Gut microbiome in the first 1000 days and risk for childhood food allergy.

OBJECTIVE: To summarize recent data on the association between gut microbiome composition and food allergy (FA) in early childhood and highlight potential host-microbiome interactions that reinforce or abrogate oral tolerance. DATA SOURCES: PubMed search of English-language articles related to FA, other atopic disease, and the gut microbiome in pregnancy and early childhood. STUDY SELECTIONS: Human studies published after 2015 assessing the relationship between the gut bacteriome and virome in the first 2 years of life and FA or food sensitization development in early childhood were prioritized. Additional human studies conducted on the prenatal gut microbiome or other atopic diseases and preclinical studies are also discussed. RESULTS: Children who developed FA harbored lower abundances of Bifidobacterium and Clostridia species and had a less mature microbiome during infancy. The early bacterial microbiome protects against FA through production of anti-inflammatory metabolites and induction of T regulatory cells and may also affect FA risk through a role in trained immunity. Infant enteric phage communities are related to childhood asthma development, though no data are available for FA. Maternal gut microbiome during pregnancy is associated with childhood FA risk, potentially through transplacental delivery of maternal bacterial metabolites, though human studies are lacking. CONCLUSION: The maternal and infant microbiomes throughout the first 1000 days of life influence FA risk through a number of proposed mechanisms. Further large, longitudinal cohort studies using taxonomic, functional, and metabolomic analysis of the bacterial and viral microbiomes are needed to provide further insight on the host-microbe interactions underlying FA pathogenesis in childhood.

Early skin inflammatory biomarker is predictive of development and persistence of atopic dermatitis in infants.

BACKGROUND: The Short-Term Topical Application for Prevention of Atopic Dermatitis (STOP AD) study, a randomized, open-label trial evaluating the effect of short-term (from the first 4 postnatal days to age 8 weeks) skin barrier protection using Aveeno Dermexa Fast & Long-Lasting Balm (Johnson & Johnson, New Brunswick, NJ) in infants with a parent with allergic disease, demonstrated decreased cumulative incidence and decreased prevalence of atopic dermatitis (AD) at age 12 months. OBJECTIVE: In the STOP AD study, we aimed to identify skin biomarkers that are associated with risk of development of AD. METHODS: Skin swabs were collected from the cheek and antecubital fossa (AF) at baseline, age 8 weeks, and age 12 months from subsets of study participants from the intervention arm (n = 43 of 119) and control arm (n = 43 of 138) and were analyzed for specific cytokines (CCL27, CXCL2, human ß-defensin-1 [hBD-1], IL-18, IL-8, IL-1α, IL-1 receptor antagonist [IL-1RA], IL-1ß, S100A8/9, and IL-36γ) by ELISA. RESULTS: Higher titers of S100A8/9 at the AF at age 8 weeks in infants with the filaggrin wild-type genotype (FLGwt), but not in those with filaggrin loss-of-function mutation (FLGmut), predicted (1) development of AD in the first year of life (P = .033), (2) presence of AD at ages 6 or 12 months (P = .009 and .035, respectively), (3) persistence of AD between ages 6 and 12 months (P < .001), and (4) development of AD with the emollient intervention. CONCLUSION: Increased titers of S100A8/9 from skin swabs of the AF in high-risk infants at age 8 weeks with FLGwt were predictive of AD development in the first year of life and other AD features. These findings suggest that there are different molecular pathways leading to AD in individuals with FLGmut and in individuals with FLGwt. Early identification of infants who are likely to develop AD will allow more targeted interventions.

Skin surface biomarkers are associated with future development of atopic dermatitis in children with family history of allergic disease.

BACKGROUND: Atopic dermatitis (AD) is a common childhood chronic inflammatory skin disorder that can significantly impact quality of life and has been linked to the subsequent development of food allergy, asthma, and allergic rhinitis, an association known as the "atopic march." OBJECTIVE: The aim of this study was to identify biomarkers collected non-invasively from the skin surface in order to predict AD before diagnosis across a broad age range of children. METHODS: Non-invasive skin surface measures and biomarkers were collected from 160 children (3-48 months of age) of three groups: (A) healthy with no family history of allergic disease, (B) healthy with family history of allergic disease, and (C) diagnosed AD. RESULTS: Eleven of 101 children in group B reported AD diagnosis in the subsequent 12 months following the measurements. The children who developed AD had increased skin immune markers before disease onset, compared to those who did not develop AD in the same group and to the control group. In those enrolled with AD, lesional skin was characterized by increased concentrations of certain immune markers and transepidermal water loss, and decreased skin surface hydration. CONCLUSIONS: Defining risk susceptibility before onset of AD through non-invasive methods may help identify children who may benefit from early preventative interventions.

Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes.

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.

Prospects for primary prevention of type 1 diabetes by restoring a disappearing microbe.

Prevention of childhood-onset type 1 diabetes has become more urgent with its marked increased incidence in recent decades in the modern world. Temporally associated with the rising incidence of type 1 diabetes, as well as other autoimmune and allergic diseases in childhood in modern times, is the disappearance of Bifidobacterium and specifically Bifidobacterium longum subsp. infantis (B. infantis) predominance in the intestinal microbiota of breastfed, vaginally-delivered infants. B. infantis efficiently metabolizes human milk oligosaccharides (HMOs) without cross-feeding free sugar monomers to other commensals or pathogens and thereby dominates the intestinal microbiota of breastfed infants. Increased levels of short-chain fatty acids (SCFA), which stimulate both immunoregulation and healthy intestinal and pancreatic ß-cell function, are generated by B. infantis. Based on recent observations of the intestinal microbiota in early life in young children who develop type 1 diabetes and demonstration of the robust preventive effects of SCFA in animal models of autoimmune diabetes, we hypothesize that restoring a B. infantis-dominant microbiota early in infancy will prevent islet autoimmunity and childhood-onset type 1 diabetes.

Type 1 Diabetes: Disease Stratification.

Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease.

Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis.

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.

JDRF's vision and strategy for prevention of type 1 diabetes.

The increasing incidence and lower threshold of developing type 1 diabetes (T1D) increases the urgency of its prevention. Insights from past and current natural history studies have provided the framework for a compelling strategy for primary and secondary prevention. Primary prevention of T1D should target the general childhood population with vaccines (viral or tolerogenic) or by altering microbiota-induced immunoregulation. Secondary prevention will likely require combination therapies (anti-inflammatories, immunomodulatory agents, beta cell survival agents, and/or agents improving glucose control) used sequentially or simultaneously to preserve residual beta cell function and prevent symptomatic disease. Critical gaps and challenges for prevention of T1D include an incomplete understanding of disease pathogenesis and heterogeneity, the lack of cost-effective risk screening and validated biomarkers for precise staging of disease and optimizing design of shorter and smaller prevention clinical trials, and the lack of appreciation of the impact and burden of T1D and the potential for its prevention. A comprehensive and concerted effort of funders, academia, industry, regulatory authorities, payers, government bodies, health care providers, and the T1D community will be required to deliver on JDRF's vision and strategy for prevention of T1D.

American Diabetes Association and JDRF Research Symposium: Diabetes and the Microbiome.

From 27-29 October 2014, more than 100 people gathered in Chicago, IL, to participate in a research symposium titled "Diabetes and the Microbiome," jointly sponsored by the American Diabetes Association and JDRF. The conference brought together international scholars and trainees from multiple disciplines, including microbiology, bioinformatics, endocrinology, metabolism, and immunology, to share the current understanding of host-microbe interactions and their influences on diabetes and metabolism. Notably, this gathering was the first to assemble specialists with distinct expertise in type 1 diabetes, type 2 diabetes, immunology, and microbiology with the goal of discussing and defining potential pathophysiologies linking the microbiome and diabetes. In addition to reviewing existing evidence in the field, speakers presented their own original research to provide a comprehensive view of the current understanding of the topics under discussion.Presentations and discussions throughout the conference reflected a number of important concepts. The microbiota in any host represent a complex ecosystem with a high degree of interindividual variability. Different microbial communities, comprising bacteria, archaea, viruses, and fungi, occupy separate niches in and on the human body. Individually and collectively, these microbes provide benefits to the host-including nutrient harvest from food and protection against pathogens. They are dynamically regulated by both host genes and the environment, and they critically influence both physiology and lifelong health. The objective of the symposium was to discuss the relationship between the host and the microbiome-the combination of microbiota and their biomolecular environment and ecology-specifically with regard to metabolic and immunological systems and to define the critical research needed to understand and potentially target the microbiome in the prevention and treatment of diabetes. In this report, we present meeting highlights in the following areas: 1) relationships between diabetes and the microbiome, 2) bioinformatic tools, resources, and study design considerations, 3) microbial programming of the immune system, 4) the microbiome and energy balance, 5) interventions, and 6) limitations, unanswered questions, and resource and policy needs.

Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association.

Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of ß-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of ß-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.

General population screening for type 1 diabetes: has its time come?

PURPOSE OF REVIEW: The purpose of this review was to describe the potential for general childhood population-based screening of risk of symptomatic type 1 diabetes (T1D) RECENT FINDINGS: The earliest stages of T1D can be identified and risk and rate of progression to symptomatic disease can be estimated by the presence of multiple islet autoantibodies and glucose intolerance (dysglycemia) in individuals screened for risk. Screening for human leukocyte antigen risk genotypes in neonates with follow-up detection of islet autoantibodies in childhood has been explored. An alternative approach of general childhood population-based detection of autoantibodies at well child visits provides an approach to detect a high proportion of children who will develop T1D. The Fr1da study was launched in Bavaria in 2015 to explore this concept. SUMMARY: General childhood population-based screening for risk of T1D will allow detection of an at-risk population that can participate in natural history studies to better understand disease pathogenesis and intervention trials to prevent symptomatic disease and will provide a framework for public health-based prevention of childhood-onset T1D.

Protein kinase C-associated kinase regulates NF-κB activation through inducing IKK activation.

Activation of the transcription factor NF-κB induced by extracellular stimuli requires IKKα and IKKß kinase activity. How IKKα and IKKß are activated by various upstream signaling molecules is not fully understood. We previously showed that protein kinase C-associated kinase (PKK, also known as DIK/RIP4), which belongs to the receptor-interacting protein (RIP) kinase family, mediates the B cell activating factor of the TNF family (BAFF)-induced NF-κB activation in diffuse large B cell lymphoma (DLBCL) cell lines. Here we have investigated the mechanism underlying NF-κB activation regulated by PKK. Our results suggest that PKK can activate both the classical and the alternative NF-κB activation pathways. PKK associates with IKKα and IKKß in mammalian cells and induces activation of both IKKα and IKKß via phosphorylation of their serine residues 176/180 and 177/181, respectively. Unlike other members of the RIP family that activate NF-κB through a kinase-independent pathway, PKK appears to activate IKK and NF-κB mainly in a kinase-dependent manner. Suppression of PKK expression by RNA interference inhibits phosphorylation of IKKα and IKKß as well as activation of NF-κB in human cancer cell lines. Thus, PKK regulates NF-κB activation by modulating activation of IKKα and IKKß in mammalian cells. We propose that PKK may provide a critical link between IKK activation and various upstream signaling cascades, and may represent a potential target for inhibiting abnormal NF-κB activation in human cancers.

Delivering on George Eisenbarth's visionary pursuit of understanding pathogenesis and prevention of type 1 diabetes.

George Eisenbarth's pioneering and visionary research has provided a critical foundation that will be built on in the years ahead as we progress toward prevention of type 1 diabetes. His almost 30-year old model that type 1 diabetes was a chronic and predictable autoimmune disease with multiple identifiable progressive stages with a potential for interventions to prevent progression to symptomatic diabetes has stood the test of time. To deliver on the Eisenbarth vision and his "unfinished journey," the field needs: (1) to improve detection of risk of type 1 diabetes, (2) to improve staging and prediction of progression, (3) to perform smaller, shorter, practical, and an increased number of prevention clinical trials, and (4) to increase awareness of the potential for risk detection, staging, and prevention of type 1 diabetes and benefit/risk of prevention.

Mad1 is a transcriptional repressor of Bcl-6.

Bcl-6, a major regulator of B lymphocyte function that contributes to neoplastic transformation of B cells, is expressed in activated germinal center (GC) B cells and down-regulated during terminal differentiation to plasma cells. Regulation of Bcl-6 expression is incompletely characterized. Terminal B cell differentiation is associated with down-regulation of Bcl-6, activation of Blimp-1, modulation of Myc, and specifically with the up-regulation of the Mad1 and Mad4 transcription factors, which play a critical role in cell differentiation and cell cycle regulation. Because the Mad E-box consensus binding site is present in the upstream promoter of Bcl-6, we investigated whether Bcl-6 may be under control of the Mad1 transcription factor. Anti-sense Mad1 oligonucleotides abrogated the down-regulation of Bcl-6 expression that occurred during in vitro differentiation of mouse splenic B cells induced by dextran-conjugated anti-IgD Ab and IL-5. Transduction of the WEHI 231 B cell line with retroviruses expressing Mad1 down-regulated Bcl-6 expression. Expression of the 5' upstream promoter region of Bcl-6 was down-regulated by co-expression of Mad1. Last, chromatin immunoprecipitation assays with anti-Mad1 Ab demonstrated in vivo interaction of Mad1 with the Bcl-6 promoter region. The findings suggest that Mad1 is a transcriptional repressor of Bcl-6.

Human embryonic stem cell research and the Juvenile Diabetes Research Foundation International - a work in progress.

The Juvenile Diabetes Research Foundation International (JDRF) was founded in 1970 by parents of children with juvenile diabetes to find a cure for diabetes and its complications through the support of research. The foundation was an early supporter of stem cell research, recognizing the promise of stem cells to quicken the pace of discovery for a cure for juvenile diabetes. The JDRF has committed considerable resources to supporting stem cell research in both the United States and abroad. In the United States, the organization has been an advocate on the state and national level for increased funding and for expansion of current federal policy restricting embryonic stem (ES) cell research.

Activation of terminal B cell differentiation by inhibition of histone deacetylation.

A role for histone acetylation, which can alter the accessibility of DNA to transcriptional regulatory proteins and contribute to gene expression, in regulating terminal B cell differentiation was investigated in the mature B lymphoma L10A and mouse splenic B cells. Incubation of the L10A cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and butyrate increased expression of Blimp-1, J chain, and mad genes, decreased expression of c-myc and BSAP/Pax-5 genes, increased the expression of surface CD43 and Syndecan-1, and decreased surface IgM. Incubation of splenic B cells with TSA and dextran conjugated anti-IgD Ab increased Blimp-1 gene and Syndecan-1 surface expression. The alteration in gene expression and cell surface markers was consistent with induction of the onset of terminal B cell differentiation. Co-incubation of L10A cells with TSA and cycloheximide (CHX) abrogated the up-regulation of Blimp-1 expression, indicating that TSA-activated Blimp-1 expression required synthesis of a transcriptional activator. In contrast, mad expression was increased in L10A cells cultured with TSA and cycloheximide or cycloheximide alone, suggesting mad expression may occur independent of Blimp-1 expression and is regulated by a labile, HDAC associated transcriptional repressor. The results demonstrate that histone acetylation regulates transcription of genes controlling terminal B cell differentiation.