Offspring Gut Microbiota Research Articles

Neurobehavioural effects of Lactobacillus rhamnosus GG alone and in combination with prebiotics polydextrose and galactooligosaccharide in male rats exposed to early-life stress

Early life is a period of significant brain development when the brain is at its most plastic and vulnerable. Stressful episodes during this window of development have long-lasting effects on the central nervous system. Rodent maternal separation (MS) is a reliable model of early-life stress and induces alterations in both physiology and behaviour. Intriguingly, the gut microbiota of MS offspring differ from that of non-separated offspring, suggesting a mechanistic role for the microbiota–gut–brain axis. Hence, we tested whether dietary factors known to affect the gut microbiota alter the neurobehavioural effects of MS. The impact of consuming diet containing prebiotics polydextrose (PDX) and galactooligosaccharide (GOS) alone or in combination with live bacteria Lactobacillus rhamnosus GG (LGG) from weaning onwards in rats subjected to early-life MS was assessed. Adult offspring were assessed for anxiety-like behaviour in the open field test, spatial memory using the Morris water maze, and reactivity to restraint stress. Brains were examined via PCR for changes in mRNA gene expression. Here, we demonstrate that diets containing a combination of PDX/GOS and LGG attenuates the effects of early-life MS on anxiety-like behaviour and hippocampal-dependent learning with changes to hippocampal mRNA expression of genes related to stress circuitry, anxiety and learning.

Preconception Prebiotic and Sitagliptin Treatment in Obese Rats Affects Pregnancy Outcomes and Offspring Microbiota, Adiposity, and Glycemia.

Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p < 0.05). Gestational weight gain was lowest in Obese-OFS + S rats and highest in Obese-HFS rats (p < 0.05). Prepregnancy intervention did not affect reproductive parameters but did affect pregnancy outcomes including litter size. Male Obese-OFS offspring had significantly lower percent body fat than Obese-HFS at 17 weeks. Female Obese-S and Obese-OFS offspring had significantly lower fasting glucose at 17 weeks compared with Obese-Control and Obese-HFS. Clostridium cluster XI was higher in Obese-HFS and Obese-S dams at birth compared with all other groups. Dams with an adverse pregnancy outcome had significantly lower (p = 0.035) Lactobacillus spp. compared with dams with normal or small litters. At weaning, male offspring of Obese-HFS had higher levels of Methanobrevibacter than all other groups except Obese-S and female Obese-HFS offspring had higher Enterobacteriaceae compared with all other groups. At 11 and 17 weeks of age, Bacteroides/Prevotella spp. was significantly lower in male and female offspring of Obese-HFS dams compared with all other groups except Obese-OFS + S. Modest weight loss induced with a diet-drug combination did not affect maternal fecundity but did have sex-specific effects on offspring adiposity and glycemia that may be linked to changes in offspring microbiota.

Omega-3 polyunsaturated fatty acids critically regulate behaviour and gut microbiota development in adolescence and adulthood

BackgroundNeurodevelopment is strongly influenced by maternal and early-postnatal diet. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are vital structural and functional components of the developing brain. The gut microbiota is also influenced by n-3 PUFA status, however, little is known about the role of maternal and early-life n-3 PUFA intake on offspring gut microbiota development and subsequent interactions with central nervous system functioning and behavioural outcomes. MethodsPregnant female C57BL/6 mice and their male offspring were fed a control (CON), omega-3 deficient (O3−) or omega-3 supplemented (O3+) diet. Cognitive, depressive and social behaviours were assessed through a battery of behaviour tests in the male offspring at both adolescence (week 4–5) and adulthood (week 11–13). Hypothalamic-pituitary-adrenal axis (HPA) activation was assessed by analysis of stress-induced corticosterone production. Fecal microbiota composition was analysed by 16S sequencing at both adolescent and adulthood. In addition, stimulated spleen cytokine levels were assessed. Resultsn-3 PUFA interventions induced subtle changes in offspring early-life and adolescent behaviours, which were further evident in adulthood, such that O3− animals displayed impaired communication, social and depression-related behaviours and O3+ animals displayed enhanced cognition. O3− mice displayed an elevated Firmicutes:Bacteroidetes ratio and blunted systemic LPS responsiveness. Contrastingly, O3+ mice displayed greater fecal Bifidobacterium and Lactobacillus abundance and dampened HPA-axis activity. ConclusionsNeurobehavioural development related to cognitive, anxiety and social behaviours, is highly dependent upon in utero and lifelong n-3 PUFA availability. In addition, neurobehavioural changes induced by altering n-3 PUFA status are closely associated with comprehensive alterations in gut microbiota composition, HPA-axis activity and inflammation.

The effects of maternal and post-weaning diet interaction on glucose metabolism and gut microbiota in male mice offspring.

Substantial studies demonstrated that maternal nutrition can significantly determine the susceptibility to developing some metabolic diseases in offspring. However, investigations into the later-life effects of these diets on gut microbiota in the offspring are limited. Our objective was to explore the effects of maternal and post-weaning diet interaction on offspring's gut microbiota and glucose metabolism in later life. The male offspring of dams fed on either a high-fat (HF) diet or control (C) diet and then weaned to either a HF or C diet, generating four groups: C-C, HF-C, C-HF and HF-HF (n=8in each group). The C-C offspring had lower body weight than C-HF group at 16weeks of age (P<0.01) and both C-HF and HF-HF offspring had higher body weight than C-C group at 24 and 32weeks of age (P<0.001 respectively). The blood glucose (BG) levels of the male offspring from the C and HF dams weaned HF diet were significantly higher at 30min, 60min and 120min (P<0.001) after intraperitoneal glucose administration compared with those of the C-C group. The C-HF group had higher BG at 30min than HF-HF group (P<0.01). Furthermore, area under the curve (AUC) in C-HF and HF-HF groups was also significantly larger than C-C group (P<0.001). Fasting BG and homoeostasis model assessment of insulin resistance (HOMA-IR) of the offspring were significantly higher in C-HF and HF-HF groups than C-C group at 32weeks of age (P<0.05). Operational taxonomic unit (OTU), Chao and Shannon indexes showed a significantly lower diversity in C-HF offspring compared with HF-C and C-C groups (P<0.05). The dominant phyla of all the groups were Bacteroidetes, Firmicutes and Proteobacteria, which also showed significantly different percentages in the group (P<0.05). Furthermore, it is indicated that Lactobacillus and Bacteroides were significantly associated with glucose response to a glucose load (P<0.05). In conclusion, maternal and post-weaning diet interaction predisposes the offspring to aberrant glucose metabolism and alterations of gut microbiota in later life. Our study is novel in focusing on the effects of maternal and post-weaning diet interaction on offspring gut microbiota and glucose metabolism in later life.

Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain.

The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. Because perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could be a contributing factor in significant and long-term consequences for the offspring. Therefore, to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain, we used genomic, proteomic and metabolomic technologies to examine outcomes in our mouse model of early prenatal stress. Multivariate modeling identified broad proteomic changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus, the prominent taxa in the maternal vagina. Loss of maternal vaginal Lactobacillus resulted in decreased transmission of this bacterium to offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Taken together, these results identify the vaginal microbiota as a novel factor by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.

Maternal obesity alters gut microbial ecology in offspring of NOD mice

BackgroundGut microbiota (GM) are increasingly recognized as a significant factor in the pathogenesis of T1D. High Bacteroidetes/Firmicutes (B/F) is associated with the development of T1D. Previously we reported that maternal obesity (MO) increases the incidence of T1D in the offspring of nonobese diabetic (NOD) mice, and the current study investigated the possible link of GM to the exaggerated insulitis in offspring due to MO. Methods: 4‐wk‐old female NOD mice were fed either a control or a high fat diet for 8 weeks before mating. Mice were maintained in their respective diets during pregnancy and lactation. All offspring were fed the control diet to 16‐wk‐old.ResultsPyrosequencing examination revealed that GM of offspring born to obese mothers was distinct from those of control mothers. At phylum level, MO increased Bacteroidetes, Defferibacteres and Proteobacteria, while decreased Firmicutes in offspring GM, resulting in increased B/F ratio in GM of obese offspring. Family level analysis indicated that GM of offspring from obese mothers had increased levels of Deferribacteraceae, Bacteroidaceae, Desulfovibrionaceae, Helicobacteraceaev, and Porphyromonadaceae. Reciprocally, the abundance of Rikenellaceae and Lachnospiraceae‐Ruminococcaceae were decreased in offspring from obese mothers. The analysis at the genus level revealed that Bacteriodes, Barnesiella, Desulfovibrio and Mucispirillum were more abundance, while Alistipes, Clostridium XIVa, Dorea and Osillibacter were less abundance in offspring of obese mothers.ConclusionMO resulted in a dysbiosis in offspring, suggesting a GM‐mediated mechanism on diabetogenesis by MO (NIH R15HD073864).

Lessons from mother: Long-term impact of antibodies in breast milk on the gut microbiota and intestinal immune system of breastfed offspring

From birth to adulthood, the gut microbiota matures from a simple community dominated by a few major bacterial groups into a highly diverse ecosystem that provides both benefits and challenges to the host. Currently there is great interest in identifying environmental and host factors that shape the development of our gut microbiota. Breast milk is a rich source of maternal antibodies, which provide the first source of adaptive immunity in the newborn's intestinal tract. In this addendum, we summarize our recent data demonstrating that maternal antibodies in breast milk promote long-term intestinal homeostasis in suckling mice by regulating the gut microbiota and host gene expression. We also discuss important unanswered questions, future directions for research in this field, and implications for human health and disease.

53. Maternal obesity is associated with alternations in the gut microbiome in toddlers

Background: Alterations in bacteria that naturally reside in the intestines may contribute to obesity. Because the infant microbiota are largely derived from the mother, differences in the maternal microbiota may link maternal and child obesity. Methods: This study included 77 mother–child pairs, with children assessed at ∼2 years of age. Women completed measures of maternal health, child diet and collected stool samples from their children which were analyzed by deep sequencing. Shannon Diversity Index (SDI) was used to measure alpha-diversity and the adonis statistic was used to measure differences in distance matrices between variables. Results: Children born to obese mothers had a significantly higher SDI ( p p Faecalibacterium , Oscillibacter , and Roseburia in the child. These effects were not attributable do differences in child body composition. Obese and non-obese mothers were demographically similar and showed no significant differences in child feeding behavior. Conclusions: Maternal obesity may predict differences in the gut microbiota of offspring. In particular, we observed greater Faecalibacterium and Oscillibacter in toddlers, microbial populations that have previously been associated with obesity. This may be a mechanism by which maternal obesity confers risk of obesity in offspring.

Maternal high-protein or high-prebiotic-fiber diets affect maternal milk composition and gut microbiota in rat dams and their offspring.

Maternal gut microbiota and milk composition could modify offspring microbiota and therefore disease susceptibility. The effect of maternal high-protein (HP) or prebiotic diets on maternal milk composition and gut microbiota in rat dams and offspring was examined. Wistar rat dams were fed a control, HP (40% wt/wt), or high-prebiotic-fiber (21.6% wt/wt) (HF) diet throughout pregnancy and lactation. Pups were challenged with a high-fat/sucrose diet from 14.5 to 22.5 weeks of age. Dam milk was analyzed for fat, protein, and oligosaccharides (OS). Fecal microbiota was analyzed in dams at parturition and 2 weeks post-partum and in offspring at 5 and 22 weeks along with cecal digesta at termination. Maternal milk differed only in OS content, each diet group being distinguishable. HF1 and HP1 offspring had decreased plasma lipopolysaccharide compared with C1. Offspring sex, maternal diet, and time (5 weeks vs. 22 weeks of age) affected the microbial groups examined. Bifidobacteria was higher in HF dams and offspring. Increasing protein or fiber content in maternal diet during pregnancy and lactation modifies milk OS content and gut microbiota of dams which may influence establishment of gut microbiota in offspring.

The Impact of Cesarean Section on Offspring Overweight and Obesity

Concerns have arisen regarding the long-term impacts of cesarean section (CS) on the health of offspring. One mechanism linking CS with later diseases is the hygiene hypothesis, based on the concept of different bacteria present in the newborns depending on mode of delivery. This early-life difference in bacteria acquisition could have lasting effects on offspring gut microbiota composition and related disorders. This review and meta-analysis were performed to determine whether an association exists between CS and overweight/obesity in offspring and to evaluate the strength of the possible association. Relevant articles and abstracts were obtained from searches of PubMed, EMBASE, and Web of Science databases through June 2012. Studies were cohort or case-control investigations that examined the association of CS compared with vaginal delivery with overweight/obesity in childhood (3–8 years), adolescence (9–18 years), or adulthood (>19 years). Statistical heterogeneity across estimates was assessed by I2 statistics; values of 25%, 50%, and 75% indicated low, medium, and high heterogeneity, respectively. The primary analysis was to estimate the overall pooled OR for offspring delivered by CS versus vaginal delivery and specific pooled ORs for children, adolescents, and adults. Two-sided P < 0.05 indicated statistical significance. Eight of an initial 2454 studies met the inclusion criteria along with 1 unpublished study, for a total of 7 cohort and 2 case-control studies. Overall, 10 childhood, 2 adolescence, and 3 adulthood estimates were included in the meta-analysis. The pooled OR of overweight/obesity for offspring delivered by CS compared with those born vaginally was 1.33 (95% CI, 1.19–1.48), with moderate to high heterogeneity (I2 = 63%) across the 15 estimates. Pooled ORs of overweight and obesity were 1.22 (95% CI, 0.99–1.50; I2 = 64%) and 1.37 (95% CI, 1.21–2.56; I2 = 45%; P for interaction = 0.33), respectively. The pooled OR for childhood overweight/obesity was 1.32 (95% CI, 1.15–1.51; I2 = 66%) across the 10 estimates. The pooled OR of overweight was 1.22 (95% CI, 0.99–1.50; I2 = 64%), and that for obesity was 1.40 (95% CI, 1.17–1.67; I2 = 50%; P for interaction = 0.31). The pooled ORs for adolescence and adult obesity were 1.24 (95% CI, 1.00–1.54; I2 = 0%) and 1.50 (95% CI, 1.02–2.20; I2 = 74%), respectively. The pooled ORs for male and female offspring did not differ significantly. Compared with vaginal delivery, CS was associated with a 33% increased risk of later overweight and obesity in offspring. The underlying mechanism of this association is unclear, although the hygiene hypothesis is one possible mechanism. Future studies should examine the causal relationship between CS and obesity, particularly in adolescents and adults, and whether these associations have a common pathway with other health outcomes in offspring born by CS.