NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype
Abstract Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe −/− mice. Herein, we iden...
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Nature Portfolio
2021
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oai:doaj.org-article:76e13847e2f34a359ef1a9246eb208b92021-12-02T16:56:48ZNEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype10.1038/s41598-021-98820-02045-2322https://doaj.org/article/76e13847e2f34a359ef1a9246eb208b92021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98820-0https://doaj.org/toc/2045-2322Abstract Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe −/− mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe −/− Neil3 −/− mice and Apoe −/− mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe −/− Neil3 −/− mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.Tom Rune KarlsenXiang Yi KongSverre HolmAna Quiles-JiménezTuva B. DahlKuan YangEllen L. SagenTonje SkarpenglandJonas D. S. ØgaardKristian HolmBeate VestadMaria B. OlsenPål AukrustMagnar BjøråsJohannes R. HovBente HalvorsenIda GregersenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021) |
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Medicine R Science Q Tom Rune Karlsen Xiang Yi Kong Sverre Holm Ana Quiles-Jiménez Tuva B. Dahl Kuan Yang Ellen L. Sagen Tonje Skarpengland Jonas D. S. Øgaard Kristian Holm Beate Vestad Maria B. Olsen Pål Aukrust Magnar Bjørås Johannes R. Hov Bente Halvorsen Ida Gregersen NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| description |
Abstract Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe −/− mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe −/− Neil3 −/− mice and Apoe −/− mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe −/− Neil3 −/− mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice. |
| format |
article |
| author |
Tom Rune Karlsen Xiang Yi Kong Sverre Holm Ana Quiles-Jiménez Tuva B. Dahl Kuan Yang Ellen L. Sagen Tonje Skarpengland Jonas D. S. Øgaard Kristian Holm Beate Vestad Maria B. Olsen Pål Aukrust Magnar Bjørås Johannes R. Hov Bente Halvorsen Ida Gregersen |
| author_facet |
Tom Rune Karlsen Xiang Yi Kong Sverre Holm Ana Quiles-Jiménez Tuva B. Dahl Kuan Yang Ellen L. Sagen Tonje Skarpengland Jonas D. S. Øgaard Kristian Holm Beate Vestad Maria B. Olsen Pål Aukrust Magnar Bjørås Johannes R. Hov Bente Halvorsen Ida Gregersen |
| author_sort |
Tom Rune Karlsen |
| title |
NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| title_short |
NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| title_full |
NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| title_fullStr |
NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| title_full_unstemmed |
NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| title_sort |
neil3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/76e13847e2f34a359ef1a9246eb208b9 |
| work_keys_str_mv |
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