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Gut-liver axis calibrates intestinal stem cell fitness via PEDF

ABSTRACT: The gut and liver have been recognized to mutually communicate through the biliary tract, portal vein and systemic circulation, but it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy, transcriptomics and proteomics profiling, we identified pigment epithelium-derived factor (PEDF), as a liver-derived soluble Wnt inhibitor, that can restrain intestinal stem cells (ISC) hyperproliferation for gut homeostasis by competing with Wnt ligands and suppressing Wnt/beta-catenin signaling pathway. In turn, microbial danger signals from intestinal inflammation can be sensed by the liver to repress PEDF production via peroxisome proliferator-activated receptor-alpha (PPAR alpha), liberating ISC proliferation to accelerate tissue repair in the gut. Further, treatment of mice with fenofibrate, a clinical agent of PPARalpha agonist for hypolipidemia enhances the susceptibility of colitis via PEDF activity. Therefore, we identified a distinct role of PEDF to calibrate ISC expansion for intestinal homeostasis via reciprocal interactions between the gut and liver.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Yan Wang

PROVIDER: MSV000091409 | MassIVE | Fri Mar 03 13:20:00 GMT 2023

SECONDARY ACCESSION(S): PXD040586

REPOSITORIES: MassIVE

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Project description:The liver is located at the interface between the intestinal portal vasculature and the general circulation, employing a complex set of innate and adaptive immune cells to protect from the continuous systemic threat of gut-translocating pathogens. In contrast to lymphoid tissues in which asymmetric, polarized spatial positioning of distinct cell types plays an essential role in optimal host defense, the relationship between liver phagocytes and lymphoid element distribution and their immune functions is currently unknown. This lack of organization stands in marked contrast to the extensively documented zonation of hepatocyte metabolic function controlled by Wnt signaling during development. Here we used quantitative multi-parameter confocal imaging to re-examine resident immune cells distribution in the liver, finding that both myeloid (Kupffer cell -KC) and lymphoid (NKT cell) components are substantially enriched in the peri-portal regions of the liver lobule, the entry point for portal venous blood rich in gut-derived pathogens and molecules. Peri-portal immune enrichment of KCs was lost in germ-free (GF) animals and coincided temporally with weaning and microbial colonization, suggesting that immune cell positioning was not a developmentally programmed process but rather dependent on extrinsic factors. Conditional ablation of MyD88-dependent bacterial product sensing by liver sinusoidal endothelial cells (LSECs) disrupted KC spatial organization animals, consistent with immune cell positioning within the liver architecture arising from sustained, active responses of LSECs to microbial stimuli. Bacterial challenge studies revealed that this asymmetric peri-portal-biased immune cell localization protects the liver and the host against bacterial dissemination. Together, these data reveal that LSECs act as microbiome sensors, actively promoting concentration of protective immune components in the sub-regions of the liver most susceptible to infection to provide optimal host defense against systemic pathogen spread.

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Gut-liver axis calibrates intestinal stem cell fitness via PEDF

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