Tag Archives: Medical Research and Development

Researchers Explore Effects of Probiotics Supplements on Intestinal Microbiota of Food Allergic Mice

Exploration of the effect of probiotics supplementation on intestinal microbiota of food allergic mice

Abstract

Environmental factor-induced alterations in intestinal microbiota have been demonstrated to be associated with increasing prevalence of food allergy. However, it is not clear to what extent oral administration of probiotics can affect gut microbiota composition, thus inhibiting food allergy development. Using ovalbumin (OVA)-sensitized murine model, it was demonstrated that probiotics ameliorated allergic symptoms, including reducing OVA specific-IgE, and -IgG1 levels in the serum, Th2 cytokines release in spleen, and occurrence of diarrhea. Moreover, 16S rRNA analysis showed that the probiotics-mediated protection was conferred by an enrichment of Coprococcus and Rikenella. The present study supports the theory that probiotics can treat food allergy by modulating specific genera of the gut microbiota.

Introduction

Food allergy is an adverse immune response to certain kinds of food. It is estimated that food allergy affects about 8% of children and 4% of adults [1,2]. The rapid increase in the prevalence of food allergy over past several decades cannot be explained by genetic variation alone. In current, avoidance of dietary allergens is the only proven remedy available for food allergic suffers.

Growing evidence suggests that gut microbiota exerts profound influence on immune system maturation and tolerance acquisition. Intestinal microflora alteration, caused by environmental factors (e.g., mode of birth, antibiotics, diet, vaccination, sanitation), has been observed to be associated with many gastrointestinal diseases, including food allergy [3], inflammatory bowel diseases [4], or colorectal cancer [58]. Of note, intestinal microflora has been demonstrated to play an important role in maintaining the Th1/Th2 balance [9], which is the key mechanism involved in allergic diseases.

The role of probiotics in allergic disease has been highlighted recently. Bifidobacteria and lactobacilli, which are common species of probiotics existing in most people, can affect immune function by various pathways. In many cases, probiotics supplementation was demonstrated to induce TGF-β expression, which ameliorates food allergy by suppressing Th2 response, and inducing Foxp3+ Treg production [1015]. A microarray analysis of intestinal epithelial cells from gnotobiotic mice revealed a mechanism that Clostridia facilitated immune cells to produce interleukin-22 (IL-22), regulated innate lymphoid cell function and intestinal epithelial permeability to protect against allergen sensitization [3]. Besides, the suppressive effect of probiotics on Th17 response has been shown both in murine asthma [16] and atopic dermatitis model [17]. However, whether probiotics treatment elicited changes in the composition of the intestinal microbiota, thereby regulating allergic disease remains poorly understood.

The current study investigated the beneficial effect of Bifidobacterium Infantis (BB) in a murine model of food allergy at the level of commensal microbiota. Sequencing of the V4-V5 regions of 16S rRNA genes revealed that BB could modulate specific genera of intestinal microbiota in mice, which may induce immune responses in gastrointestinal tract to defend against food allergens.

Materials and methods

Animals

All the animal experimental procedures were conducted according to the guidelines approved by the Experimental Animal Ethic Committee at Shenzhen University, and were carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 1996). 6-8 weeks old female Balb/c mice were housed in a SPF animal facility with a 12 h light-dark cycle and were free to access standard diet and water.

Food allergic animal model

Mice were intragastrically administered with 100 mg OVA plus 20 mg cholera toxin (CT) in a final volume of 300 ml using a ball-end mouse feeding tube once a week for 4 consecutive weeks. At the end of sensitization, mice were challenged with 5 mg OVA orally. After 24 h, the mice were killed and serum and splenocytes were collected for the following analysis as reported previously (referred to as FA group) [25].

BB preparation and supplementation

BB was kindly provided by Shenzhen Kexing Biotech CO., LTD (Shenzhen, China) as lyophilized powder and inoculated before giving to mice. From Day 15 to Day 28, sensitized mice were orally administered with 200 ml/mouse of normal saline containing 108 cfu/ml as previously described (referred to as FAPro group) [13]. On day 29, the mice were challenged as described above.

Serum immunoglobulin levels

Serum was collected, and OVA-specific IgE was detected by commercial ELISA kit (Biolegend, USA) according to the manufacturer’s instructions. OVA-specific IgG1 was measured by an in-house ELISA as previously described [26].

DNA extraction, amplification and sequencing

During the process of food allergy model establishment, fecal samples (up to ~1 g) were collected on Day 0, 7, 14, 28, 29, and stored at -80°C. The total DNA from fecal samples was extracted by reported method [27]. The 16S rRNA was amplified and sequenced on the Ion Torrent Personal Genome Machine as reported in previous study [28].

Bioinformatics analysis

The data was treated with in-house pipeline developed based on mothur v.1.33.3 [29]. The community structure was calculated based on the membership and relative abundance of taxonomic groups in the sample. In this study, the Permutational multivariate analysis of variance (PERMANOVA) was used to assess the effect of BB (covariate) on operational taxonomic units (OTUs) profiles. A two-tailed Wilcoxon rank-sum test was used in the profile to identify the different OTUs and KEGG Orthologs (KOs). In addition, we used PICRUSt [30] to produce predicted KOs from the 16S rRNA gene sequence data.

Statistical analysis

In Figure 1, all values are presented as the means ± SEM. Differences between two groups were evaluated with the Student t test, while data among three or more groups were evaluated with one-way ANOVA (Prism version 5, GraphPad Software; CA, USA). A P value less than 0.05 was considered to indicate significant differences.

Figure 1

Allergic reactions in the mouse intestine were attenuated by BB. Balb/c mice were treated with PBS (Naïve group), OVA/CT (FA group), OVA/CT+BB (FAPro group). The bars indicate the levels of serum OVA-specific IgE (A), -IgG1 (B), IL-4, -5, and

Results

BB showed significant protective effect on food allergic mice

Food allergic mice model was established using OVA as allergen, CT as adjuvant. As shown in Figure 1A and and1B,1B, treatment with BB for two weeks attenuated sIgE and sIgG1 by 33% and 32% respectively, when compared with FA group. Moreover, spleneocytes were harvested from all the three groups of mice and incubated with OVA for 3 days. The levels of typical Th2-type cytokines in supernatant were determined by commercial ELISA. Intragastrically administered with BB significantly reduced IL-4, -5, and -13 by 31%, 24%, and 50% respectively in FA mice (Figure 1C). In addition, after challenge with OVA, the FA mice showed significant diarrhea (Figure 1D), which could be ameliorated by BB.

BB-induced phenotypic improvement was associated with specific OTUs

Next, to investigate the effect of BB on gut microbiome, we carried out metagenomic sequencing of fecal samples from FA and FAPro mice. All sequencing reads were finally classified into 1195 operational taxonomic units (OTUs). The correlation between food allergic phenotypes and OTUs was calculated. It was found that 61 OTUs were significantly related to sIgE, sIgG1, IL-4, IL-5, and IL-13. Among them, 45 OTUs were positively correlated with these phenotypes and 16 OTUs were negatively correlated (Figure 2). For instance, Otu0724, annotated to the family S24-7, was significantly positive correlated with allergic phenotypes. On the contrary, Otu0543, annotated to the genus Bacteroides, was significantly negatively correlated. Upregulation or downregulation of the relative abundances of these OTUs could trigger certain immune responses. The results indicated that BB treatment may change immune indexes of food allergy through modulation of these OTUs.

Figure 2

The heatmap of correlation between five phenotypes and OTUs profile. Red means positive correlation, while blue represents negative correlation.

Treatment with BB shows no effect on alpha-diversity of intestinal microflora

Chao [18] and ACE [19] are usually used to compute community richness; the higher score, the more richness. Shannon and Simpson metrics are commonly used to calculate community diversity [20]. The higher Shannon index indicates the greater community diversity, while the higher Simpson index indicates the lesser community diversity. We used these 4 kinds of alpha diversity parameters to describe the microbiologic species diversity changes between FA group and FAPro group (Figure 3). Student’s t-test showed that there were no significant differences of these four indexes (Figure 3). The results indicated that BB was not strong enough to change population diversity and richness of intestinal microbiota.

Figure 3

Boxplot of 4 kinds of alpha diversity between FA and FAPro group. Chao, ACE, Shannon, simpson are the four kinds of alpha diversity metrics. FA (n=27), FAPro (n=34). Mean values ± SEM are plotted.

BB didn’t alter intestinal microbiota compositon in mice

In order to investigate whether probiotics treatment change the composition of intestinal microbiota, we used principal coordinate analysis (PCoA) to compare FA and FAPro group. As shown in Figure 4, there was no significant difference between FA and FAPro group. Thus, it was implied that BB showed no effect on modulation of microbiota composition.

Figure 4

The PCoA of OTU profile between FA and FAPro mice. 16S rRNA gene surveys (analyzed by JSD-based PCoA) from mice fed PBS (red) or probiotics (blue) diets are presented in a different clustering pattern. Principal coordinate1 (PC)1 and PC2 are the x axis

The taxonomic classification of gut microbiota in mice

We found that Bacteroidetes and Firmicutes were two most prevalent phyla present in food allergic mice treated with or without probiotics, the same as that under physiological status [3]. Furthermore, Lachnospiraceae, S24-7, Rikenellaceae, and Ruminococcaceae accounted for four major components at family levels (Figure 5A). Further analysis revealed that 2-wk of BB treatment resulted in a significant change in fecal microbiota composition at genus level. As shown in Figure 5B, the levels of Coprococcus and Rikenella were significantly increased by 66% and 60% respectively, after BB treatment. Thus, the relative abundances of Coprococcus and Rikenella may be used as microbial biomarkers to diagnose food allergy.

Figure 5

A. Taxonomic distributions in gut communities. Values represent the relative abundance of bacteria at family level across all samples within FA group and FAPro group. A small amount of microorganism is unknown. B. Comparision of 12 major genera between

Comparison of OTUs levels between FA and FAPro mice

Next, Wilcoxon rank test showed that 92 OTUs were significantly different between FA group and FAPro group. Among them, 40 OTUs (43.5%) were enriched in FA group. 33 OTUs were picked out through a FDR adjust and make a heatmap with the OTU percentage profile (Figure 6). Moreover, we found that probiotics administration could enrich more bacteria assigned to Coprococcus, Rikenella and Bacteroides in the mice gut (Figure 6).

Figure 6

Heatmap of gut bacteria in FA and FAPro group at OTU level. Blue regions represent relatively low OUT abundance, while red regions means relatively high OTU abundance.

Mice gut microflora changed across time

In order to monitor the change of gut bacteria during the period of probiotics administration, we collected fecal samples at 5 time points: before oral treatment of probiotics (FAPro1), after one week’s probiotics administration (FAPro2), after two weeks’ administration (FAPro3), 1 h after allergen challenge (FAPro4), 24 h after allergen challenge (FAPro5). Intriguingly, we selected 12 most abundant genera and found that at least 6 genera of gut bacteria, including Odoribacter, Bacteroides, Coprococcus, Blautia, Eubacterium, Prevotella changed with time after probiotics treatment (Figure 7). For example, the levels of Odoribacter were significantly increased by 3.3 fold at the time point of 24 h after challenge compared to the time point of 1 h after challenge.

Figure 7

Time-dependent manner of gut bacteria changes at genus level. During the period of probiotics administration, we collected fecal samples at 5 time points: before oral treatment of probiotics (FAPro1), after one week’s probiotics administration

Metabolic pathways of gut microbiota was altered by BB supplementation

We used PICRUSt to produce predicted metagenomes from 16S rRNA gene sequence database. 143 KOs were found to be significantly different between FA and FAPro mice, using Wilcoxon rank test, p value < 0.05. Among them, only 4 KOs were enriched in FAPro group (Table 1). The results implied that BB supplementation significantly modified metabolic pathways of gut microbiota.

Table 1

Four KEGG Orthologs were enriched in FAPro group

Discussion

Gut microbiota plays an important role in the pathogenesis of food allergy. In this study, we found that oral administration of BB induced significant improvement on allergic symptoms in mice. Furthermore, the results demonstrated that BB conferred a protective effect on food allergic mice through up-regulation of the relative abundance of Coprococcus and Rikenella at genus level. Furthermore, the genera of gut microflora were presented in a time-dependent pattern after BB treatment.

Growing evidence suggests that the relationship among diet, probiotics, immune system and gut microbiota ecology determines the disease susceptibility to allergy [21]. Thus, it is very likely that intragastrical administration of probiotics may treat food allergy by restoring the unbalanced indigenous microbiota and controlling the inflammatory responses. Until now, there is no investigation targeting the direct effect of probiotic supplementation on intestinal microbiota. Although there are more than 1000 species of intestinal bacteria, most of them belong to just a few phyla. Bacteroidetes and Firmicutes phyla dominate the adult intestine. The intestinal microbiota is of high variation from people to people at species-level, but bifidobacteria and lactobacilli are common species existing in most people [22]. Thus, in the present study we chose BB to treat a classical animal model sensitized by OVA. In this study, animals treated with probiotics for two weeks showed improvement in all major indicators of experimental mucosal allergy, in line with the results previously reported [23].

When use traditional culture based techniques to determine the composition of the gut microbiota, there are only ~10% of gut bacteria possibly to be studied since others are not culturable [24]. Therefore, in order to further determine the different components of intestinal microbiota caused by probiotics, we chose state-of-the-art next-generation sequencing method to detect the 16S rRNA of faces samples and determine the frequency of microbes and its metabolic pathway in gastrointestinal tract. We found that there were 12 genera of gut bacteria existing in both FA and FAPro groups. After supplementation with BB for two weeks, each genus changed periodically. Based on their relative abundances, BB administration could up-regulate Rikenlla and down-regulate Eubacterium. These two genera of bacteria have never been highlighted by other related researches. Instead, Stefka [3] et al demonstrated that a Clostridia-containing microbiota was associated with innate lymphoid cell function and intestinal epithelial permeability. The divergence may be attributed to that they didn’t use a kind of probiotics to treat allergic mice.

In conclusion, this is the first study to explore microbial population changes in food allergic animal model, in case of probiotics administration. Likely, specific gut bacterial changes contributed to disease process altered by probiotics. Still, patients study are warranted in the future to determine whether the findings herein reported can be validated and correlated with the clinical features.

Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (No. 81300292 to B.Y., No. 81271950 to Q.M.J., and 81460252 to X.Y.L.), Guangdong Foreign Scientific Technology Cooperative Project (No. 2013B051000088 to Z.G.L.), Shenzhen Scientific Technology Basic Research Projects (No. 005177 to Q.M.J., JCYJ20140418095735538 to Z.G.L., and JCYJ20130402151227168 to S.G.H.).

Disclosure of conflict of interest

None.

Authors’ contribution

B.Y., L.X. and S.L. performed experiments and analyzed data. B.Y. wrote the manuscript. X.Y.L. and Y.L. performed experiments. Q.M.J, P.C.Y. and Z.G.L. organized the project and supervised the experiments. P.C.Y. revised the manuscript.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340674/

President Obama Will Announce Launch of $215M Precision Medicine Initiative

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President Obama today will announce the launch of a $215 million precision medicine initiative to leverage advances in genomics, informatics, and health information technology to accelerate biomedical discoveries in the hopes of yielding more personalized medical treatments for patients in the US.

The public-private initiative, which will be included in the President’s 2016 budget proposal to be released next week, will provide new funding to the National Institutes of Health, the National Cancer Institute, the US Food and Drug Administration, and the Office of the National Coordinator for Health Information.

That funding will help those agencies to, among other things, develop a voluntary national research cohort of more than 1 million people, obtain sequencing data for as many of those individuals as possible, identify genomic drivers of cancer, improve how next-generation sequencing-based tests are evaluated and marketed, and develop methods for managing and analyzing large patient data sets while protecting individual privacy.

“Precision medicine is about moving beyond this one-size-fits-all kind of approach to medicine and instead approaching disease prevention and treatment by taking into account individual differences in people’s genes, their microbiomes, their environments, and their lifestyles,” Jo Handelsman, associate director for science at the White House Office of Science and Technology Policy, said yesterday in a press briefing previewing today’s announcement. “The idea is to give clinicians tools to better understand the mechanisms underlying a patient’s condition, and to better predict which treatments will be most effective and safe.”

The largest part of the initiative will provide $130 million to the NIH to help develop a national research cohort of a million or more volunteers whose data — including medical records, genetic and metabolomic profiles, microbiomes, and environmental and lifestyle information — will contribute to a further understanding of disease and help establish a new way of doing research through engaged participants and open, responsible data sharing, the White House said.

In addition, the NCI will be budgeted for $70 million to scale up efforts to understand the genetic basis of cancer by expanding genetically based clinical trials, exploring fundamental aspects of cancer biology, and establishing a national “cancer knowledge network” that will generate and share new knowledge.

Meantime, $10 million will be earmarked for the FDA to help it acquire additional tools and expertise to develop high-quality, curated databases that will be used in its efforts to evaluate next-generation sequencing technologies and ensure their accuracy, reliability, and safety for patients.

And, finally, the initiative calls for a $5 million investment in the ONC to support the development of interoperability standards and requirements that address patient privacy and enable the secure exchange of data across systems.

“This concept of precision medicine – that is, prevention and treatment strategies that take individual differences into account – is not entirely new,” NIH Director Francis Collins said during the briefing. “But for much of medicine, this kind of personalizing just has not been possible. We just didn’t know enough. That’s all changing now, and at an unprecedented pace, which makes now the right time to launch this initiative.”

Collins pointed to advances over the past several years in basic research, data science, mobile connectivity, use of electronic medical records, and “perhaps most dramatic of all in terms of the scale, the decline in the cost of DNA sequencing. It cost us $400 million for that first genome, and now a genome can be sequenced for a cost approximating $1,000. That’s more than 100,000-fold drop in 15 years.”

Regarding the NIH’s plan to create a longitudinal cohort of more than 1 million patients, Collins noted that the agency and its partners will not need to start from scratch, but will instead tap into already-established cohorts, both public and private.

“We are aware that there is something like 200 cohorts that have already been put in place that have at least 10,000 participants,” Collins said. “They’re in different sorts of shape as far as the kind of information that’s already been collected. But there is a wealth of potential there.”

Collins noted that a large part of this cohort effort will be trying to piece together many of these existing cohorts, and he said that this could be aided by existing projects such as the Electronic Medical Records and Genomics (eMERGE) program, which aims to combine electronic medical records technologies with DNA biorepositories for use in large-scale, high-throughput genomics research projects.

In terms of the types of existing cohorts that could be tapped into, Collins mentioned the attractiveness of the cohorts generated so far under Kaiser Permanente’s Research Program on Genes, Environment, and Health, which includes more than 430,000 adult members of Kaiser’s system in Northern California and has generated a 100,000-individual cohort in partnership with the University of California, San Francisco. However, Collins stressed that the NIH will be encouraging new participants to volunteer to help build the national cohort.

Another large part of the cohort effort will be attempting to obtain sequencing data for as many of the participants as possible. Although the cost of sequencing has dropped dramatically in recent years, this component of the initiative remains a major hurdle.

“We would love to have whole-genome sequence [data] on all the participants in the cohort, but the expense has to be considered, and where are we going to find those funds?” Collins said. Although it now costs about $1,000 to sequence a whole genome, “that curve is coming down, and that is actually quite reassuring,” Collins added. “It will take us, of course, a matter of some time to assemble this cohort. Our expectation would be that, as it’s being assembled, the cost [of sequencing] would be coming down, and so ultimately the goal would be to have a full-genome sequence on as many of the cohort as are comfortable.”

Another important aspect of the national cohort project will be its interactive nature. “The precision medicine initiative is not just about scale,” Collins said. “It’s also intended to be a new model of research, one in which people who participate are true partners – not subjects, not even patients – partners.”

To that end, the ONC is charged with developing new and better ways to ensure secure data exchange with patients’ consent, and the initiative overall will be committed to protecting patients’ privacy by launching a “multi-stakeholder process” that will solicit input from patient groups, bioethicists, privacy and civil liberties advocates, technologists, and other experts to identify legal and technical issues.

Summarizing, Collins noted that although the cohort initiative will likely yield its greatest benefits many years into the future, “there should be some successes in the relatively near future, as well, especially in the areas of cancer, and the field called pharmacogenomics – how to provide the right drug at the right dose to the right patient at the right time. This initiative will provide a wonderful platform for finding out how to apply that strategy to more and more people.”

On the regulatory side, FDA Commissioner Margaret Hamburg noted during the briefing that the agency’s funding would primarily be used to improve the way it oversees the marketing of new types of precision medicine technologies, particularly NGS.

“Our current market review approaches for evaluating a test’s analytical and clinical performance are designed around a more traditional one test-one disease paradigm,” Hamburg said. “In contrast, next-generation sequencing produces a massive amount of data, potentially bearing on a huge range of diseases, conditions, and risk factors that will be better handled using a new approach.”……………………………………….

…………. the FDA is currently in the process of considering what that approach should be, referring to the fact that the agency has scheduled a public meeting on Feb. 20 to discuss the challenges of regulating NGS technologies. Ahead of the meeting, last year the agency issued a white paper to lay out its current thinking and provide the basis for future discussion.

President Obama plans to fully announce the precision medicine initiative at an 11:00 AM event at the White House today.

 

To read the article in its entirety please click on the following link:

https://www.genomeweb.com/policy-legislation/president-obama-launch-215m-precision-medicine-initiative?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20News:%20President%20Obama%20to%20Launch%20$215M%20%27Precision%20Medicine%27%20Initiative%20-%2001/30/2015%2011:10:00%20AM