Imbalance in gut microbes from babies born to obese mothers increases gut permeability and myeloid cell adaptations that provoke obesity and NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease affecting nearly 40% of obese youth and up to 10% of the general pediatric population. A key aspect of NAFLD pathogenesis is proinflammatory hepatic macrophage activation and hepatic recruitment of circulating monocytes, which originate from the bone marrow. In neonates, the activation and polarization of myeloid immune cells are normally shaped in part by systemic factors derived from intestinal microbiota during the first 1000 days of life. Perturbations of the gut microbiome, and in turn the metabolites and bacterial products released systemically, can affect the functional phenotype of these immune cells. Evidence in germ-free mice has shown that fecal microbial transfer from obese mice or obese human donors promotes obesity and inflammation in the recipients, suggesting a direct role for the gut microbiome in promoting obesity and possibly NAFLD. Indeed, patients suffering from NAFLD show evidence for dysbiosis, increased gut permeability, and changes in bile acids that drive the progression of hepatic inflammation toward non-alcoholic steatohepatitis (NASH), the more severe form of the disease. Compared with infants born to normal-weight mothers, we previously showed that the gut microbiome from neonates born to obese mothers is compositionally distinct. However, whether this alteration in early gut microbiota in infants born to obese mothers can cause inflammatory processes that initiate development of NAFLD or obesity is unknown. How these alterations contribute to long-term immune cell mediated liver inflammation and progression of NAFLD needs to be determined. Our recently published work (Soderborg et al., Nat Commun 9:4462) demonstrates a causative role of early life microbiome dysbiosis in infants born to mothers with obesity in novel pathways that promote developmental programming of NAFLD

Gestational Diabetes Is Uniquely Associated With Altered Early Seeding of the Infant Gut Microbiota

Gestational diabetes mellitus (GDM) is a worldwide public health problem affecting up to 27% of pregnancies with high predictive values for childhood obesity and inflammatory diseases. Compromised seeding of the infant gut microbiota is a risk factor for immunologic and metabolic diseases in the offspring; however, how GDM along with maternal obesity interact to alter colonization remains unknown. We hypothesized that GDM individually and in combination with maternal overweight/obesity would alter gut microbial composition, diversity, and short-chain fatty acid (SCFA) levels in neonates. We investigated 46 full-term neonates born to normal-weight or overweight/obese mothers with and without GDM, accounting for confounders including cesarean delivery, lack of breastfeeding, and exposure to antibiotics. Gut microbiota in 2-week-old neonates born to mothers with GDM exhibited differences in abundance of 26 microbial taxa; 14 of which showed persistent differential abundance after adjusting for pre-pregnancy BMI. Key pioneering gut taxa, including potentially important taxa for establishing neonatal immunity, were reduced. Lactobacillus, Flavonifractor, Erysipelotrichaceae, and unspecified families in Gammaproteobacteria were significantly reduced in neonates from mothers with GDM. GDM was associated with an increase in microbes involved in suppressing early immune cell function (Phascolarctobacterium). No differences in infant stool SCFA levels by maternal phenotype were noted; however, significant correlations were found between microbial abundances and SCFA levels in neonates. Our results suggest that GDM alone and together with maternal overweight/obesity uniquely influences seeding of specific infant microbiota in patterns that set the stage for future risk of inflammatory and metabolic disease.</jats:p

Low Neonatal Plasma n-6/n-3 PUFA Ratios Regulate Offspring Adipogenic Potential and Condition Adult Obesity Resistance

Adipose tissue expansion progresses rapidly during postnatal life, influenced by both prenatal maternal factors and postnatal developmental cues. The ratio of omega-6 (n-6) relative to n-3 polyunsaturated fatty acids (PUFAs) is believed to regulate perinatal adipogenesis, but the cellular mechanisms and long-term effects are not well understood. We lowered the fetal and postnatal n-6/n-3 PUFA ratio exposure in wild-type offspring under standard maternal dietary fat amounts to test the effects of low n-6/n-3 ratios on offspring adipogenesis and adipogenic potential. Relative to wild-type pups receiving high perinatal n-6/n-3 ratios, subcutaneous adipose tissue in 14-day-old wild-type pups receiving low n-6/n-3 ratios had more adipocytes that were smaller in size; decreased Pparγ2, Fabp4, and Plin1; several lipid metabolism mRNAs; coincident hypermethylation of the PPARγ2 proximal promoter; and elevated circulating adiponectin. As adults, offspring that received low perinatal n-6/n-3 ratios were diet-induced obesity (DIO) resistant and had a lower positive energy balance and energy intake, greater lipid fuel preference and non–resting energy expenditure, one-half the body fat, and better glucose clearance. Together, the findings support a model in which low early-life n-6/n-3 ratios remodel adipose morphology to increase circulating adiponectin, resulting in a persistent adult phenotype with improved metabolic flexibility that prevents DIO.</jats:p

Author Correction: The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD

An amendment to this paper has been published and can be accessed via a link at the top of the paper.</jats:p

Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring

Summary: Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to increasing prevalence of these diseases, yet mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, and functional levels in bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring and in hematopoietic stem and progenitor cells (HSPCs) from fetal and juvenile bone marrow and fetal liver. mWSD exposure is also associated with increased oleic acid in fetal and juvenile bone marrow and fetal liver. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling of HSPCs and BMDMs from mWSD-exposed juveniles supports a model in which HSPCs transmit pro-inflammatory memory to myeloid cells beginning in utero. These findings show that maternal diet alters long-term immune cell developmental programming in HSPCs with proposed consequences for chronic diseases featuring altered immune/inflammatory activation across the lifespan

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

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)

Entrepreneurship in Peace Operations

Journal of Civic Society," 6(01), (2010), pp. 1-21.A central question guides this article: To what extent can entrepreneurship be a force for change and transformation in war-torn areas? To address the question, this article introduces the topic of social entrepreneurship and illustrates how social entrepreneurs are serving as change agents in rebuilding and reconstructing areas devastated by conflict. The social enterprise of Kiva, the brainchild of social entrepreneurs Matthew Flannery and Jessica Jackley, provides an example. It is notable for its innovative idea—a Web-based, internet-facilitated micro-loan process that attracts individual investors worldwide in support of business entrepreneurs in the developing world. As a counter example to top-down, mandate-driven, organization-centric intervention strategies that many organizations pursue in peace operations, Kiva’s enduring legacy may very well be its bottom-up, entrepreneur-driven, network-centric model of change. Its most salient features are: a supply chain that ‘contractually’ connects all the partners in the loan process to minimize coordination problems and ensure that each step in the workflow sequentially adds value; processes and systems that guarantee work is transparent, efficient and accountable; a model of learning that enables global and local partners to co-create a complex, worldwide community-based learning system in support of entrepreneurship; and a rich network of social relations built from face-to-face and online interactions to help generate social capital needed for development