Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome

Lemas, Dominick J.; Young, Bridget E.; Baker, Peter R.; Tomczik, Angela; Soderborg, Taylor K.; Hernandez, Teri L.; Houssaye, Becky A. de la; Robertson, Charles E.; Rudolph, Michael C.; Ir, Diana; Patinkin, Zachary W; Krebs, Nancy F.; Santorico, Stephanie A.; Weir, Tiffany L.; Barbour, Linda A.; Frank, Daniel N.; Friedman, Jacob E.

doi:10.3945/ajcn.115.126375

Cited by 125 publications

(127 citation statements)

References 68 publications

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“…Gammaproteobacteria are a major source of LPS and are considered transient pioneering bacteria important for developing endotoxin tolerance and protection against excessive inflammatory and autoimmune gastrointestinal disorders later in life 132–134 . A statistically significant 50% reduction in Gammaproteobacteria abundance was found in stool of 2weekold babies born to mothers with obesity, along with increased levels of acetate 135 , which promotes hepatic de novo lipogenesis and NAFLD. We have transferred gut microbes from infants born to mothers who are obese into germfree mice; these mice showed signs of elevated cytokines in portal blood and liver endoplasmic reticulum stress (increased gene expression of spliced Xbp1 ) when compared with mice colonized with stool from babies born to mothers of a normal weight (J. E. Friedman, unpublished work).…”

Section: Early Postnatal Factorsmentioning

confidence: 99%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

179

167

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Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.NAFLD is a general term used to describe a broad spectrum of liver abnormalities, ranging from simple, uncomplicated hepatic steatosis to NASH, accompanied by different degrees of Correspondence to J.E.F. jed.friedman@ucdenver.edu. Author contributionsAll authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Gastroenterol Hepatol. Author manuscript; available in PMC 2017 December 12. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inflammation and fibrosis. NAFLD is increasing in prevalence, especially in adolescents 1 , despite the levellingoff of the obesity epidemic from 2003-2004 to 2013-2014 in children and adolescents aged 2-19 years (REF.2). The most common chronic liver disease worldwide, NAFLD increases the risk of cardiovascular events eightfold and type 2 diabetes mellitus (T2DM) threefold 3 , and is a strong risk factor for hepatocellular carcinoma (HCC) 4 . At the time of paediatric NAFLD diagnosis, 25-50% of children have NASH and 10-25% have advanced fibrosis 5 . For many decades, it was thought that NAFLD was predominantly driven by obesity in the setting of genetic suscep...

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Section: Early Postnatal Factorsmentioning

confidence: 99%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

179

167

View full text Add to dashboard Cite

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“…Breast milk from overweight and obese mothers has been reported to have higher levels of insulin and leptin, lower levels of omega-3 PUFA, and higher omega-6:omega-3 PUFA ratios, 153 while showing no differences in macronutrient composition. [154][155][156] Immunological modulators transforming growth factor β2 and sCD-14 have also been reported to be lower in breast milk from obese women. 157 Several other hormones and cytokines present in milk have as yet uncharacterized biological effects on the gastrointestinal and immune systems of the offspring.…”

Section: Alterations In Neonatal Nutrition and Infant Microbiomementioning

confidence: 99%

“…More recently, the microbiome of exclusively breastfed infants from lean and obese women was characterized at 2 weeks of age. 156 These studies showed that both maternal obesity status and milk insulin concentrations were associated with early changes in the infant's microbiome. The persistence of the changes in later life remains to be ascertained.…”

Section: Alterations In Neonatal Nutrition and Infant Microbiomementioning

confidence: 99%

Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child

Catalano

Shankar

2017

BMJ

882

749

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Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms.

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“…We have recently shown in a prospective study on vaginally-delivered, exclusively breastfed infants with no neonatal or postnatal exposure to antibiotics that neonates born to mothers with obesity showed a significant 50% reduction in Gammaproteobacteria at 2 weeks of age compared with infants of normal-weight mothers (Lemas et al 2016). A striking relative depletion in Proteobacteria species was recently found in 2-day-old neonates delivered vaginally, but not by cesarean section, to overweight/obese mothers (Mueller et al 2016), suggesting the differences in relative abundance of Gram-negative bacteria may stem from vertical transmission of the maternal microbiota.…”

Section: The Importance Of Proteobacteria To Immune Education In Earlmentioning

confidence: 99%

Maternal modifiers of the infant gut microbiota: metabolic consequences

Mulligan

Friedman

2017

Journal of Endocrinology

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Transmission of metabolic diseases from mother to child is multifactorial and includes genetic, epigenetic, and environmental influences. Evidence in rodents, humans and non-human primates support the scientific premise 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 diseases. In neonates, gastrointestinal microbes introduced through the mother are noted for their ability to serve as direct inducers/regulators of the infant immune system. Neonates have a limited capacity to initiate an immune response. Thus, disruption of microbial colonization during the early neonatal period results in disrupted postnatal immune responses that highlight the neonatal period as a critical developmental window. Although the mechanisms are poorly understood, increasing evidence suggests that maternal obesity or poor diet influences the development and modulation of the infant liver and other end-organs through direct communication via the portal system, metabolite production, alterations in gut barrier integrity, and the hematopoietic immune cell axis. This review will focus on how maternal obesity and dietary intake influence the composition of the infant gut microbiota and how an imbalance or maladaptation in the microbiota, including changes in early pioneering microbes, might contribute to the programming of offspring metabolism with special emphasis on mechanisms that promote chronic inflammation in the liver. Comprehension of these pathways and mechanisms will elucidate our understanding of developmental programming, and may expand the avenue of opportunities for novel therapeutics.

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Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome

Cited by 125 publications

References 68 publications

Developmental origins of NAFLD: a womb with a clue

Developmental origins of NAFLD: a womb with a clue

Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child

Maternal modifiers of the infant gut microbiota: metabolic consequences

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