Maternal microbiome in preeclampsia pathophysiology and implications on offspring health.

Preeclampsia is a devastating hypertensive pregnancy disorder that currently affects 2%-8% of pregnancies worldwide. It is associated with maternal and fetal mortality and morbidity and adverse health outcomes both in mom and offspring beyond pregnancy. The pathophysiology is not completely understood, and there are no approved therapies to specifically treat for the disease, with only few therapies approved to manage symptoms. Recent advances suggest that aberrations in the composition of the microbiome may play a role in the pathogenesis of various diseases including preeclampsia. The maternal and uteroplacental environments greatly influence the long-term health outcomes of the offspring through developmental programming mechanisms. The current review summarizes recent developments on the role of the microbiome in adverse pregnancy outcomes with a focus on preeclampsia. It also discusses the potential role of the maternal microbiome in fetal programming; explores gut-targeted therapeutics advancement and their implications in the treatment of preeclampsia.

Mice derived from in vitro αMEM-cultured preimplantation embryos exhibit postprandial hyperglycemia and higher inflammatory gene expression in peripheral leukocytes.

We examined whether peripheral leukocytes of mice derived from in vitro αMEM-cultured embryos and exhibiting type 2 diabetes had higher expression of inflammatory-related genes associated with the development of atherosclerosis. Also, we examined the impact of a barley diet on inflammatory gene expression. Adult mice were produced by embryo transfer, after culturing two-cell embryos for 48 h in either α minimal essential media (α-MEM) or potassium simplex optimized medium control media. Mice were fed either a barley or rice diet for 10 weeks. Postprandial blood glucose and mRNA levels of several inflammatory genes, including Tnfa and Nox2, in blood leukocytes were significantly higher in MEM mice fed a rice diet compared with control mice. Barley intake reduced expression of S100a8 and Nox2. In summary, MEM mice exhibited postprandial hyperglycemia and peripheral leukocytes with higher expression of genes related to the development of atherosclerosis, and barley intake reduced some gene expression.

Supplemental Berberine in a High-Fat Diet Reduces Adiposity and Cardiac Dysfunction in Offspring of Mouse Dams with Gestational Diabetes Mellitus.

BACKGROUND: There are few evidence-based strategies to attenuate the risk of metabolic syndrome in offspring exposed to gestational diabetes mellitus (GDM). Berberine (BBR) is an isoquinoline alkaloid extracted from Chinese herbs and exhibits glucose lowering properties. OBJECTIVES: We hypothesized that dietary BBR would improve health outcomes in the mouse offspring of GDM dams. METHODS: Wild-type C57BL/6 female mice were fed either a Lean-inducing low-fat diet (L-LF,10% kcal fat, 35% kcal sucrose) or a GDM-inducing high-fat diet (GDM-HF, 45% kcal fat, 17.5% sucrose) for 6 wk prior to breeding with wild-type C57BL/6 male mice throughout pregnancy and the suckling period. The resulting Lean and GDM-exposed male and female offspring were randomly assigned an LF (10% kcal fat, 35% kcal sucrose), HF (45% kcal fat, 17.5% sucrose), or high-fat berberine (HFB) (45% kcal fat, 17.5% sucrose diet) containing BBR (160 mg/kg/d, HFB) at weaning for 12 wk. The main outcome was to evaluate the effects of BBR on obesity, pancreatic islet function, and cardiac contractility in GDM-exposed HF-fed offspring. Significance between measurements was determined using a 2 (gestational exposure) × 3 (diet) factorial design by a 2- way ANOVA using Tukey post-hoc analysis. RESULTS: In the GDM-HF group, body weights were significantly increased (16%) compared with those in baseline (L-LF) animals (P < 0.05). Compared with the L-LF animals, the GDM-HF group had a reduction in pancreatic insulin glucose-stimulated insulin secretion (74%) and increased cardiac isovolumetric contraction time (IVCT; ∼150%) (P < 0.05). Compared with GDM-HF animals, the GDM-HFB group with the dietary addition of BBR had significantly reduced body weight (16%), increased glucose-stimulated insulin secretion from pancreatic islets (254%), and reduced systolic heart function (46% IVCT) (P < 0.05). CONCLUSIONS: In a mouse model of GDM, dietary BBR treatment provided protection from obesity and the development of pancreatic islet and cardiac dysfunction.

Effect of early and late prenatal vitamin D and maternal asthma status on offspring asthma or recurrent wheeze.

BACKGROUND: Childhood asthma developmental programming is complex. Maternal asthma is a strong risk factor for childhood asthma, whereas vitamin D (VD) has emerged as a modifiable prenatal exposure. OBJECTIVE: Our aim was to examine the combined effect of early and late prenatal VD status in during pregnancies in women with and without asthma on childhood asthma or recurrent wheeze development. METHODS: We conducted a cohort study using prospectively collected data from the Vitamin D Antenatal Asthma Reduction Trial, a randomized, double-blinded, placebo-controlled VD supplementation trial in pregnant women at high risk of offspring asthma (N = 806 mother-offspring pairs). 25-Hydroxyvitamin-D (25(OH)D) level was measured in early and late pregnancy. Our main exposure was an ordered variable representing early and late prenatal VD sufficiency (25(OH)D level ≥ 30 ng/mL) status during pregnancy in women with and without asthma. The primary outcome was offspring with asthma or recurrent wheeze by age 3 years. We also examined the effect of prenatal VD level on early life asthma or recurrent wheeze progression to active asthma at age 6 years. RESULTS: Among mothers with asthma versus among mothers with early and late prenatal VD insufficiency, those with early or late VD sufficiency (adjusted odds ratio = 0.56; 95% CI = 0.31-1.00) or early and late VD sufficiency (adjusted odds ratio = 0.36; 95% CI = 0.15-0.81) had a lower risk of offspring with asthma or recurrent wheeze by age 3 years (Pfor trend = .008). This protective trend was reiterated in asthma or recurrent wheeze progression to active asthma from age 3 to 6 years (Pfor trend = .04). CONCLUSION: This study implies a protective role for VD sufficiency throughout pregnancy, particularly in attenuating the risk conferred by maternal asthma on childhood asthma or recurrent wheeze development.

Early exposure to a methyl donor supplemented diet and the development of repetitive motor behavior in a mouse model.

Motor behaviors that are repetitive and exhibit little variability in form are common in neurodevelopmental disorders (e.g., autism spectrum disorder). C58 mice exhibit persistent, high levels of repetitive motor behavior when reared in restricted, but not enriched, environments implicating epigenetic mechanisms (e.g., DNA methylation). We sought to determine if alteration of DNA methylation played a role in the development of repetitive behavior in C58 mice. Thus, we tested the hypothesis that early exposure (in utero and preweaning) to a methyl donor supplemented diet would alter the developmental trajectory of repetitive behavior. Such dietary exposure resulted in significant attenuation of repetitive motor behavior development, persisting through early adulthood. This was despite mice being housed in standard cages and maintained on a standard diet, postweaning. Early exposure to methyl donor supplementation not only affected the frequency of repetitive behavior but also its temporal structure, resulting in more variable patterns of repetitive behavior. Early exposure to the diet was also shown to induce long-lasting increases in DNA methylation in brain tissue of female mice. The role for alterations in DNA methylation in this model may be one mechanism accounting for the robust effects of the environment on the development of repetitive behavior.

Prenatal Exposure to Environmentally-Relevant Contaminants Perturbs Male Reproductive Parameters Across Multiple Generations that are Partially Protected by Folic Acid Supplementation.

The paternal environment is thought to influence sperm quality and future progeny may also be impacted. We hypothesized that prenatal exposure to environmentally-relevant contaminants impairs male reproduction, altering embryo gene expression over multiple generations. Folic acid (FA) can improve sperm quality and pregnancy outcomes, thus we further hypothesized that FA mitigates the contaminants. Sprague-Dawley F0 female rats treated with persistent organic pollutants (POPs) or corn oil and fed basal or supplemented FA diets, then used to yield four generations of litters. Only F0 females received POPs and/or FA treatments. In utero POPs exposure altered sperm parameters in F1, which were partly rescued by FA supplementation. Paternal exposure to POPs reduced sperm quality in F2 males, and the fertility of F3 males was modified by both POPs and FA. Ancestral FA supplementation improved sperm parameters of F4 males, while the POPs effect diminished. Intriguingly, F3 males had the poorest pregnancy outcomes and generated the embryos with the most significantly differentially expressed genes. Early-life exposure to POPs harms male reproduction across multiple generations. FA supplementation partly mitigated the impact of POPs. The two-cell embryo transcriptome is susceptible to paternal environment and could be the foundation for later pregnancy outcomes.

Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) risk begins in utero in offspring of obese mothers. A critical unmet need in this field is to understand the pathways and biomarkers underlying fetal hepatic lipotoxicity and whether maternal dietary intervention during pregnancy is an effective countermeasure. METHODS: We utilized a well-established non-human primate model of chronic, maternal, Western-style diet induced obesity (OB-WSD) compared with mothers on a healthy control diet (CON) or a subset of OB-WSD mothers switched to the CON diet (diet reversal; OB-DR) prior to and for the duration of the next pregnancy. Fetuses were studied in the early 3rd trimester. RESULTS: Fetuses from OB-WSD mothers had higher circulating triglycerides (TGs) and lower arterial oxygenation suggesting hypoxemia, compared with fetuses from CON and OB-DR mothers. Hepatic TG content, oxidative stress (TBARs), and de novo lipogenic genes were increased in fetuses from OB-WSD compared with CON mothers. Fetuses from OB-DR mothers had lower lipogenic gene expression and TBARs yet persistently higher TGs. Metabolomic profiling of fetal liver and serum (umbilical artery) revealed distinct separation of CON and OB-WSD groups, and an intermediate phenotype in fetuses from OB-DR mothers. Pathway analysis identified decreased tricarboxylic acid cycle intermediates, increased amino acid (AA) metabolism and byproducts, and increased gluconeogenesis, suggesting an increased reliance on AA metabolism to meet energy needs in the liver of fetuses from OB-WSD mothers. Components in collagen synthesis, including serum protein 5-hydroxylysine and hepatic lysine and proline, were positively correlated with hepatic TGs and TBARs, suggesting early signs of fibrosis in livers from the OB-WSD group. Importantly, hepatic gluconeogenic and arginine related intermediates and serum levels of lactate, pyruvate, several AAs, and nucleotide intermediates were normalized in the OB-DR group. However, hepatic levels of CDP-choline and total ceramide levels remained high in fetuses from OB-DR mothers. CONCLUSIONS: Our data provide new metabolic evidence that, in addition to fetal hepatic steatosis, maternal WSD creates fetal hypoxemia and increases utilization of AAs for energy production and early activation of gluconeogenic pathways in the fetal liver. When combined with hyperlipidemia and limited antioxidant activity, the fetus suffers from hepatic oxidative stress and altered intracellular metabolism which can be improved with maternal diet intervention. Our data reinforce the concept that multiple "first hits" occur in the fetus prior to development of obesity and demonstrate new biomarkers with potential clinical implications for monitoring NAFLD risk in offspring.

Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation.

Maternal immune activation (MIA) contributes to behavioral abnormalities relevant to schizophrenia in adult offspring, although the molecular mechanisms underlying MIA-induced behavioral changes remain unclear. Here we demonstrated that dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane, during juvenile and adolescent stages prevented cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial prefrontal cortex (mPFC) of adult offspring after MIA. Gene set enrichment analysis by RNA sequencing showed that MIA caused abnormal expression of centrosome-related genes in the PFC and hippocampus of adult offspring, and that dietary intake of GF improved these abnormal gene expressions. Particularly, MIA increased the expression of suppressor of fermentation-induced loss of stress resistance protein 1 (Sfi1) mRNA in the PFC and hippocampus of adult offspring, and dietary intake of GF prevented the expression of Sfi1 mRNA in these regions. Interestingly, we found altered expression of SFI1 in the postmortem brains and SFI1 mRNA in hair follicle cells from patients with schizophrenia compared with controls. Overall, these data suggest that centrosome-related genes may play a role in the onset of psychosis in offspring after MIA. Therefore, dietary intake of GF-rich vegetables in high-risk psychosis subjects may prevent the transition to psychosis in young adulthood.

The Evaluation of Folic Acid-Deficient or Folic Acid-Supplemented Diet in the Gestational Phase of Female Rats and in Their Adult Offspring Subjected to an Animal Model of Schizophrenia.

Although folic acid (FA) supplementation is known to influence numerous physiological functions, especially during pregnancy, little is known about its direct effects on the mothers' health. However, this vitamin is essential for the health of the mother and for the normal growth and development of the fetus. Thus, the aim of this study was (1) to evaluate the cognitive effects and biochemical markers produced by the AIN-93 diet (control), the AIN-93 diet supplemented with different doses of FA (5, 10, and 50 mg/kg), and a FA-deficient diet during pregnancy and lactation in female mother rats (dams) and (2) to evaluate the effect of maternal diets on inflammatory parameters in the adult offspring which were subjected to an animal model of schizophrenia (SZ) induced by ketamine (Ket). Our study demonstrated through the Y-maze test that rats subjected to the FA-deficient diet showed significant deficits in spatial memory, while animals supplemented with FA (5 and 10 mg/kg) showed no deficit in spatial memory. Our results also suggest that the rats subjected to the FA-deficient diet had increased levels of carbonylated proteins in the frontal cortex and hippocampus and also increased plasma levels of homocysteine (Hcy). Folate was able to prevent cognitive impairments in the rats supplemented with FA (5 and 10 mg/kg), data which may be attributed to the antioxidant effect of the vitamin. Moreover, FA prevented protein damage and elevations in Hcy levels in the rats subjected to different doses of this vitamin (5, 10, and 50 mg/kg). We verified a significant increase of the anti-inflammatory cytokine (interleukin-4 (IL-4)) and a reduction in the plasma levels of proinflammatory cytokines (interleukin-6 (IL-6)) and TNF-α) in the dams that were subjected to the diets supplemented with FA (5, 10, and 50 mg/kg), showing the possible anti-inflammatory effects of FA during pregnancy and lactation. In general, we also found that in the adult offspring that were subjected to an animal model of SZ, FA had a protective effect in relation to the levels of IL-4, IL-6, and TNF-α, which indicates that the action of FA persisted in the adult offspring, since FA showed a lasting effect on the inflammatory response, which was similar in both the dams and their offspring. In conclusion, the importance of supplementation with FA during pregnancy and lactation should be emphasized, not only for the benefit of the offspring but also for the health of the mother. All this is due to the considerable protective effect of this vitamin against oxidative damage, cognitive impairment, hyperhomocysteinemia, immune function, and also its ability in preventing common processes in post-pregnancy stages, as well as in reducing the risks of neurodevelopmental disorders and enhancing fetal immune development.

Effects of Highly-pure-enriched-cellulose Diet on Digestibility, Lipid Metabolism and Redox Status in Obese Offspring of Streptozotocin-Induced Diabetic Rats.

The long-term nutritional efficacy of a highly-pure-enriched-cellulose (HPEC) diet and its effects on lipid metabolism and oxidant/antioxidant status were investigated in obese offspring of streptozotocin-induced diabetic rats. Diabetes in pregnant rats was induced by intraperitoneal injection of streptozotocin on day 5 of gestation. Control pregnant rats were injected with citrate buffer. At weaning offspring of diabetic and control rats were fed HPEC or control diet, they were housed individually in metabolic cage for 2 months to investigate the nutritional efficacy of the diets. Consumption of HPEC diet decrease weight gain and energy intake, increase fecal weight and reduce lipid and protein digestibility; however, these diet had no effect on protein utilization, and nitrogen balance remained positive which confirms that HPEC diet had no significant long-term nutritional risks. Indeed for obese offspring from diabetic rats, these diet associated with high satiety promote weight loss, and provide reasonable glycemic control, these diet also lower blood lipids concentration and correct the imbalance of oxidant/antioxidant system. HPEC diet had a protective effect against long-term metabolic abnormalities associated with macrosomia.

Pre-birth origins of allergy and asthma.

Allergy is a chronic disease that can develop as early as infancy, suggesting that early life factors are important in its aetiology. Variable associations between size at birth, a crude marker of the fetal environment, and allergy have been reported in humans and require comprehensive review. Associations between birth weight and allergy are however confounded in humans, and we and others have therefore begun exploring the effects of early life events on allergy in experimental models. In particular, we are using ovine models to investigate whether and how a restricted environment before birth protects against allergy, whether methyl donor availability contributes to allergic protection in IUGR, and why maternal asthma during pregnancy is associated with increased risks of allergic disease in children. We found that experimental intrauterine growth restriction (IUGR) in sheep reduced cutaneous responses to antigens in progeny, despite normal or elevated IgE responses. Furthermore, maternal methyl donor supplementation in late pregnancy partially reversed effects of experimental IUGR, consistent with the proposal that epigenetic pathways underlie some but not all effects of IUGR on allergic susceptibility. Ovine experimental allergic asthma with exacerbations reduces relative fetal size in late gestation, with some changes in immune populations in fetal thymus suggestive of increased activation. Maternal allergic asthma in mice also predisposes progeny to allergy development. In conclusion, these findings in experimental models provide direct evidence that a perturbed environment before birth alters immune system development and postnatal function, and provide opportunities to investigate underlying mechanisms and develop and evaluate interventions.

Obesogenic diet intake during pregnancy programs aberrant synaptic plasticity and addiction-like behavior to a palatable food in offspring.

Contextual food conditioned behaviors require plasticity of glutamatergic neurotransmission in the reward system, involving changes in the expression of including a-amino-3-hydroxy-5-methylisoxazole 4-propionate receptors (AMPA), N-methyl-d-aspartic acid (NMDA) and metabotropic glutamate 2,3 (mGlur 2,3). However, the role of changes in glutamatergic synaptic markers on energy-dense palatable food preference during development has not been described. Here, we determine the effect of nutritional programing during gestation on fat food choices using a conditioned place preference (CPP) test and an operant training response and its effect on glutamatergic markers in the nucleus accumbens (Nac) shell and prefrontal cortex (PFC). Our data showed that rats displayed preference for palatable fat food and an increase in caloric intake when compared to a chow diet. Notably, 74% of rats showing a preference for fat food intake correlate with a positive HFD-paired score whereas 26% failed to get HFD-conditioned. Also, male rats trained under an operant training response schedule (FR1, FR5 and PR) showed high and low responder groups to work for food. Notably, hypercaloric nutritional programing of female rats leads to exacerbation for reinforcers in female offspring compared to offspring from chow diet. Finally, we found that an operant training response to palatable reinforcers correlates with upregulation of mGlur 2,3 in the NAc shell and PFC of male rats and female offspring. Also, we found selective Nr1 upregulation in NAc shell and the PFC of female offspring. Our data suggest that nutritional programing by hypercaloric intake leads to incentive motivation to work for food and synaptic plasticity alteration in the mesolimbic system.

In utero Exposure to Germinated Brown Rice and Its GABA Extract Attenuates High-Fat-Diet-Induced Insulin Resistance in Rat Offspring.

BACKGROUND: Numerous studies have reported on the influence of diet on insulin resistance. Our study provides insight into the effect of germinated brown rice (GBR) and γ-aminobutyric acid (GABA) on early environment-driven programming and susceptibility to insulin resistance in rat offspring. METHODS: Male rat offspring from female Sprague-Dawley rats fed with a high-fat diet (HFD) alone, HFD + GBR, or HFD + GABA extract throughout pregnancy and lactation were weaned 4 weeks after delivery and followed up for 8 weeks. A biochemical analysis and an assessment of the hepatic expression of insulin signaling genes were performed. RESULTS: The results showed that intrauterine exposure to HFD caused metabolic perturbations in rat offspring which gravitated towards insulin resistance even though the rat offspring did not consume an HFD. GBR and GABA attenuated the HFD-induced changes by underlying regulation of the insulin signaling genes. CONCLUSIONS: The results suggest that intake of GBR and GABA during pregnancy and lactation can influence the programming of genes in rat offspring, thereby enhancing insulin sensitivity.

Adverse early life environment increases hippocampal microglia abundance in conjunction with decreased neural stem cells in juvenile mice.

BACKGROUND: Adverse maternal lifestyle resulting in adverse early life environment (AELE) increases risks for neuropsychiatric disorders in offspring. Neuropsychiatric disorders are associated with impaired neurogenesis and neuro-inflammation in the hippocampus (HP). Microglia are neuro-inflammatory cells in the brain that regulate neurogenesis via toll-like receptors (TLR). TLR-9 is implicated in neurogenesis inhibition and is responsible for stress-related inflammatory responses. We hypothesized that AELE would increase microglia cell count and increase TLR-9 expression in juvenile mouse HP. These increases in microglia cell count and TLR-9 expression would be associated with decrease neural stem cell count and neuronal cell count. METHODS: We developed a mouse model of AELE combining Western diet and a stress environment. Stress environment consisted of random change from embryonic day 13 (E13) to E17 as well as static change in maternal environment from E13 to postnatal day 21(P21). At P21, we measured hippocampal cell numbers of microglia, neural stem cell and neuron, as well as hippocampal TLR-9 expression. RESULTS: AELE significantly increased total microglia number and TLR-9 expression in the hippocampus. Concurrently, AELE significantly decreased neural stem cell and neuronal numbers. CONCLUSIONS: AELE increased the neuro-inflammatory cellular response in the juvenile HP. We speculate that increased neuro-inflammatory responses may contribute to impaired neurogenesis seen in this model.

Consumption of broccoli sprouts during late gestation and lactation confers protection against developmental delay induced by maternal inflammation.

BACKGROUND: The presence of a fetal inflammatory response is linked to cerebral palsy. Unfortunately no preventive therapies are available. In this study, we determined whether dietary supplementation with broccoli sprouts (BrSp), a phase-II enzyme inducer, would be effective in preventing the behavioural and pathologic manifestations in a rodent model of inflammation during late pregnancy. METHODS: Pregnant Long-Evans rats were administered i.p. Injections of saline (100µl) or lipopolysaccharide (LPS, 200µg/kg), every 12h on embryonic day (E) 19 and 20. In the treatment groups, dams were supplemented with 200mg/day of dried BrSp from E14 until postnatal day 21. Pups underwent a series of neurodevelopmental reflex tests from postnatal day 3-21 followed by neuropathological analyses. RESULTS: Pups born from the LPS group were significantly growth restricted (p<0.001) and delayed in hindlimb placing (p<0.05), cliff avoidance (p<0.05), and gait (p<0.001) compared to controls. In the open field behaviour analyses, LPS pups had an increase in grooming behaviour (p<0.05) and a decreased amount of time spent in the center of the box compared to controls. Dietary supplementation with BrSp to offspring exposed to LPS had increased birth weights (p<0.001), were no longer delayed in acquiring hindlimb placing, cliff avoidance, gait, and posture, and groomed less compared to LPS alone pups (p<0.01). Histological analyses revealed that LPS pups had reduced myelin basic protein compared to controls. CONCLUSIONS: Our data suggest that BrSp dietary supplementation during pregnancy may be effective in preventing growth restriction and neurodevelopmental delays.

Transgenerational effects of maternal diet on metabolic and reproductive ageing.

The early-life environment, in particular maternal diet during pregnancy, influences a wide range of organs and systems in adult offspring. Mounting evidence suggests that developmental programming can also influence health and disease in grand-offspring. Transgenerational effects can be defined as those persisting into an F2 generation, where the F0 mother experiences suboptimal diet during her pregnancy. In this review, we critically examine evidence for transgenerational developmental programming effects in human populations, focusing on metabolic and reproductive outcomes. We discuss evidence from historical cohorts suggesting that grandchildren of women exposed to famine and other dietary alterations during pregnancy may experience increased rates of later health complications than their control counterparts. The methodological difficulties with transgenerational studies in human cohorts are explored. In particular, the problems with assessing reproductive outcomes in human populations are discussed. In light of the relative paucity of evidence available from human cohorts, we consider key insights from transgenerational experimental animal models of developmental programming by maternal diet; data are drawn from a range of rodent models, as well as the guinea-pig and the sheep. The evidence for different potential mechanisms of transgenerational inheritance or re-propagation of developmental programming effects is evaluated. Transgenerational effects could be transmitted through methylation of the gametes via the paternal and maternal lineage, as well as other possible mechanisms via the maternal lineage. Finally, future directions for exploring these underlying mechanisms further are proposed, including utilizing large, well-characterized, prospective pregnancy cohorts that include biobanks, which have been established in various populations during the last few decades.

Does maternal diet affect infantile colic?

OBJECTIVE: The aim of this study was to investigate the effect of maternal diet on infantile colic without any interventions or food restrictions. METHODS: Thirty colicky and 29 non-colicky infants were included in this prospective study. Mother's diet and baby crying time were recorded for 1 week by mothers; nutritionist classified contents of mother's diet and compared the diet of mother in colicky and non-colicky infants. RESULTS: It was found that mothers of non-colicky infants consumed significantly more grapes and lemons than mothers of colicky infants (p = 0.044). The crying time was moderately negatively correlated with the percentage of protein in the maternal diet (R = -0.45, p = 0.01) and the presence of potatoes in the maternal diet (R = -0.38, p = 0.034) and positively correlated with the maternal consumption of walnut (R = 0.38, p = 0.034), banana (R = 0.44, p = 0.01). CONCLUSIONS: Removing bananas from the maternal diet may reduce colic. The consumption of a protein-rich maternal diet, grapes, lemons and potatoes by breastfeeding mothers may protect infants from colic.

Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring.

Obesity induces a low-grade inflammatory state and has been associated with behavioral and cognitive alterations. Importantly, maternal environmental insults can adversely impact subsequent offspring behavior and have been linked with neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (AHDH). It is unknown if maternal obesity significantly alters offspring sociability, a key ASD feature, and if altering maternal diet will provide an efficacious intervention paradigm for behavioral deficits. Here we investigated the impact of maternal high fat diet (HFD) and maternal dietary intervention during lactation on offspring behavior and brain inflammation in mice. We found that maternal HFD increased anxiety and decreased sociability in female offspring. Additionally, female offspring from HFD-fed dams also exhibited increased brain IL-1ß and TNFα and microglial activation. Importantly, maternal dietary intervention during lactation was sufficient to alleviate social deficits and brain inflammation. Maternal obesity during gestation alone was sufficient to increase hyperactivity in male offspring, a phenotype that was not ameliorated by dietary intervention. These data suggest that maternal HFD acts as a prenatal/perinatal insult that significantly impacts offspring behavior and inflammation and that dietary intervention during lactation may be an easily translatable, efficacious intervention to offset some of these manifestations.

The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Although the etiology of ASD remains elusive, converging lines of research indicate that mitochondrial dysfunction may play a substantive role in disease pathophysiology. Without an established causal link, the generation of therapeutic targets for ASD has been relatively unsuccessful and has focused solely on individual symptoms. The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has previously been used for the treatment of intractable epilepsy and is known to enhance mitochondrial function. The purpose of this study was to determine if the KD could reverse the social deficits and mitochondrial dysfunction identified in the prenatal valproic acid (VPA) rodent model of ASD. Sprague-Dawley dams were administered VPA or saline on gestational day 12.5. The pups were treated with the KD or their standard diet (SD) for 10 days beginning on postnatal day 21 (PD21). On PD35 juvenile play behavior was tested with the play-fighting paradigm and rats were then sacrificed for mitochondrial bioenergetic analysis. The offspring exposed to VPA prenatally demonstrated a significant decrease in the number of play initiations/attacks and this was reversed with the KD. Prenatal VPA exposure also disrupted the pattern of play responses; VPA/SD animals used complete rotations more often than saline control animals. Treatment with the KD did not affect the number of complete rotations. In addition, while prenatal exposure to VPA altered mitochondrial respiration, the KD was able to restore aspects of bioenergetic dysfunction. As the KD was able to modify complex social behaviors and mitochondrial respiration, it may be a useful treatment option for ASD. Future studies will need to examine the effectiveness of the KD to reverse the two additional core deficits of ASD and to explore various treatment regimens to determine optimal treatment duration and formulation.

Leucine-rich diet supplementation modulates foetal muscle protein metabolism impaired by Walker-256 tumour.

BACKGROUND: Cancer-cachexia induces a variety of metabolic disorders of protein turnover and is more pronounced when associated with pregnancy. Tumour-bearing pregnant rats have impaired protein balance, which decreases protein synthesis and increases muscle breakdown. Because branched-chain amino acids, especially leucine, stimulate protein synthesis, we investigated the effect of a leucine-rich diet on protein metabolism in the foetal gastrocnemius muscles of tumour-bearing pregnant rats. METHODS: Foetuses of pregnant rats with or without Walker 256 tumours were divided into six groups. During the 20 days of the experiment, the pregnant groups were fed with either a control diet (C, control rats; W, tumour-bearing rats; Cp, rats pair-fed the same normoprotein-diet as the W group) or with a leucine-rich diet (L, leucine rats; LW, leucine tumour-bearing rats; and Lp, rats pair-fed the same leucine-rich diet as the LW group). After the mothers were sacrificed, the foetal gastrocnemius muscle samples were resected, and the protein synthesis and degradation and tissue chymotrypsin-like, cathepsin and calpain enzyme activities were assayed. The muscle oxidative enzymes (catalase, glutathione-S-transferase and superoxide dismutase), alkaline phosphatase enzyme activities and lipid peroxidation (malondialdehyde) were also measured. RESULTS: Tumour growth led to a reduction in foetal weight associated with decreased serum protein, albumin and glucose levels and low haematocrit in the foetuses of the W group, whereas in the LW foetuses, these changes were less pronounced. Muscle protein synthesis (measured by L-[3H]-phenylalanine incorporation) was reduced in the W foetuses but was restored in the LW group. Protein breakdown (as assessed by tyrosine release) was enhanced in the L and W groups, but chymotrypsin-like activity increased only in group W and tended toward an increase in the LW foetuses. The activity of cathepsin H was significantly higher in the W group foetuses, but the proteolytic calcium-dependent pathway showed similar enzyme activity. In parallel, an intense oxidative stress process was observed only in the group W foetuses. CONCLUSIONS: These data suggested that the proteasomal and lysosomal proteolytic pathways and oxidative stress are likely to participate in the process of foetal muscle catabolism of Walker's tumour-bearing pregnant rats. The present work shows that foetal muscle can be protected by supplementation with a leucine-rich diet.