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

• Published in: Nature communications Vol. 11; no. 1; p. 483
• Main Authors: Kumar, Manish, Leon Coria, Aralia, Cornick, Steve, Petri, Björn, Mayengbam, Shyamchand, Jijon, Humberto B., Moreau, France, Shearer, Jane, Chadee, Kris
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 14/19; 14/32; 14/5; 631/250/254; 631/250/256/2515; 631/250/347; 631/326/2565; Animals; Bacteria; Cell Membrane Permeability; Cytophagocytosis; Desaturase; Digestive system; Disease Models, Animal; Erythrocytes; Fatty acids; Fatty liver; Female; Fluidity; Gastrointestinal Microbiome; Gastrointestinal tract; Health risks; Homeostasis; Humanities and Social Sciences; Inflammation - etiology; Inflammation - metabolism; Inflammation - microbiology; Inflammatory bowel disease; Inflammatory bowel diseases; Intestinal microflora; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestine; Iron; Iron - blood; Iron - metabolism; Lethal dose; Life span; Lipogenesis; Lipopolysaccharides; Liver - metabolism; Macrophages; Macrophages - metabolism; Male; Membrane fluidity; Membrane permeability; Membranes; Mice; Mice, Knockout; Microorganisms; Mucin; Mucin-2 - deficiency; Mucin-2 - genetics; Mucosa; multidisciplinary; Permeability; Risk; Science; Science (multidisciplinary); Sepsis; Sepsis - etiology; Sepsis - metabolism; Sepsis - microbiology; Spleen; Stearoyl-CoA desaturase; Stearoyl-CoA Desaturase - metabolism; Translocation; Viscosity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14182-2

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. Here Kumar et al. show that increased intestinal permeability reduces hepatic de novo lipogenesis, affecting plasma membrane fluidity and lifespan of RBCs, and the resulting increase in iron levels promotes bacterial growth. This mechanism may explain the increased risk of sepsis associated with inflammatory bowel disease.