[Relationship between gut microbiome and neurodevelopment in early life].

OBJECTIVE: To compare the differences in gut microbiome composition between children with good neurodevelopment and those with delayed neurodevelopment, and to analyze the relationship between gut microbiome and the neurodevelopment status of infants in early life. METHODS: The mothers were included at the Second West China Hospital from November 2020 to April 2021. Their infant stools were collected on day 0 and day 90 after birth, and the follow-up questionnaires at the corresponding time points were completed. Additionally, the Ages and Stages Questionnaires-Third Edition(ASQ-3) were completed by mothers at 12 months of age. The structure and diversity of gut microbiota were examined by 16S rRNA sequencing, and the relationship between gut microbiome and ASQ-3 questionnaire scores in early life was analyzed. RESULTS: According to the ASQ-3 scores, mothers and infants into neurodevelopment good group(G group, n=18) and neurodevelopmental delay group(D group, n=10). Compared with the D group, the relative abundance of the Firmicutes was significantly higher in the G group at day 0(P<0.05), while the level of the Proteobacteria was lower(P<0.05). At day 90 after birth, the relative abundance of the Actinobacteria, Bifidobacteriaceae and Enterococcaceae was significantly higher in the G group(P<0.05). In addition, alpha diversity was not statistically different between the two groups. Spearman's correlation analysis showed that Clostridiaceae of the postnatal day 0 infants was positively correlated with the communication domain score, but negatively associated with gross motor domain score in children at 12 months of age, whereas the relative abundance of Proteobacteria and Enterobacteriaceae of children at postnatal day 90 was negatively associated with communication development, while the relative abundance of Erysipelatoclostridiaceae showed a negative correlation with gross motor domain scores. CONCLUSION: The structure of the gut microbiome in early life between neurodevelopment good and delayed infants, and were associated with the development of communication and gross motor domain in infants at 12 months of age, suggesting that gut microbiome in early life may be related to the level of neurodevelopment in infants.

Breastfeeding might partially contribute to gut microbiota construction and stabilization of propionate metabolism in cesarean-section infants.

PURPOSE: This study was aimed to determine how delivery mode and feeding pattern influence the infant's gut microbiota construction and the variation of fecal microbial metabolites from a birth cohort. METHODS: Fecal samples collected from 61 full-term born Chinese infants at four time points: day 0, day 7, month 1, and month 3. Based on delivery mode (vaginal delivery [V] or cesarean section [C]) and feeding pattern (breastfeeding [B] or mixed feeding [M]), infants were divided into four groups, namely VB, CB, VM, and CM groups. The gut microbiota composition and bacterial diversity were assessed using 16S rRNA sequencing. Short-chain fatty acid (SCFA) concentrations were determined via gas chromatography-mass spectrometry (GC-MS). RESULTS: The CM group had a significantly higher relative abundance of Firmicutes (day 0 and month 1), Enterococcaceae (month 3), and Enterococcus (month 3) than the VB group and a significantly higher abundance of Firmicutes (month 1) and Blautia (month 3) than the CB group. The VB and CB groups exhibited a stable SCFA variation and a significantly lower level of propionate compared with the VM and CM groups. All groups showed an intense transition of enterotypes within 1 month and became stable at 3 months. The correlation between SCFA and enterotypes showed a significant positive correlation between Bifidobacteriaceae and acetate in the CB group (day 7 and month 3) and a significant positive correlation between Clostridiaceae and butyrate in the CB and VB groups (day 7 and month 3), respectively. CONCLUSION: These results indicated that C-section was associated with higher abundance of the phylum Firmicutes and family Enterococcaceae, and intense fluctuation of SCFA, at least propionate. And breastfeeding might partially contribute to gut microbiota construction and stabilization propionate metabolism in cesarean-section infants.

Bifidobacterium infantis and 2'-fucosyllactose supplementation in early life may have potential long-term benefits on gut microbiota, intestinal development, and immune function in mice.

The health benefits of nutritional interventions targeting the gut microbiota in early life are transient, such as probiotics, prebiotics, and synbiotics. This study sought to determine whether supplementation with Bifidobacterium infantis 79 (B79), 2'-fucosyllactose (2'-FL), or both (B79+2'FL) would lead to persistent health benefits in neonatal BALB/c mice. We found that at postnatal day (PND) 21, Ki67 and MUC2 expression increased, while total serum IgE content decreased in the B79, 2'-FL, and B79+2'-FL groups. The gut microbiota structure and composition altered as well. The levels of propionic acid, sIgA, and IL-10 increased in the 2'-FL group. Moreover, butyric acid content increased, while IL-6, IL-12p40, and tumor necrosis factor-α decreased in the B79+2'-FL group. At PND 56, Ki67 and MUC2 expression increased, whereas the gut microbiota remained altered in all 3 groups. The serum total IgG level increased only in the B79+2'-FL group. In conclusion, our study suggests that early-life supplementation with B79, 2'-FL, or their combination persistently alters the gut microbiome and promotes intestinal development; the immunomodulatory capacity of B79 and 2'-FL occurs during weaning, and their combination may persist into adulthood.

Antibiotic cocktail-induced gut microbiota depletion in different stages could cause host cognitive impairment and emotional disorders in adulthood in different manners.

Gut microbiota depletion may result in cognitive impairment and emotional disorder. This study aimed to determine the possible association between host gut microbiota, cognitive function, and emotion in various life stages and its related underlying mechanisms. Seventy-five neonatal mice were randomly divided into five groups (n = 15 per group). Mice in the vehicle group were administered distilled water from birth to death, and those in the last four groups were administered antibiotic cocktail from birth to death, from birth to postnatal day (PND) 21 (infancy), from PND 21 to 56 (adolescence), and from PND 57 to 84 (adulthood), respectively. Antibiotic exposure consistently altered the gut microbiota composition and decreased the diversity of gut microbiota. Proteobacteria were the predominant bacteria instead of Firmicutes and Bacteroidetes after antibiotic exposure in different life stages. Long-term and infant gut microbiota depletion resulted in anxiety- and depression-like behaviors, memory impairments, and increased expression of γ-aminobutyric acid type A receptor α1 of adult mice. Long-term antibiotic exposure also significantly decreased serum interleukin (IL)-1ß, IL-10, and corticosterone of adult mice. Gut microbiota depletion in adolescence resulted in anxiety-like behaviors, short-term memory decline, decreased serum interferon-γ (IFN-γ), mRNA expression of 5-hydroxytryptamine receptor 1A, and neuropeptide Y receptor Y2 in the prefrontal cortex of adult mice. Antibiotic exposure in adulthood damaged short-term memory and decreased serum IL-10, IFN-γ, and increased γ-aminobutyric acid type B receptor 1 mRNA expression of adult mice. These results suggest that antibiotic-induced gut microbiota depletion in the long term and infancy resulted in the most severe cognitive and emotional disorders followed by depletion in adolescence and adulthood. These results also suggest that gut microbes could influence host cognitive function and emotion in a life stage-dependent manner by affecting the function of the immune system, hypothalamic-pituitary-adrenal axis, and the expression of neurochemicals in the brain.

Heat-inactivated Lacticaseibacillus paracasei N1115 alleviates the damage due to brain function caused by long-term antibiotic cocktail exposure in mice.

Critical development period of intestinal microbiota occurs concurrently with brain development, and their interaction is influenced by the microbiota-gut-brain axis. This study examined how antibiotics exposure affected gut microbiota and brain development and analyzed the possible benefits of heat-inactivated Lacticaseibacillus paracasei N1115 (N1115). Thirty neonatal male mice were randomly divided into three groups and treated with sterilized water (control), an antibiotic cocktail (Abx), or antibiotics plus heat-inactivated N1115 (Abx + N1115) for 84 days. We found that while the mRNA levels of GABAAα1, GABAb1, and glucocorticoid receptor (GR) in the hippocampus and brain-derived neurotrophic factor (BDNF), GABAAα1, GABAb1, and nerve growth factor (NGF) in the prefrontal cortex were higher, the mRNA levels of 5-HT1A were lower in the Abx group. The Abx + N1115 group had lower mRNA levels of GABAAα1, GABAb1, and GR in the hippocampus and BDNF, GABAb1, and NGF in the prefrontal cortex than the Abx group. The latency period was longer in the Morris water maze test while longer rest time was seen in tail suspension test in the Abx group than the control and Abx + N1115 groups. In the open field test, the moving time and distance of the Abx group were reduced. Further, the alpha-diversity indexes of the Abx and Abx + N1115 groups were significantly lower than the control. Further, long-term exposure to antibiotics disrupted the intestinal microbiota as evidenced by decreased Bacteroides, Firmicutes, and Lactobacillus, and increased Proteobacteria and Citrobacter. However, N1115 significantly decreased the abundance of Citrobacter when compared with those in the Abx group. These results indicate that antibiotics can substantially damage the intestinal microbiota and cognitive function, causing anxiety and depression, which can be alleviated by heat-inactivated N1115 via modulation of the microbiota-gut-brain axis.

[Bifidobacterium bifidum TMC3115 Promotes Early Life Intestinal Microbiota Building to Alleviate Symptoms of Inflammatory Bowel Disease].

Objective: To investigate the effects of using Bifidobacterium bifidum TMC3115 in early life on intestinal microbiota and immune functions and the long-term impact on inflammatory bowel disease. Methods: Fourteen pregnant BALB/c mice were purchased and 84 newborn BALB/c mice were subsequently obtained. Then, the newborn mice were randomly assigned to a normal saline (NS) group and a TMC3115 group, given via oral gavage normal saline and TMC3115, respectively, at a daily volume of 0.2 mL for each mouse. About 42 mice were assigned to each group. The gavage was stopped after 3 weeks. At this point, half of the mice in each group were sacrificed, and then the remaining mice in each group were randomly divided into NS-water group, NS-DSS group, TMC3115-water group, and TMC3115-DSS group, with about 10 mice in each group. The mice were given regular feed until the end of week 6 when they were given 3% dextran sulphate sodium (DSS) ad libitum for 4 days to establish the enteritis model, while the non-modeling groups were given pure water ad libitum. The experiment ended after 6 weeks and 4 days. The weekly body mass changes of the mice were documented. The intestinal tissue at the end of the experiment and the fecal samples, spleen and serum of the mice at 3 weeks and at the end of the experiment were collected to determine the pathology scores of colonic inflammation, the composition of fecal gut microbiota, spleen organ index and the mass concentration of serum cytokines. Results: 1) At the end of the experiment, the inflammatory pathology score was significantly lower in the TMC3115-DSS group compared with that of the Saline-DSS group ( P<0.05), with less disruption of colonic crypt structures and other structures, less inflammatory infiltration, and more intact epithelial structures. 2) At 3 weeks, in comparison with those of the NS group, the relative abundance of Bifidobacteriumwas significantly higher in the feces of the TMC3115 ( P<0.05), the relative abundance of both Enterococcusand Staphylococcuswas lower ( P<0.05), the splenic organ index was significantly higher ( P<0.05), and interleukin (IL)-10 was significantly decreased ( P<0.05), while there was no significant change in IL-6 or TNF-α ( P>0.05). At the end of the experiment, in comparison with those of the NS-DSS group that undergone DSS induction, the TMC3115-DSS group had reduced relative abundance of Staphylococcus, Staphylococcus tumefaciens and Escherichia/ Shigellain the feces ( P<0.05), while the splenic organ index was significantly higher ( P<0.05), and there were no significant changes in IL-6 or TNF-α ( P>0.05). Conclusion: The use of TMC3115 in early life promotes the construction of gut microbiota in neonatal mice, thereby producing a long-term effect that alleviates colitis in mice, but the mechanisms involved are still not fully understood.

Gut Microbiota Perturbation in Early Life Could Influence Pediatric Blood Pressure Regulation in a Sex-Dependent Manner in Juvenile Rats.

The present study aimed to investigate whether gut dysbiosis induced by ceftriaxone in early life could influence pediatric blood pressure regulation in childhood with or without exposure to a high-fat diet (HFD). Sixty-three newborn pups of Sprague-Dawley rats were administered ceftriaxone sodium or saline solution until weaning at 3 weeks, and the rats were fed a HFD or regular diet from 3 to 6 weeks. Tail-cuff blood pressure, the expression levels of genes of the renin-angiotensin system (RAS), the concentrations of IL-1ß, IL-6, and TNF-α in the colon and prefrontal cortex, and the composition of fecal microbiota were analyzed. Ceftriaxone treatment significantly increased the diastolic blood pressure of male rats at 3 weeks. At 6 weeks, systolic blood pressure (SBP) was significantly increased only in ceftriaxone treated male rats fed with HFD. The RAS showed increased activation in the kidney, heart, hypothalamus, and thoracic and abdominal aorta of male rats, but only in the kidney, heart, and hypothalamus of female rats. HFD-fed female rats showed a decreased level of IL-6 in the colon. α diversity of gut microbiota decreased and the Firmicutes to Bacteroidetes ratio increased in both male and female rats at 3 weeks; however, these parameters recovered to various degrees in female rats at 6 weeks. These results revealed that early-life gut dysbiosis induced by antibiotics combined with a HFD in childhood could be involved in pediatric blood pressure regulation and an increase in SBP in juvenile rats, and these effects occurred in a sex-dependent manner.

A New Dietary Fiber Can Enhance Satiety and Reduce Postprandial Blood Glucose in Healthy Adults: A Randomized Cross-Over Trial.

BACKGROUND: Dietary fiber plays a potential role in regulating energy intake and stabilizing postprandial blood glucose levels. Soluble dietary fiber has become an important entry point for nutritional research on the regulation of satiety. METHODS: this was a double-blind, randomized cross-over trial enrolling 12 healthy subjects to compare the effects of RPG (R+PolyGly) dietary fiber products (bread, powder, and capsule) and pectin administered with a standard meal on satiety, blood glucose, and serum insulin level. RESULTS: Adding 3.8% RPG dietary fiber to bread significantly increased the volume, water content, hardness, and chewiness of bread compared to 3.8% pectin bread and white bread and significantly improved the sensory quality of bread. RPG bread had better appetite suppression effects at some time points than the other two groups and the best postprandial blood glucose lowering effects among the three groups. Administration of RPG capsules containing 5.6 g of RPG dietary fiber with meals improved satiety and reduced hunger compared to 6 g of RPG powder and 6 g of pectin, which had the greatest effect on suppressing appetite and reducing prospective food consumption. The peak level of serum glucagon-like peptide-1 (GLP-1) in the RPG capsule group (578.17 ± 19.93 pg/mL) was significantly higher than that in other groups at 0 min and 30 min after eating. RPG powder had the best effect in reducing postprandial blood glucose and increasing serum insulin levels; the total area under the curve (AUC) of serum insulin with RPG powder was higher than other groups (5960 ± 252.46 µU min/mL). CONCLUSION: RPG dietary fiber products can improve the sensory properties of food, reduce postprandial blood glucose, and enhance satiety, especially in capsule and powder forms. Further research on the physiological effects of RPG dietary fiber is required to facilitate its use as a functional ingredient in food products.

Early life administration of Bifidobacterium bifidum BD-1 alleviates long-term colitis by remodeling the gut microbiota and promoting intestinal barrier development.

Inflammatory bowel disease (IBD) is a chronic intestinal disease characterized by microbiota disturbance and intestinal mucosal damage. The current study aimed to investigate the preventive effects of Bifidobacterium bifidum BD-1 (BD-1) against long-term IBD and possible mechanism by which it alters the gut microbiota, immune response, and mucosal barrier. Our study found that early treatment of BD-1 + Ceftri (ceftriaxone followed by BD-1) and BD-1 confers a certain protective effect against the occurrence of long-term Dextran sulfate sodium-induced colitis, which manifests as a decrease in inflammation scores and MPO activity levels, as well as a relatively intact intestinal epithelial structure. Moreover, compared to BD-1, Ceftri, and NS, early treatment with BD-1 + Ceftri promoted greater expression levels of mucosal barrier-related proteins [KI67, MUC2, ZO-1, secretory immunoglobulin A (slgA), Clauding-1, and Occludin], better local immune responses activation, and moderately better modulation of systemic immune responses during long-term colitis. This may be due to the fact that BD-1 + Ceftri can deliberately prolong the colonization time of some beneficial microbiota (e.g., Bifidobacterium) and reduce the relative abundance of inflammation-related microbiota (e.g., Escherichia/Shigella and Ruminococcus). Interestingly, we found that the changes in the gut barrier and immunity were already present immediately after early intervention with BD-1 + Ceftri, implying that early effects can persist with appropriate intervention. Furthermore, intervention with BD-1 alone in early life confers an anti-inflammatory effect to a certain degree in the long-term, which may be due to the interaction between BD-1 and the host's native gut microbiota affecting intestinal metabolites. In conclusion, BD-1 was not as effective as BD-1 + Ceftri in early life, perhaps due to its failure to fully play the role of the strain itself under the influence of the host's complex microbiota. Therefore, further research is needed to explore specific mechanisms for single strain and native microbiota or the combination between probiotics and antibiotics.

Potential Health-Promoting Effects of Two Candidate Probiotics Isolated from Infant Feces Using an Immune-Based Screening Strategy.

Commensal microorganisms in the human gut are a good source of candidate probiotics, particularly those with immunomodulatory effects that may improve health outcomes by regulating interactions between the gut microbiome and distal organs. Previously, we used an immune-based screening strategy to select two potential probiotic strains from infant feces in China, Bifidobacterium breve 207-1 (207-1) and Lacticaseibacillus paracasei 207-27 (207-27). In this study, the in vitro immunological effects and potential in vivo general health benefits of these two strains were evaluated using Lacticaseibacillus rhamnosus GG (LGG) as the control. The results showed that 207-1 and 207-27 significantly and differentially modulated the cytokine profiles of primary splenic cells, while did not induce abnormal systemic immune responses in healthy mice. They also modulated the gut microbiota composition in a strain-dependent manner, thus decreasing Gram-negative bacteria and increasing health-promoting taxa and short-chain fatty acid levels, particularly butyric acid. Conclusively, 207-1 and 207-27 shaped a robust gut environment in healthy mice in a strain-specific manner. Their potential immunomodulatory effects and other elite properties will be further explored using animal models of disease and subsequent clinical trials. This immune-based screening strategy is promising in efficiently and economically identifying elite candidate probiotics.