has hypothesized genetic predispositions, environmental triggers and microbiome dysbiosis.^1-3 Helicobacter pylori (H. pylori), a gram-negative spiral pathogenic bacteria, lives in the stomach of @50% of the human population and causes atrophic gastritis in 10-20% and gastric cancer in 1-2% of infected patients. ^3-4 Despite this, H. pylori positive patients have significantly lower rates of UC than patients without H. pylori. ^{3, 5-8} The nucleotide-binding-domain leucine-rich-repeat receptor 12 (NLRP12), an innate immunity receptor inhibitory to the NF- κB pathways of inflammation, is downregulated in UC.^9,10 It has been shown that H. pylori exosomes cause an upregulation in NLRP12 expression from intestinal epithelial cells suggesting a mechanism for decreased UC NF- κB driven inflammation in H. pylori positive patients.¹¹ Methods: DSS colitis was induced in NLRP12 knockout mice and immunoblotting for NF- κB protein expression, histopathological examination and 16S rRNA gene sequencing was performed.¹⁰ NLRP12 knockout mice were either single-housed with fellow NLRP12 knockout mice or cohoused with wildtype mice. Coprophagia resulted in fecal microbiome transplant (FMT) of wildtype to NLRP12 knockout mice.¹⁰ H. pylori positive serum exosomes were extracted and exposed to human intestinal epithelial cell lines as well as intraperitoneally injected into DSS colitis induced mice.¹¹ Western blotting and qRT-PCR were used to determine the effects of the exosomes on cytokine levels and signaling pathways.¹¹ Results: Colitis is more easily induced and severe with increased weight loss, mortality and worse histology scores In NLRP12 knockout mice,.¹⁰ NF- κB pro-inflammatory subunits p52/p65, were upregulated and microbiome diversity was decreased resulting in the same dysbiosis seen in human UC.¹⁰ FMT from cohoused wildtype mice to NLRP12 knockout mice resulted in normalization of p52/p65 as well as improved weight and survival when compared to single-housed NLRP12 knockout mice.¹⁰ H. pylori exosomes upregulated NLRP12 in human intestinal epithelial cell lines as well as attenuating DSS induced colitis in mice. The NLRP12 upregulation  inhibited the NOTCH pathway, and NOTCH signaling interacts with and inhibits the NF- κB pathway.^11,13-16 Conclusions: It has been shown that H. pylori exosomes upregulate NLRP12 expression which leads to inhibition of pro-inflammatory NF- κB pathways and explains the inverse relationship between H. pylori infection and UC. These findings question the necessity of H. pylori eradication in asymptomatic patients especially those with genetic predisposition to UC, and also suggest upregulation of NLRP12 as a pharmaceutical target for UC.

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