PMID- 29507905 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201031 IS - 2471-254X (Electronic) IS - 2471-254X (Linking) VI - 2 IP - 3 DP - 2018 Mar TI - Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice. PG - 313-328 LID - 10.1002/hep4.1139 [doi] AB - Increasingly, evidence suggests that exposure to maternal obesity creates an inflammatory environment in utero, exerting long-lasting postnatal signatures on the juvenile innate immune system and microbiome that may predispose offspring to development of fatty liver disease. We found that exposure to a maternal Western-style diet (WD) accelerated fibrogenesis in the liver of offspring and was associated with early recruitment of proinflammatory macrophages at 8-12 weeks and microbial dysbiosis as early as 3 weeks of age. We further demonstrated that bone marrow-derived macrophages (BMDMs) were polarized toward an inflammatory state at 8 weeks of age and that a potent antioxidant, pyrroloquinoline quinone (PQQ), reversed BMDM metabolic reprogramming from glycolytic toward oxidative metabolism by restoring trichloroacetic acid cycle function at isocitrate dehydrogenase. This resulted in reduced inflammation and inhibited collagen fibril formation in the liver at 20 weeks of age, even when PQQ was withdrawn at 3 weeks of age. Beginning at 3 weeks of age, WD-fed mice developed a decreased abundance of Parabacteroides and Lactobacillus, together with increased Ruminococcus and decreased tight junction gene expression by 20 weeks, whereas microbiota of mice exposed to PQQ retained compositional stability with age, which was associated with improved liver health. Conclusion: Exposure to a maternal WD induces early gut dysbiosis and disrupts intestinal tight junctions, resulting in BMDM polarization and induction of proinflammatory and profibrotic programs in the offspring that persist into adulthood. Disrupted macrophage and microbiota function can be attenuated by short-term maternal treatment with PQQ prior to weaning, suggesting that reshaping the early gut microbiota in combination with reprogramming macrophages during early weaning may alleviate the sustained proinflammatory environment, preventing the rapid progression of nonalcoholic fatty liver disease to nonalcoholic steatohepatitis in offspring of obese mothers. (Hepatology Communications 2018;2:313-328). FAU - Friedman, Jacob E AU - Friedman JE AD - Section of Neonatology, Department of Pediatrics. FAU - Dobrinskikh, Evgenia AU - Dobrinskikh E AD - Division of Renal Diseases and Hypertension, Department of Medicine University of Colorado Anschutz Medical Campus Aurora CO. FAU - Alfonso-Garcia, Alba AU - Alfonso-Garcia A AD - Department of Biomedical Engineering and Beckman Laser Institute University of California Irvine, Irvine CA. FAU - Fast, Alexander AU - Fast A AD - Department of Biomedical Engineering and Beckman Laser Institute University of California Irvine, Irvine CA. FAU - Janssen, Rachel C AU - Janssen RC AD - Section of Neonatology, Department of Pediatrics. FAU - Soderborg, Taylor K AU - Soderborg TK AD - Section of Neonatology, Department of Pediatrics. FAU - Anderson, Aimee L AU - Anderson AL AD - Children's Hospital Colorado, Digestive Disease Institute and Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics. FAU - Reisz, Julie A AU - Reisz JA AD - Department of Biochemistry and Molecular Genetics. FAU - D'Alessandro, Angelo AU - D'Alessandro A AD - Department of Biochemistry and Molecular Genetics. FAU - Frank, Daniel N AU - Frank DN AD - Division of Infectious Diseases, Department of Medicine. FAU - Robertson, Charles E AU - Robertson CE AD - Division of Infectious Diseases, Department of Medicine. FAU - de la Houssaye, Becky A AU - de la Houssaye BA AD - Section of Neonatology, Department of Pediatrics. FAU - Johnson, Linda K AU - Johnson LK AD - Department of Pathology. FAU - Orlicky, David J AU - Orlicky DJ AD - Department of Pathology. FAU - Wang, Xiaoxin X AU - Wang XX AD - Division of Renal Diseases and Hypertension, Department of Medicine University of Colorado Anschutz Medical Campus Aurora CO. FAU - Levi, Moshe AU - Levi M AD - Division of Renal Diseases and Hypertension, Department of Medicine University of Colorado Anschutz Medical Campus Aurora CO. FAU - Potma, Eric O AU - Potma EO AUID- ORCID: 0000-0003-3916-6131 AD - Department of Biomedical Engineering and Beckman Laser Institute University of California Irvine, Irvine CA. FAU - El Kasmi, Karim C AU - El Kasmi KC AD - Children's Hospital Colorado, Digestive Disease Institute and Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics. FAU - Jonscher, Karen R AU - Jonscher KR AUID- ORCID: 0000-0002-7929-4886 AD - Department of Anesthesiology University of Colorado Anschutz Medical Campus Aurora CO. LA - eng GR - P30 DK048520/DK/NIDDK NIH HHS/United States GR - P41 EB015890/EB/NIBIB NIH HHS/United States GR - R56 DK114711/DK/NIDDK NIH HHS/United States GR - R01 DK098336/DK/NIDDK NIH HHS/United States GR - P30 DK020593/DK/NIDDK NIH HHS/United States GR - K25 DK098615/DK/NIDDK NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States GR - P41 RR001192/RR/NCRR NIH HHS/United States GR - S10 OD016257/OD/NIH HHS/United States GR - R24 DK090964/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20180122 PL - United States TA - Hepatol Commun JT - Hepatology communications JID - 101695860 PMC - PMC5831029 EDAT- 2018/03/07 06:00 MHDA- 2018/03/07 06:01 PMCR- 2018/01/22 CRDT- 2018/03/07 06:00 PHST- 2017/05/31 00:00 [received] PHST- 2017/11/02 00:00 [revised] PHST- 2017/12/05 00:00 [accepted] PHST- 2018/03/07 06:00 [entrez] PHST- 2018/03/07 06:00 [pubmed] PHST- 2018/03/07 06:01 [medline] PHST- 2018/01/22 00:00 [pmc-release] AID - HEP41139 [pii] AID - 10.1002/hep4.1139 [doi] PST - epublish SO - Hepatol Commun. 2018 Jan 22;2(3):313-328. doi: 10.1002/hep4.1139. eCollection 2018 Mar.