Microbiome conjugated fatty acids drive postnatal liver development

Muneef Ayyash ¹ Avner Ehrlich ^1,2 Michal Zimerman ^1,2 Robert Schwartz ³ Matan Hofree ⁴ Yishai Avior ¹ Merav Cohen ^1,2 Hagit Shapiro ⁶ Eran Elinav ⁶ Aviv Regev ^4,5 Yaakov Nahmias ^1,2

¹Alexander Grass Center for Bioengineering, Hebrew University, Israel
²Department of Cell and Developmental Biology, Hebrew University, Israel
³Department of Medicine, Weill Cornell Medical College, USA
⁴Klarman Cell Observatory, The Broad Institute of Harvard and MIT, USA
⁵Department of Medical Oncology,, Dana-Farber Cancer Institute, Boston, Ma, USA
⁶Department of Immunology, Weizmann Institute of Science, Israel

Organ development proceeds after birth driven by established genetic programs. However, diet rapidly changes after birth, increasing lipids that are actively modified by the developing gut microbiome. We show that germ free mice fail to silence the fetal program of hepatocytes after birth, showing disruption in PPAR-signaling and linoleic acid metabolism. These results have leaded us to hypothesize about the role of different postpartum nutritional cues on hepatic development and maturation, with special emphasis on mitochondrial development.

Using human pluripotent stem cell-derived hepatocytes, we mimic the postnatal dietary shift showing a dramatic increase in oxidative metabolism, fetal silencing, and mitochondrial proliferation in the presence of oleic acid and microbiome-conjugated linoleic acid (9-CLA). We found that these metabolic changes were mainly mediated by the induction of a dose-dependent activation of key hepatic nuclear receptors: PPAR, PXR and LXR, which are known to be essential for the metabolic functionality of the mature hepatocyte. Inhibiting PPAR signaling using a small molecule reversed maturation. Findings were validated in isolated human fetal tissue demonstrating a critical shift toward oxidative function. Our work demonstrates that fetal silencing is driven in part by PPAR, induced by the dietary transition to microbiome modified lipid-rich nutrition in the first weeks of life. Such lipid-rich maturation could be a missing ingredient needed to drive the final maturation of other stem cell-derived parenchyma.