NLRX1 Deficiency Alters the Gut Microbiome and Is Further Exacerbated by Adherence to a Gluten-Free Diet

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dc.contributor.authorMorrison, Holly A.en
dc.contributor.authorLiu, Yangen
dc.contributor.authorEden, Kristinen
dc.contributor.authorNagai-Singer, Margaret A.en
dc.contributor.authorWade, Paul A.en
dc.contributor.authorAllen, Irving C.en
dc.date.accessioned2022-06-29T18:15:05Zen
dc.date.available2022-06-29T18:15:05Zen
dc.date.issued2022-04-28en
dc.description.abstractPatients with gluten sensitivities present with dysbiosis of the gut microbiome that is further exacerbated by a strict adherence to a gluten-free diet (GFD). A subtype of patients genetically susceptible to gluten sensitivities are Celiac Disease (CeD) patients, who are carriers of the HLA DR3/DQ2 or HLA DR4/DQ8 haplotypes. Although 85-95% of all CeD patients carry HLA DQ2, up to 25-50% of the world population carry this haplotype with only a minority developing CeD. This suggests that CeD and other gluten sensitivities are mediated by factors beyond genetics. The contribution of innate immune system signaling has been generally understudied in the context of gluten sensitivities. Thus, here we examined the role of NOD-like receptors (NLRs), a subtype of pattern recognition receptors, in maintaining the composition of the gut microbiome in animals maintained on a GFD. Human transcriptomics data revealed significant increases in the gene expression of multiple NLR family members, across functional groups, in patients with active CeD compared to control specimens. However, NLRX1 was uniquely down-regulated during active disease. NLRX1 is a negative regulatory NLR that functions to suppress inflammatory signaling and has been postulate to prevent inflammation-induced dysbiosis. Using Nlrx1(-/-) mice maintained on either a normal or gluten-free diet, we show that loss of NLRX1 alters the microbiome composition, and a distinctive shift further ensues following adherence to a GFD, including a reciprocal loss of beneficial microbes and increase in opportunistic bacterial populations. Finally, we evaluated the functional impact of an altered gut microbiome by assessing short- and medium-chain fatty acid production. These studies revealed significant differences in a selection of metabolic markers that when paired with 16S rRNA sequencing data could reflect an overall imbalance and loss of immune system homeostasis in the gastrointestinal system.en
dc.description.notesGrants were awarded from the US National Institutes of Health (IA; R03 DK105975 and K01 DK092355); the Via College of Osteopathic Medicine (VCOM) One Health Center Seed Funding (IA); Virginia Maryland College of Veterinary Medicine Internal Research Competition (IA), and the Virginia Tech Institute for Critical Technology and Applied Sciences (IA). This work was supported, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences (ES101965 to PW).en
dc.description.sponsorshipUS National Institutes of Health [R03 DK105975, K01 DK092355]; College of Osteopathic Medicine (VCOM) One Health Center Seed Funding; Virginia Maryland College of Veterinary Medicine Internal Research Competition; Virginia Tech Institute for Critical Technology and Applied Sciences; National Institute of Environmental Health Sciences [ES101965]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fimmu.2022.882521en
dc.identifier.issn1664-3224en
dc.identifier.other882521en
dc.identifier.pmid35572547en
dc.identifier.urihttp://hdl.handle.net/10919/110979en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectpattern recognition receptors (PRRs)en
dc.subjectNOD-like receptors (NLRs)en
dc.subjectgluten free dieten
dc.subjectmicrobiomeen
dc.subjectdysbiosisen
dc.subjectmetabolitesen
dc.subjectprobioticsen
dc.titleNLRX1 Deficiency Alters the Gut Microbiome and Is Further Exacerbated by Adherence to a Gluten-Free Dieten
dc.title.serialFrontiers in Immunologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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