Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling

Manish Kumar, Aralia Leon Coria, Steve Cornick, Björn Petri, Shyamchand Mayengbam, Humberto B. Jijon, France Moreau, Jane Shearer and Kris Chadee ()
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Manish Kumar: University of Calgary Health Sciences Centre
Aralia Leon Coria: University of Calgary Health Sciences Centre
Steve Cornick: University of Calgary Health Sciences Centre
Björn Petri: University of Calgary Health Sciences Centre
Shyamchand Mayengbam: University of Calgary
Humberto B. Jijon: University of Calgary
France Moreau: University of Calgary Health Sciences Centre
Jane Shearer: University of Calgary
Kris Chadee: University of Calgary Health Sciences Centre

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Inflammatory bowel disease is associated with changes in the mucosal barrier, increased intestinal permeability, and increased risk of infections and sepsis, but the underlying mechanisms are incompletely understood. Here, we show how continuous translocation of gut microbial components affects iron homeostasis and facilitates susceptibility to inflammation-associated sepsis. A sub-lethal dose of lipopolysaccharide results in higher mortality in Mucin 2 deficient (Muc2−/−) mice, and is associated with elevated circulatory iron load and increased bacterial translocation. Translocation of gut microbial components attenuates hepatic stearoyl CoA desaturase-1 activity, a key enzyme in hepatic de novo lipogenesis. The resulting reduction of hepatic saturated and unsaturated fatty acid levels compromises plasma membrane fluidity of red blood cells, thereby significantly reducing their life span. Inflammation in Muc2−/− mice alters erythrophagocytosis efficiency of splenic macrophages, resulting in an iron-rich milieu that promotes bacterial growth. Our study thus shows that increased intestinal permeability triggers a cascade of events resulting in increased bacterial growth and risk of sepsis.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14182-2

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DOI: 10.1038/s41467-019-14182-2

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