Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice

Abstract

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in reduced inflammation and inhibited collagen fibril formation in the liver at 20 weeks of age, even when PQQ was withdrawn at 3 weeks of age.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)

Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming

“…64 Furthermore, cellular changes in fetal livers are observed as early as 8-12 weeks of gestation, with increased recruitment of proinflammatory macrophages in fetuses of dams exposed to WSD. 91 Surprisingly, bone marrow-derived macrophages (BMDMs) isolated 8 weeks postnatal from pups exposed to WSD in utero were hyper-responsive to LPS, as evidenced by elevated Il1b, Tnf, Il6, and Il10 transcript levels. 91 This phenotype is in contradiction to the dampened response to LPS generated by cord blood monocytes in humans and splenocytes in mice and could potentially be explained by the extended culturing required to derive macrophages from bone marrow cells.…”

“…91 Surprisingly, bone marrow-derived macrophages (BMDMs) isolated 8 weeks postnatal from pups exposed to WSD in utero were hyper-responsive to LPS, as evidenced by elevated Il1b, Tnf, Il6, and Il10 transcript levels. 91 This phenotype is in contradiction to the dampened response to LPS generated by cord blood monocytes in humans and splenocytes in mice and could potentially be explained by the extended culturing required to derive macrophages from bone marrow cells. Taken together, these observations indicate that the impact of pregravid maternal obesity is highly dependent on the tissue examined, the stimulus used, and the age of the offspring.…”

“…Gene expression studies in infant rhesus macaques exposed to HFD during gestation provide substantial evidence of oxidative stress in fetal livers during the third trimester as evidenced by elevated expression of metabolic enzymes and lipotoxicity . Furthermore, cellular changes in fetal livers are observed as early as 8–12 weeks of gestation, with increased recruitment of proinflammatory macrophages in fetuses of dams exposed to WSD . Surprisingly, bone marrow‐derived macrophages (BMDMs) isolated 8 weeks postnatal from pups exposed to WSD in utero were hyper‐responsive to LPS, as evidenced by elevated Il1b , Tnf , Il6 , and Il10 transcript levels .…”

“…Furthermore, molecular targets (such as TBK1) for limiting inflammation in the adipose tissue have been recently identified, providing new therapeutic avenues . Recent studies using murine models have demonstrated that short‐term maternal treatment with the antioxidant pyrroloquinoline quinone can mitigate fetal immune developmental reprogramming …”

Bacteria in the ageing gut: did the taming of fire promote a long human lifespan?

“…The former compound is strongly linked to sugar and lipid metabolism, while the latter belongs to a cycle that links the gut to the liver. Both are highly sensitive to the nature of the gut microbiota, the former via monitoring a proinflammatory status of the host (Friedman et al ., ), while the latter has an important role in controlling the composition of the gut microbiota [demonstrated in a mouse model (Van den Bossche et al ., )]. Maintenance of the protein quality is another general process obviously essential for longevity.…”