The diverse collection of microorganisms that inhabit the gastrointestinal tract, collectively called the gut microbiota, profoundly influences many aspects of host physiology, including nutrient metabolism, resistance to infection and immune system development. Studies investigating the gut-brain axis demonstrate a critical role for the gut microbiota in orchestrating brain development and behavior, and the immune system is emerging as an important regulator of these interactions. Intestinal microbes modulate the maturation and function of tissue-resident immune cells in the CNS. Microbes also influence the activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity and neurogenesis. Accordingly, both the gut microbiota and immune system are implicated in the etiopathogenesis or manifestation of neurodevelopmental, psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer's disease. In this review, we discuss the role of CNS-resident and peripheral immune pathways in microbiota-gut-brain communication during health and neurological disease.

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Interactions between the microbiota, immune and nervous systems in health and disease

This review focuses on advances and updates in the epidemiology, pathogenesis, diagnosis, and treatment of food allergy over the past 3 years since our last comprehensive review. On the basis of numerous studies, food allergy likely affects nearly 5% of adults and 8% of children, with growing evidence of an increase in prevalence. Potentially rectifiable risk factors include vitamin D insufficiency, unhealthful dietary fat, obesity, increased hygiene, and the timing of exposure to foods, but genetics and other lifestyle issues play a role as well. Interesting clinical insights into pathogenesis include discoveries regarding gene-environment interactions and an increasing understanding of the role of nonoral sensitizing exposures causing food allergy, such as delayed allergic reactions to carbohydrate moieties in mammalian meats caused by sensitization from homologous substances transferred during tick bites. Component-resolved diagnosis is being rapidly incorporated into clinical use, and sophisticated diagnostic tests that indicate severity and prognosis are on the horizon. Current management relies heavily on avoidance and emergency preparedness, and recent studies, guidelines, and resources provide insight into improving the safety and well-being of patients and their families. Incorporation of extensively heated (heat-denatured) forms of milk and egg into the diets of children who tolerate these foods, rather than strict avoidance, represents a significant shift in clinical approach. Recommendations about the prevention of food allergy and atopic disease through diet have changed radically, with rescinding of many recommendations about extensive and prolonged allergen avoidance. Numerous therapies have reached clinical trials, with some showing promise to dramatically alter treatment. Ongoing studies will elucidate improved prevention, diagnosis, and treatment.

https://www.jacionline.org/article/S0091-6749(13)01836-8/pdf

Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment

This review provides general information to serve as a primer for those embarking on understanding food allergy and also details advances and updates in epidemiology, pathogenesis, diagnosis, and treatment that have occurred over the 4 years since our last comprehensive review. Although firm prevalence data are lacking, there is a strong impression that food allergy has increased, and rates as high as approximately 10% have been documented. Genetic, epigenetic, and environmental risk factors are being elucidated increasingly, creating potential for improved prevention and treatment strategies targeted to those at risk. Insights on pathophysiology reveal a complex interplay of the epithelial barrier, mucosal and systemic immune response, route of exposure, and microbiome among other influences resulting in allergy or tolerance. The diagnosis of food allergy is largely reliant on medical history, tests for sensitization, and oral food challenges, but emerging use of component-resolved diagnostics is improving diagnostic accuracy. Additional novel diagnostics, such as basophil activation tests, determination of epitope binding, DNA methylation signatures, and bioinformatics approaches, will further change the landscape. A number of prevention strategies are under investigation, but early introduction of peanut has been advised as a public health measure based on existing data. Management remains largely based on allergen avoidance, but a panoply of promising treatment strategies are in phase 2 and 3 studies, providing immense hope that better treatment will be imminently and widely available, whereas numerous additional promising treatments are in the preclinical and clinical pipeline.

Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management.

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.

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Alterations of the human gut microbiome in multiple sclerosis

Recent studies have characterized how host genetics, prenatal environment and delivery mode can shape the newborn microbiome at birth. Following this, postnatal factors, such as antibiotic treatment, diet or environmental exposure, further modulate the development of the infant's microbiome and immune system, and exposure to a variety of microbial organisms during early life has long been hypothesized to exert a protective effect in the newborn. Furthermore, epidemiological studies have shown that factors that alter bacterial communities in infants during childhood increase the risk for several diseases, highlighting the importance of understanding early-life microbiome composition. In this review, we describe how prenatal and postnatal factors shape the development of both the microbiome and the immune system. We also discuss the prospects of microbiome-mediated therapeutics and the need for more effective approaches that can reconfigure bacterial communities from pathogenic to homeostatic configurations.

The microbiome in early life: implications for health outcomes

Background:
Commensal microbiota play a critical role in maintaining oral tolerance. The effect of food allergy on the gut microbial ecology remains unknown.
Methods:
Food allergy–prone mice with a gain-of-function mutation in the IL-4 receptor α chain (Il4raF709) and wild-type (WT) control animals were subjected to oral sensitization with chicken egg ovalbumin (OVA). Enforced tolerance was achieved by using allergen-specific regulatory T (Treg) cells. Community structure analysis of gut microbiota was performed by using a high-density 16S rDNA oligonucleotide microarrays (PhyloChip) and massively parallel pyrosequencing of 16S rDNA amplicons.
Results:
OVA-sensitized Il4raF709 mice exhibited a specific microbiota signature characterized by coordinate changes in the abundance of taxa of several bacterial families, including the Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Porphyromonadaceae. This signature was not shared by similarly sensitized WT mice, which did not exhibit an OVA-induced allergic response. Treatment of OVA-sensitized Il4raF709 mice with OVA-specific Treg cells led to a distinct tolerance-associated signature coincident with the suppression of the allergic response. The microbiota of allergen-sensitized Il4raF709 mice differentially promoted OVA-specific IgE responses and anaphylaxis when reconstituted in WT germ-free mice.
Conclusion:
Mice with food allergy exhibit a specific gut microbiota signature capable of transmitting disease susceptibility and subject to reprogramming by enforced tolerance. Disease-associated microbiota may thus play a pathogenic role in food allergy.

A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis

Objectives Differences in gut bacteria have been described in several autoimmune disorders. In this exploratory pilot study, we compared gut bacteria in patients with multiple sclerosis and healthy controls and evaluated the influence of glatiramer acetate and vitamin D treatment on the microbiota. Methods Subjects were otherwise healthy white women with or without relapsing-remitting multiple sclerosis who were vitamin D insufficient. Patients with multiple sclerosis were untreated or were receiving glatiramer acetate. Subjects collected stool at baseline and after 90 days of vitamin D3 (5000 IU/d) supplementation. The abundance of operational taxonomic units was evaluated by hybridization of 16S rRNA to a DNA microarray. Results While there was overlap of gut bacterial communities, the abundance of some operational taxonomic units, including Faecalibacterium, was lower in patients with multiple sclerosis. Glatiramer acetate–treated patients with multiple sclerosis showed differences in community composition compared with untreated subjects, including Bacteroidaceae, Faecalibacterium, Ruminococcus, Lactobacillaceae, Clostridium, and other Clostridiales. Compared with the other groups, untreated patients with multiple sclerosis had an increase in the Akkermansia, Faecalibacterium, and Coprococcus genera after vitamin D supplementation. Conclusions While overall bacterial communities were similar, specific operational taxonomic units differed between healthy controls and patients with multiple sclerosis. Glatiramer acetate and vitamin D supplementation were associated with differences or changes in the microbiota. This study was exploratory, and larger studies are needed to confirm these preliminary results.

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Gut Microbiota in Multiple Sclerosis: Possible Influence of Immunomodulators

Objective: To compare the composition of gut bacteria in MS patients and healthy controls. Background Alterations in gut bacteria are associated with some autoimmune disorders but have not been assessed in MS. Design/Methods: Subjects were white women with or without relapsing-remitting MS who were vitamin D insufficient but who were otherwise relatively healthy. MS patients were untreated or were receiving glatiramer acetate. Subjects were asked to collect the first morning stool at baseline and after 90 days of daily vitamin D3 supplementation and to ship the samples overnight on ice packs to the laboratory, where they were frozen at -80 degrees. DNA was batch extracted from the stool, and the bacterial profiles were analyzed using a PhyloChip Assay (Second Genome, Inc). Abundance of operational taxonomic units (OTUs) was compared between groups (Adonis tests for significance testing; prediction analysis for microarrays to describe specific taxa). Results: Fifteen subjects participated in the study; among MS patients (n=7), one submitted the initial sample late, while two gave specimens only after supplementation. There was a trend for MS patients and controls to have differences in their microbial communities (Adonis p=0.15), punctuated by differences in Firmicutes, Bacteriodetes, and Proteobacteria OTUs. The bacterial profiles of MS patients treated with glatiramer acetate (n=5) differed from untreated MS patients (Adonis p=0.007). This was largely associated with differences in Firmicutes OTUs. Overall, among both groups, vitamin D therapy led to increased abundance of several Enterobacteriaceae OTUs although among MS patients, notable changes in abundance occurred in Firmicutes, Actinobacteria, and Proteobacteria. Conclusions: MS patients treated with glatiramer acetate may have differences in overall gut bacteria and in the abundance of some taxa compared to untreated patients. Although there was no statistically significant difference in the overall gut microbiome of MS patients and controls, there were some differences in taxa abundances between these populations. Supported by: NIH (EMM: K23NS067055). Disclosure: Dr. Mowry has nothing to disclose. Dr. Waubant has received personal compensation for activities with Teva Neuroscience, Actelion, Sanofi-Aventis Pharmaceuticals, Roche Diagnostics Corporation and Biogen Idec as a speaker and/or consultant. Dr. Waubant has received research support from Biogen Idec and Sanofi-Aventis Pharmaceuticals. Dr. Chehoud has received personal compensation for activities with Second Genome as a consultant. Dr. DeSantis has received personal compensation for activities with Second Genome.Dr. DeSantis holds stock and/or stock options in Second Genome.Dr. DeSantis has received (royalty or license fee or contractual rights) payments from Lawrence Berkeley Laboratories. Dr. Kuczynski has received personal compensation for activities with Second Genome as an employee. Dr. Kuczynski has received research support from Second Genome. Dr. Warrington has received personal compensation for activities with Second Genome, Inc. and Cernostics as an employee and/or participant on an advisory board.

Gut Bacterial Populations in Multiple Sclerosis and in Health (P05.106)

Clostridium difficile infections (CDI) are caused by colonization and growth of toxigenic strains of C difficile in individuals whose intestinal microbiota has been perturbed, in most cases following antimicrobial therapy Determination of the protective commensal gut community members could inform the development of treatments for CDI Here, we utilized the lethal enterocolitis model in Syrian golden hamsters to analyze the microbiota disruption and recovery along a 20-day period following a single dose of clindamycin on day 0, inducing in vivo susceptibility to C difficile infection To determine susceptibility in vitro, spores of strain VPI 10463 were cultured with and without soluble hamster fecal filtrates and growth was quantified by quantitative PCR and toxin immunoassay Fecal microbial population changes over time were tracked by 16S ribosomal RNA gene analysis via V4 sequencing and the PhyloChip assay C difficile culture growth and toxin production were inhibited by the presence of fecal extracts from untreated hamsters but not extracts collected 5 days post-administration of clindamycin In vitro inhibition was re-established by day 15, which correlated with resistance of animals to lethal challenge A substantial fecal microbiota shift in hamsters treated with antibiotics was observed, marked by significant changes across multiple phyla including Bacteroidetes and Proteobacteria An incomplete return towards the baseline microbiome occurred by day 15 correlating with the inhibition of C difficile growth in vitro and in vivo These data suggest that soluble factors produced by the gut microbiota may be responsible for the suppression of C difficile growth and toxin production

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An in vitro culture model to study the dynamics of colonic microbiota in Syrian golden hamsters and their susceptibility to infection with Clostridium difficile.

Janet Warrington

Papers

A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis

Gut Microbiota in Multiple Sclerosis: Possible Influence of Immunomodulators

Gut Bacterial Populations in Multiple Sclerosis and in Health (P05.106)

An in vitro culture model to study the dynamics of colonic microbiota in Syrian golden hamsters and their susceptibility to infection with Clostridium difficile.