Читать книгу Nutrition and Growth - Группа авторов - Страница 46

Soderborg TK¹, Clark SE², Mulligan CE¹, Janssen RC¹, Babcock L¹, Ir D³, Young B^4,13, Kriebs N⁴, Lemas DJ^1,14, Johnson LK⁵, Weir T⁶, Lenz LL², Frank DN³, Hernandez TL^7,8, Kuhn KA⁹, D’Alessandro A¹⁰, Barbour LA^7,11, El Kasmi KC¹², Friedman JE^1,7,11

¹Department of Pediatrics, Section of Neonatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ²Department of Microbiology and Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ³Department of Medicine, Division of Infectious Disease, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ⁴Department of Pediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ⁵Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ⁶Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA; ⁷Department of Medicine, Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ⁸College of Nursing, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ⁹Department of Medicine, Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ¹⁰Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ¹¹Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ¹²Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; ¹³Present address: Department of Pediatrics; Allergy and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; ¹⁴resent address: Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville, FL, USA

Nat Commun 2018;9:4462

Abstract: Maternal obesity is associated with increased risk for offspring obesity and non-alcoholic fatty liver disease (NAFLD), but the causal drivers of this association are unclear. Early colonization of the infant gut by microbes plays a critical role in establishing immunity and metabolic function. Here, we compare germ-free mice colonized with stool microbes (MB) from 2-week-old infants born to obese (Inf-ObMB) or normal-weight (Inf-NWMB) mothers. Inf-ObMB-colonized mice demonstrate increased hepatic gene expression for endoplasmic reticulum stress and innate immunity together with histological signs of periportal inflammation, a histological pattern more commonly reported in pediatric cases of NAFLD. Inf-ObMB mice show increased intestinal permeability, reduced macrophage phagocytosis, and dampened cytokine production suggestive of impaired macrophage function. Furthermore, exposure to a Western-style diet in Inf-ObMB mice promotes excess weight gain and accelerates NAFLD. Overall, these results provide functional evidence supporting a causative role of maternal obesity-associated infant dysbiosis in childhood obesity and NAFLD.

Unmodified reproduction. This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/deed.en)

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Evidence in rodents, humans, and non-human primates support the scientific evidence that exposure to maternal obesity or high-fat diet during pregnancy creates a long-lasting metabolic signature on the infant innate immune system and the juvenile microbiota, which predisposes the offspring to obesity and metabolic disease. Alteration of the early infant gut microbiome has been correlated with the development of childhood obesity. This is likely to be due to complex interactions between mode of delivery, antibiotic use, maternal diet, components of breastfeeding, and a network of regulatory events involving both the innate and adaptive immune systems within the infant host. Each of these factors are critical for informing microbiome development and can affect immune signaling, toxin release, and metabolic signals, including short-chain fatty acids and bile acids, that regulate appetite, metabolism, and inflammation. Clinical data also support correlations between pediatric obesity, non-alcoholic fatty liver disease (NAFLD), and gut dysbiosis [29].The current study is the first experimental evidence to support the hypothesis that changes in the gut microbiome in infants born to obese mothers directly initiate obesity and NAFLD pathways. The study evaluated infants born to normal weight (NW) and obese (Ob) mothers; these infants were born vaginally, exclusively breastfed, and were without exposure to antibiotics after delivery.By using germ-free (GF) mice, the researchers investigate the hypothesis that early gut dysbiosis noted in 2-week-old infants born to Ob mothers cause metabolic and inflammatory changes characteristic of obesity and NAFLD. Their results demonstrate that altered gut microbiota in 2-week-old infants born to Ob mothers induced changes in intestinal permeability and hepatic metabolism, including inflammation and a dysfunctional macrophage phenotype in in the liver and bone marrow cells of GF mice that might be causal factors underlying the increased transmission of obesity and NAFLD risk in children born to Ob mothers. These mice were predisposed to accelerated weight gain and the development of fatty liver following exposure to a Western-style diet (WSD).Mice colonized with stool microbes from infants born to obese mothers (Inf-ObMB) had increased hepatic endoplasmic reticulum stress, hepatic inflammation, and liver macrophage accumulation, consistent with the concept that Inf-ObMB provokes an inflammatory microenvironment in the livers of these mice. Inf-ObMB colonized mice showed also histological evidence for increased periportal inflammation that is seen also in humans with advanced forms of pediatric NAFLD and features of the metabolic syndrome, suggesting that it has clinical relevance as an early manifestation of leaky gut.Other important findings of this study were a significant increase in bile acid (BA) levels in feces from Inf-ObMB mice and the evidence of reduced gut barrier gene expression and increased intestinal permeability, as has been reported in children with established NAFLD [30]. The findings also indicate that a macrophage dysfunction, in addition to other consequences of dysbiosis on liver inflammation, accelerates steatosis and weight gain when exposed to WSD.The strengths of the study include the study cohort of infants was relatively a homogenous group (infants who were born vaginally, exclusively breastfed, and were without exposure to antibiotics after delivery) that allowed exclusion of confounding factors that may impact the gut microbiota and bias the results. Also, the design of pooling infant stool samples allowed to create one inoculum for each round of colonization treatment group. Although it might have limited the variability seen between individual infants at this stage of development, the microbiota compositions of the Inf-NWMB and Inf-ObMB mice at 21 days post-gavage were significantly different and consistent with the major compositional differences in the NW and Ob infant donor stool. This, along with the replication of the findings with 3 rounds of colonization using unique pools of stool for each round, strengthens the likelihood that the results are relevant for a larger human infant population.In conclusion, maternal obesity dramatically increases the long-term risk for obesity in the next generation partially by altering the offspring gut microbiome. Therefore, pregnancy and lactation may be critical periods at which to aim primary prevention to break the obesity cycle.Future studies utilizing interventional strategy as changes in maternal diet and the use of pre/probiotics, as well as understanding their bioactive metabolites that might prevent metabolic perturbations, are needed to modify the epidemic of childhood obesity and NAFLD risk in infants born to obese mothers.