Network analysis of temporal functionalities of the gut induced by perturbations in new-born piglets

Background

Evidence is accumulating that perturbation of early life microbial colonization of the gut induces long-lasting adverse health effects in individuals. Understanding the mechanisms behind these effects will facilitate modulation of intestinal health. The objective of this study was to identify biological processes involved in these long lasting effects and the (molecular) factors that regulate them. We used an antibiotic and the same antibiotic in combination with stress on piglets as an early life perturbation. Then we used host gene expression data from the gut (jejunum) tissue and community-scale analysis of gut microbiota from the same location of the gut, at three different time-points to gauge the reaction to the perturbation. We analysed the data by a new combination of existing tools. First, we analysed the data in two dimensions, treatment and time, with quadratic regression analysis. Then we applied network-based data integration approaches to find correlations between host gene expression and the resident microbial species.

Results

The use of a new combination of data analysis tools allowed us to identify significant long-lasting differences in jejunal gene expression patterns resulting from the early life perturbations. In addition, we were able to identify potential key gene regulators (hubs) for these long-lasting effects. Furthermore, data integration also showed that there are a handful of bacterial groups that were associated with temporal changes in gene expression.

Conclusion

The applied systems-biology approach allowed us to take the first steps in unravelling biological processes involved in long lasting effects in the gut due to early life perturbations. The observed data are consistent with the hypothesis that these long lasting effects are due to differences in the programming of the gut immune system as induced by the temporary early life changes in the composition and/or diversity of microbiota in the gut.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1733-8) contains supplementary material, which is available to authorized users.     

Restricting microbial exposure in early life negates the immune benefits associated with gut colonization in environments of high microbial diversity

Background

Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity.

Methodology/Principal Findings

Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolator-reared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals.

Conclusions/Significance

Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis.     

"肠道微生物-肠道-脑轴"机制--肠道微生物干预神经退行性病变研究进展

肠道微生物是人体中最为庞大和复杂的微生物群落,其对机体的健康,尤其是中枢神经退行性病变具有重要调节作用。其中,"肠道微生物-肠道-脑轴"机制是肠道微生物干预中枢神经退行性病变的重要途径。该机制主要通过以下三种方式来调节大脑功能:一是肠道微生物直接产生神经递质通过肠神经细胞上行至中枢神经系统;二是肠道微生物代谢产物刺激肠内分泌细胞产生神经肽类和胃肠激素类物质,影响大脑功能;三是肠道微生物或其代谢产物直接刺激肠道免疫系统,产生干扰素类物质干扰大脑免疫反应。本文对"肠道微生物-肠道-脑轴"机制的概念及研究进展进行了详细的介绍,同时总结了有关肠道微生物与阿尔兹海默症、帕金森症和多发性硬化症等神经退行性疾病相互作用的相关文献。依据"肠道微生物-肠道-脑轴"机制,利用肠道微生物预防和治疗神经退行性病变,或将成为解决中枢神经系统疾病的新措施。     

Transcriptional Modulation of Intestinal Innate Defense/Inflammation Genes by Preterm Infant Microbiota in a Humanized Gnotobiotic Mouse Model

Background and Aims

It is known that postnatal functional maturation of the small intestine is facilitated by microbial colonization of the gut. Preterm infants exhibit defects in gut maturation, weak innate immunity against intestinal infection and increased susceptibility to inflammatory disorders, all of which may be related to the inappropriate microbial colonization of their immature intestines. The earliest microbes to colonize the preterm infant gut encounter a naïve, immature intestine. Thus this earliest microbiota potentially has the greatest opportunity to fundamentally influence intestinal development and immune function. The aim of this study was to characterize the effect of early microbial colonization on global gene expression in the distal small intestine during postnatal gut development.

Methods

Gnotobiotic mouse models with experimental colonization by early (prior to two weeks of life) intestinal microbiota from preterm human infants were utilized. Microarray analysis was used to assess global gene expression in the intestinal epithelium.

Results and Conclusion

Multiple intestinal genes involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication, and immune function are developmental- and intestinal microbiota- regulated. Using a humanized gnotobiotic mouse model, we demonstrate that certain early preterm infant microbiota from prior to 2 weeks of life specifically induce increased NF-κB activation and a phenotype of increased inflammation whereas other preterm microbiota specifically induce decreased NF-κB activation. These fundamental differences correlate with altered clinical outcomes and suggest the existence of optimal early microbial communities to improve health outcomes.     

The gut bacterial community affects immunity but not metabolism in a specialist herbivorous butterfly

1. Plant tissues often lack essential nutritive elements and may contain a range of secondary toxic compounds. As nutritional imbalance in food intake may affect the performances of herbivores, the latter have evolved a variety of physiological mechanisms to cope with the challenges of digesting their plant‐based diet. Some of these strategies involve living in association with symbiotic microbes that promote the digestion and detoxification of plant compounds or supply their host with essential nutrients missing from the plant diet. In Lepidoptera, a growing body of evidence has, however, recently challenged the idea that herbivores are nutritionally dependent on their gut microbial community. It is suggested that many of the herbivorous Lepidopteran species may not host a resident microbial community, but rather a transient one, acquired from their environment and diet. Studies directly testing these hypotheses are however scarce and come from an even more limited number of species.
2. By coupling comparative metabarcoding, immune gene expression, and metabolomics analyses with experimental manipulation of the gut microbial community of prediapause larvae of the Glanville fritillary butterfly (Melitaea cinxia, L.), we tested whether the gut microbial community supports early larval growth and survival, or modulates metabolism or immunity during early stages of development.
3. We successfully altered this microbiota through antibiotic treatments and consecutively restored it through fecal transplants from conspecifics. Our study suggests that although the microbiota is involved in the up‐regulation of an antimicrobial peptide, it did not affect the life history traits or the metabolism of early instars larvae.
4. This study confirms the poor impact of the microbiota on diverse life history traits of yet another Lepidoptera species. However, it also suggests that potential eco‐evolutionary host‐symbiont strategies that take place in the gut of herbivorous butterfly hosts might have been disregarded, particularly how the microbiota may affect the host immune system homeostasis.

     

Host‐microbe interaction in the gastrointestinal tract

The gastrointestinal tract is a highly complex organ in which multiple dynamic physiological processes are tightly coordinated while interacting with a dense and extremely diverse microbial population. From establishment in early life, through to host‐microbe symbiosis in adulthood, the gut microbiota plays a vital role in our development and health. The effect of the microbiota on gut development and physiology is highlighted by anatomical and functional changes in germ‐free mice, affecting the gut epithelium, immune system and enteric nervous system. Microbial colonisation promotes competent innate and acquired mucosal immune systems, epithelial renewal, barrier integrity, and mucosal vascularisation and innervation. Interacting or shared signalling pathways across different physiological systems of the gut could explain how all these changes are coordinated during postnatal colonisation, or after the introduction of microbiota into germ‐free models. The application of cell‐based in‐vitro experimental systems and mathematical modelling can shed light on the molecular and signalling pathways which regulate the development and maintenance of homeostasis in the gut and beyond.     

Early life microbial colonization of the gut and intestinal development differ between genetically divergent broiler lines

Background

Host genetic makeup plays a role in early gut microbial colonization and immune programming. Interactions between gut microbiota and host cells of the mucosal layer are of paramount importance for a proper development of host defence mechanisms. For different livestock species, it has already been shown that particular genotypes have increased susceptibilities towards disease causing pathogens.The objective of this study was to investigate the impact of genotypic variation on both early microbial colonization of the gut and functional development of intestinal tissue. From two genetically diverse chicken lines intestinal content samples were taken for microbiota analyses and intestinal tissue samples were extracted for gene expression analyses, both at three subsequent time-points (days 0, 4, and 16).

Results

The microbiota composition was significantly different between lines on each time point. In contrast, no significant differences were observed regarding changes in the microbiota diversity between the two lines throughout this study. We also observed trends in the microbiota data at genus level when comparing lines X and Y. We observed that approximately 2000 genes showed different temporal gene expression patterns when comparing line X to line Y. Immunological related differences seem to be only present at day 0, because at day 4 and 16 similar gene expression is observed for these two lines. However, for genes involved in cell cycle related processes the data show higher expression over the whole course of time in line Y in comparison to line X.

Conclusions

These data suggest the genetic background influences colonization of gut microbiota after hatch in combination with the functional development of intestinal mucosal tissue, including the programming of the immune system. The results indicate that genetically different chicken lines have different coping mechanisms in early life to cope with the outside world.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1646-6) contains supplementary material, which is available to authorized users.     

Importance of microbial colonization of the gut in early life to the development of immunity

The mammalian gastrointestinal tract harbors a complex microbiota consisting of between 500 and 1000 distinct microbial species. Comparative studies based on the germ-free gut have provided clear evidence that the gut microbiota is instrumental in promoting the development of both the gut and systemic immune systems. Early microbial exposure of the gut is thought to dramatically reduce the incidence of inflammatory, autoimmune and atopic diseases further fuelling the scientific viewpoint, that microbial colonization plays an important role in regulating and fine-tuning the immune system throughout life. Recent molecular diversity studies have provided additional evidence that the human gut microbiota is compositionally altered in individuals suffering from inflammatory bowel disorders, suggesting that specific bacterial species are important to maintaining immunological balance and health. New and exciting insights into how gut bacteria modulate the mammalian immune system are emerging. However, much remains to be elucidated about how commensal bacteria influence the function of cells of both the innate and adaptive immune systems in health and disease.     

Differential Effects of Antibiotic Therapy on the Structure and Function of Human Gut Microbiota

The human intestinal microbiota performs many essential functions for the host. Antimicrobial agents, such as antibiotics (AB), are also known to disturb microbial community equilibrium, thereby having an impact on human physiology. While an increasing number of studies investigate the effects of AB usage on changes in human gut microbiota biodiversity, its functional effects are still poorly understood. We performed a follow-up study to explore the effect of ABs with different modes of action on human gut microbiota composition and function. Four individuals were treated with different antibiotics and samples were taken before, during and after the AB course for all of them. Changes in the total and in the active (growing) microbiota as well as the functional changes were addressed by 16S rRNA gene and metagenomic 454-based pyrosequencing approaches. We have found that the class of antibiotic, particularly its antimicrobial effect and mode of action, played an important role in modulating the gut microbiota composition and function. Furthermore, analysis of the resistome suggested that oscillatory dynamics are not only due to antibiotic-target resistance, but also to fluctuations in the surviving bacterial community. Our results indicated that the effect of AB on the human gut microbiota relates to the interaction of several factors, principally the properties of the antimicrobial agent, and the structure, functions and resistance genes of the microbial community.     

The Enterocyte-Associated Intestinal Microbiota of Breast-Fed Infants and Adults Responds Differently to a TNF-α-Mediated Pro-Inflammatory Stimulus

Co-evolved as an integral component of our immune system, the gut microbiota provides specific immunological services at different ages, supporting the immune education during our infancy and sustaining a well-balanced immunological homeostasis during the course of our life. In order to figure out whether this involves differences in the microbial groups primarily interacting with the host immune system, we developed a non-invasive HT29 cell-based minimal model to fingerprint the enterocyte-associated microbiota fraction in infants and adults. After depicting the fecal microbial community of 12 breast-fed infants and 6 adults by 16S rDNA amplicon pools 454 pyrosequencing, their respective HT29 cell-associated gut microbiota fractions were characterized by the universal phylogenetic array platform HTF-Microbi.Array, both in the presence and absence of a tumor necrosis factor-alpha (TNF-α)-mediated pro-inflammatory stimulus. Our data revealed remarkable differences between the enterocyte-associated microbiota fractions in breast-fed infants and adults, being dominated by Bifidobacterium and Enterobacteriaceae the first and Bacteroides-Prevotella and Clostridium clusters IV and XIVa the second. While in adults TNF-α resulted in a profound impairment of the structure of the enterocyte-associated microbiota fraction, in infants it remained unaffected. Differently from the adult-type gut microbial community, the infant-type microbiota is structured to cope with inflammation, being co-evolved to prime the early immune response by means of transient inflammatory signals from gut microorganisms.     

Feeding modes shape the acquisition and structure of the initial gut microbiota in newborn lambs

Early gut microbial colonization is important for postnatal metabolic and immune development. However, little is known about the effects of different feeding modes (suckling versus bottle-feeding) or microbial sources on this process in farm animals. We found that suckled and bottle-fed newborn lambs had their own distinct gut microbiota. Results from 16S rRNA gene sequencing and qPCR showed that, compared with suckling, bottle feeding significantly increased the abundances of Escherichia/Shigella, Butyricicoccus, and Clostridium XlVa, while significantly decreased the abundance of Clostridium XI. The higher levels of Escherichia/Shigella in bottle-fed lambs suggest that artificial feeding may increase the number of potential pathogens and delay the establishment of the anaerobic environment and anaerobic microbes. Feeding modes also affected the direct transmission of bacteria from the mother and the environment to newborns. The SourceTracker analysis estimated that the early gut microbes of suckled lambs were mainly derived from the mother's teats (43%) and ambient air (28%); whereas those of bottle-fed lambs were dominated by bacteria from the mother's vagina (46%), ambient air (31%), and the sheep pen floor (12%). These findings advance our understanding of gut microbiota in early life and may help design techniques to improve gut microbiota and health.     

长链菊粉对抗生素处理后小鼠肠道菌群重建的影响

【目的】评价长链菊粉对抗生素致小鼠肠道菌群失调后肠道菌群的恢复情况。【方法】选择50只健康的10周龄BALB/c小鼠,随机分为2组,其中15只为正常对照组,余下35只饮用水中含4种抗生素连续喂养7 d,诱导小鼠肠道菌群严重失调后,再随机分为长链菊粉恢复组(饮用水中添加5%(W/W)长链菊粉)和自发恢复组(饮用水为无菌水),连续处理21 d。受试小鼠在抗生素治疗后的第7天以及恢复喂养的第7、14和21天,取结肠组织进行切片然后进行HE染色分析,无菌取粪便进行16Sr RNA测序分析,观察小鼠肠道组织及菌群恢复情况。【结果】抗生素处理7 d后,小鼠结肠组织有轻微炎症,但肠道菌群严重失调。组织学分析表明,在补充长链菊粉或自发恢复21d后,结肠炎症逐渐减轻;但相比于自发恢复,长链菊粉干预延迟了结肠组织的恢复。16S r RNA基因V3–V4区扩增子测序分析显示无论是长链菊粉补充还是自发恢复都无法在属水平上恢复肠道菌群组成。尤其是长链菊粉的补充,反而导致了某些机会致病菌的选择性扩增,并提高了与肠道菌群相关的疾病途径。【结论】抗生素诱导肠道菌群严重失调后补充长链菊粉会延迟肠道菌群的重建,可能会导致潜在的不良影响。     

Amino acid supplements and metabolic health: a potential interplay between intestinal microbiota and systems control

Dietary supplementation of essential amino acids (EAAs) has been shown to promote healthspan. EAAs regulate, in fact, glucose and lipid metabolism and energy balance, increase mitochondrial biogenesis, and maintain immune homeostasis. Basic science and epidemiological results indicate that dietary macronutrient composition affects healthspan through multiple and integrated mechanisms, and their effects are closely related to the metabolic status to which they act. In particular, EAA supplementation can trigger different and even opposite effects depending on the catabolic and anabolic states of the organisms. Among others, gut-associated microbial communities (referred to as gut microbiota) emerged as a major regulator of the host metabolism. Diet and host health influence gut microbiota, and composition of gut microbiota, in turn, controls many aspects of host health, including nutrient metabolism, resistance to infection, and immune signals. Altered communication between the innate immune system and the gut microbiota might contribute to complex diseases. Furthermore, gut microbiota and its impact to host health change largely during different life phases such as lactation, weaning, and aging. Here we will review the accumulating body of knowledge on the impact of dietary EAA supplementation on the host metabolic health and healthspan from a holistic perspective. Moreover, we will focus on the current efforts to establish causal relationships among dietary EAAs, gut microbiota, and health during human development.     

Microbial programming of health and disease starts during fetal life

The pioneer microbiota of the neonatal gut are essential for gut maturation, and metabolic and immunologic programming. Recent research has shown that early bacterial colonization may impact the occurrence of disease later in life (microbial programming). Despite early conflicting evidence, it has long been considered that the womb is a sterile environment and human microbial colonization begins at birth. In the last few years, several findings have reiterated the presence of microbes in infant first stool (meconium) and pointed to the existence of in utero microbial colonization of the infant gut. The dominant bacterial taxa detected in meconium specimens belong to the Enterobacteriaceae family (Escherichia genus) and lactic acid bacteria (notably members of the genera Leuconostoc, Enterococcus, and Lactococcus). Maternal atopy promotes dominance of Enterobacteriaceae in newborn meconium, which in turn may lead to respiratory problems in the infant. This microbial interaction with the host immune system may in fact, originate during fetal life. Our review evaluates the evidence for an intrauterine origin of meconium microbiota, their composition and influences, and potential clinical implications on infant health. Birth Defects Research (Part C) 105:265–277, 2015. © 2015 Wiley Periodicals, Inc.     

Modelling the effect of birth and feeding modes on the development of human gut microbiota

The human gut microbiota is transmitted from mother to infant through vaginal birth and breastfeeding. Bifidobacterium, a genus that dominates the infants’ gut, is adapted to breast milk in its ability to metabolize human milk oligosaccharides; it is regarded as a mutualist owing to its involvement in the development of the immune system. The composition of microbiota, including the abundance of Bifidobacteria, is highly variable between individuals and some microbial profiles are associated with diseases. However, whether and how birth and feeding practices contribute to such variation remains unclear. To understand how early events affect the establishment of microbiota, we develop a mathematical model of two types of Bifidobacteria and a generic compartment of commensal competitors. We show how early events affect competition between mutualists and commensals and microbe-host-immune interactions to cause long-term alterations in gut microbial profiles. Bifidobacteria associated with breast milk can trigger immune responses with lasting effects on the microbial community structure. Our model shows that, in response to a change in birth environment, competition alone can produce two distinct microbial profiles post-weaning. Adding immune regulation to our competition model allows for variations in microbial profiles in response to different feeding practices. This analysis highlights the importance of microbe–microbe and microbe–host interactions in shaping the gut populations following different birth and feeding modes.     

The influence of the young microbiome on inflammatory diseases—Lessons from animal studies

Chronic inflammatory diseases are on the rise in the Westernized world. This rise has been correlated to a range of environmental factors, such as birth mode, rural versus urban living conditions, and use of antibiotics. Such environmental factors also influence early life gut microbiota (GM) colonization and maturation—and there is growing evidence that the negative effects of these factors on human health are mediated via GM alterations. Colonization of the gut initiates priming of the immune system from birth, driving tolerance towards non‐harmful microorganisms and dietary antigens and proper reactions towards invading pathogens. This early colonization is crucial for the establishment of a healthy GM, and throughout life the balanced interaction of GM and immune system is a key element in maintaining health. An immune system out of balance increases the risk for later life inflammatory diseases. Animal models are indispensable in the studies of GM influence on disease mechanisms and progression, and focus points include studies of GM modification during pregnancy and perinatal life. Here, we present an overview of animal studies which have contributed to our understanding of GM functions in early life and how alterations affect risk and expression of certain inflammatory diseases with juvenile onset, including interventions, such as birth mode, antibiotics, and probiotics. Birth Defects Research (Part C) 105:278–295, 2015. © 2015 Wiley Periodicals, Inc.     

A metagenomic study of the gut microbiome in PTB’S disease

BackgroundThere is an abundant link between the gut microbiota and human health and it plays a critical role in the clinic. It is recognized that microbial dysregulation contributes to the pathogenesis of tuberculosis (TB) but the underlying mechanisms remain unclear. In this study, we investigated the association of gut microbiome composition with TB as well as its possible roles in the development of this disease.MethodsFecal samples were collected from 10 TB patients and 20 healthy control samples. DNA extracted from fecal samples was subjected to 16S rDNA gene sequencing analysis on the Illumina MiSeq platform.ResultsCompared with healthy control samples, the gut microbiome of patients with TB was characterized by the decreased Alpha diversity. Perhaps, the decrease of microbial diversity which results in microbial dysregulation is the reason for clinical patients with more symptoms. The PTB group showed the most unique microbiota by higher abundance of Bifidobacteriaceae, Bifidobacteriales, Coriobacteriaceae, Coriobacteriales, Actinobacteria, Caulobacteraceae, Phyllobacteriaceae, Rhizobiales, Burkholderiaceae, Burkholderiaceae. Inflammatory status in PTB patients may be associated with the increased abundance of Clostridia and decreased abundance of Prevotella. We found that the abundance of Solobacterium and Actinobacteria was higher in the patients. There were 4 significant differences (p < 0.05) in the two groups which belonged to four metabolic categories, including endocytosis, phosphotransferase system (PTS), toluene degradation, and amoebiasis.ConclusionWe applied the approach of metagenomic sequencing to characterize the features of gut microbiota in PTB patients. The present study provided a detailed analysis of the characterization of the gut microbiota in patients based on the clinic. According to the metagenome analysis, our results indicated that the gut microbiota in PTB patients was significantly different from healthy control samples as characterized by the bacteria and metabolic pathway. The richness of the gut microbiota in patients was revealed. It was hypothesized that the above-mentioned changes of the gut microbiota could exert an impact on the development of PTB through the downstream regulation of the immune status of the host by way of the gut–lung axis.     

The cardiac protection of Baoyuan decoction via gut-heart axis metabolic pathway

BackgroundGut-heart axis has emerged as a novel concept to provide new insights into the complex mechanisms of heart failure (HF) and offer new therapeutic targets. Cardiac hypertrophy (CH) is one of the etiological agents contributing to the development of HF. Baoyuan Decoction (BYD), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating CH and preventing HF. Previously, we have reported that BYD-targeted endogenous metabolites are potentially linked to gut microbiota metabolism, but the contribution of gut microbiota and metabolic interaction to the cardioprotective efficacy of BYD remains to be elucidated.PurposeTo investigate whether the gut microbiota plays a key role in anti-CH effects of BYD.Study designA comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and microflora suppression model was adopted to investigate the links between the microbiota–host metabolic interaction and BYD efficacy in CH rats.MethodFirstly, the efficacy evaluation of BYD in treating chronic isoproterenol (ISO)-induced CH rats was performed by using multiple pharmacodynamic approaches. Then, the fecal metabolomics and 16S rRNA sequencing techniques were used to obtain the microbial and metabolic features of BYD against CH. After that, the potential gut-heart axis-based mechanism of BYD against CH was predicted by bioinformatic network analysis and validated by multiple molecular biology approaches. Finally, the antibiotics (AB)-induced gut microbiota suppression was employed to investigate whether the anti-CH effects of BYD is associated with the gut microflora.ResultsThe fecal microbial communities and metabolic compositions were significantly altered in ISO-induced CH rats, while BYD effectively ameliorated the CH-associated gut microbiota dysbiosis, especially of Firmicutes and Bacteroidetes, and time-dependently alleviated the disturbance of fecal metabolome and reversed the changes of key CH and gut microbiota-related metabolites, such as short/medium chain fatty acids, primary/secondary bile acids, and amino acids. The mechanism study showed that the anti-CH effect of BYD was related to inhibition of the derivatives of arginine and tryptophan and their downstream pro-hypertrophic, pro-inflammatory, and pro-oxidant signaling pathways. The following microflora suppression test showed that BYD-mediated myocardial protection was decreased either in pharmacodynamics or in metabolic modulation.ConclusionThis study demonstrates that the protection of BYD against CH is partially gut microbiota dependent, and the regulatory effects of gut metabolism-related tryptophan and arginine derivatives is an important cardioprotection mechanism of BYD.     

The very low birth weight infant microbiome and childhood health

This review describes current understandings about the nature of the very low birth weight infant (VLBW) gut microbiome. VLBW infants often experience disruptive pregnancies and births, and prenatal factors can influence the maturity of the gut and immune system, and disturb microbial balance and succession. Many VLBWs experience rapid vaginal or Caesarean births. After birth these infants often have delays in enteral feeding, and many receive little or no mother's own milk. Furthermore the stressors of neonatal life in the hospital environment, common use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis. These infants experience gastrointestinal dysfunction, sepsis, transfusions, necrotizing enterocolitis, oxygen toxicity, and other pathophysiological consditions that affect the normal microbiota. The skin is susceptible to dysbiosis, due to its fragility and contact with NICU organisms. Dysbiosis in early life may resolve but little is known about the timing of the development of the signature gut microbiome in VLBWs. Dysbiosis has been associated with a number of physical and behavioral problems, including autism spectrum disorders, allergy and asthma, gastrointestinal disease, obesity, depression, and anxiety. Dysbiosis may be prevented or ameliorated in part by prenatal care, breast milk feeding, skin to skin contact, use of antibiotics only when necessary, and vigilance during infancy and early childhood. Birth Defects Research (Part C) 105:252–264, 2015. © 2015 Wiley Periodicals, Inc.     

Effects of long-term antibiotic treatment on mice urinary aromatic amino acid profiles

The gut microbiota–host co-metabolites are good indicators for representing the cross-talk between host and gut microbiota in a bi-direct manner. There is increasing evidence that levels of aromatic amino acids (AAAs) are associated with the alteration of intestinal microbial community though the effects of long-term microbial disturbance remain unclear. Here we monitored the gut microbiota composition and host–microbiota co-metabolites AAA profiles of mice after gentamicin and ceftriaxone treatments for nearly 4 months since their weaning to reveal the relationship between host and microbiome in long- term microbial disturbances. The study was performed employing targeted LC-MS measurement of AAA-related metabolites and 16S RNA sequence of mice cecal contents. The results showed obvious decreased gut microbial diversity and decreased Firmicutes/Bacteroidetes ratio in the cecal contents after long-term antibiotics treatment. The accumulated AAA (tyrosine, phenylalanine and tryptophan) and re-distribution of their downstreaming metabolites that produced under the existence of intestinal flora were found in mice treated with antibiotics for 4 months. Our results suggested that the long-term antibiotic treatment significantly changed the composition of the gut microbiota and destroyed the homeostasis in the intestinal metabolism. And the urinary AAA could be an indicator for exploring interactions between host and gut microbiota.