The Impact of Starvation on the Microbiome and Gut-Brain Interaction in Anorexia Nervosa

Interactions between the gut microbiome and the brain are of increasing interest to both researchers and clinicians. Evidence is mounting on the causal role of an altered gut microbiome in inflammatory diseases such as arthritis, inflammatory bowel disease, obesity and diabetes, and psychiatric diseases like anxiety and depression. Mechanisms include altered energy harvest from food, hormonal changes, increased gut permeability, inflammation, immune response, and a direct influence on the brain and behavior. Anorexia nervosa (AN) is the third most common disease in adolescence and exacts a high burden on patients and caregivers. It often becomes chronic and has the highest mortality of all psychiatric diseases. As AN is characterized by nutritional restrictions, weight loss, and severe behavioral symptoms including weight phobia, comorbid anxiety and depression, accompanied by endocrine alterations, increased inflammation, and immune response, exploring the role of the gut microbiome is crucial. Here, we present an overview of the potential mechanisms of interaction between the gut microbiome, the host and particularly the brain in AN and summarize the initial findings of microbiome research on AN. We conclude by identifying future research directions and potential therapeutic approaches, including nutritional interventions, probiotics, prebiotics and food supplements, that could become important additions to current AN therapy

Gut microbiota alteration in adolescent anorexia nervosa does not normalize with short-term weight restoration

Objective Gut microbiota are linked to metabolic function, body weight regulation, and brain and behavioral changes. Alteration of gut microbiota is repeatedly demonstrated in adults with anorexia nervosa (AN) and transplantation of stool from adult patients with AN reduces weight gain, food consumption and food efficiency in germ-free mice. No similar data are available for adolescents, who might differ from adults due to their shorter duration of illness. Method Nineteen female adolescent patients with AN at admission and after short-term weight recovery were included in a longitudinal study and compared to 20 healthy controls (HC). DNA was extracted from stool samples and subjected to 16S rRNA gene sequencing and analysis. Group comparisons, indicator genera and simper analysis were applied. Taxon abundances at admission was used to predict inpatient treatment duration. Results Alpha diversity is increased in patients with AN after short-term weight recovery, while beta diversity shows clear group differences with HC before and after weight gain. A reduction in Romboutsia and taxa belonging to Enterobacteriaceae at both timepoints and an increase in taxa belonging to Lachnospiraceae at discharge are most indicative of patients. Lachnospiraceae abundance at admission helped to predict shorter inpatient treatment duration. Discussion This pilot study provides first evidence of gut microbiota alterations in adolescent patients with AN that do not normalize with weight gain. If verified in larger studies, the predictive power of taxa belonging to Lachnospiraceae for clinical outcome could complement known predictors at admission, inform clinicians and serve as a target for nutritional interventions

Lower serum levels of IL-1β and IL-6 cytokines in adolescents with anorexia nervosa and their association with gut microbiota in a longitudinal study

Introduction Anorexia nervosa (AN) is an often chronic and debilitating psychiatric disease whose etiology is not completely understood. Recently, a potential role of inflammation has emerged in other psychiatric diseases, such as depression, PTSD and schizophrenia. The first results in adults with AN seemed to confirm a low-grade proinflammatory state until recent studies presented more differential findings. Studying adolescents with a shorter illness duration and fewer confounding factors might help elucidate the role of inflammation in the underlying pathophysiology of AN; however, the few available studies in adolescents remain ambiguous, and no longitudinal data are available in this age range. Results TNF-α serum levels were significantly elevated in patients with AN at admission, while IL-1β and IL-6 levels were lower at admission and discharge than in HC. After treatment, we also found significantly elevated levels of IL-6 Rα compared to HC, while IL-15 did not show significant changes. Exploratory analyses revealed positive associations of cytokine and genus-level changes between admission and discharge for IL-1β (Bacteroides) and IL-15 (Romboutsia), and negative associations for IL-15 (Anaerostipes) and TNF-α (uncultured Lachnospiraceae). Conclusion We confirmed a previous finding of elevated levels of TNF-α also in adolescents with AN; however, the reduced IL-1β and IL-6 levels differed from the mostly increased levels found in adults. A mixed pro- and anti-inflammatory state appears to be present in adolescents, potentially due to their shorter illness duration. The gut microbiota, with its regulatory function on cytokine production, might play a role in mediating these inflammatory processes in AN and could offer targets for new therapeutic approaches

Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, September 2016

Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lubeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases. Considerable advances have been made in describing incidences and prevalences of these diseases and linking comorbidities with autoantibody reactivities and clinical variants, for example, dipeptidyl peptidase-IV inhibitor-associated noninflammatory bullous pemphigoid. Although new entities are still being described, diagnosis of most autoimmune blistering diseases can now be achieved using standardized and widely available serological test systems. Various experimental mouse models of pemphigus and pemphigoid disease are increasingly being used to understand mechanisms of central and peripheral tolerance and to evaluate more specific treatment approaches for these disorders, such as molecules that target autoreactive T and B cells and anti-inflammatory mediators, that is, dimethyl fumarate, phosphodiesterase 4, and leukotriene B4 inhibitors in pemphigoid disorders, and chimeric antigen receptor T cells in pemphigus. Very recent experimental data about the immunopathology and the determinants of autoantibody formation and keratinocyte susceptibility in pemphigus were discussed. With regard to cellular mechanisms leading to the loss of cell-cell adhesion, new ideas were shared in the field of signal transduction. Major steps were taken to put the various partly contradictory and controversial findings about the effects of pemphigus autoantibodies and other inflammatory mediators into perspective and broaden our view of the complex pathophysiology of this disease. Finally, two investigator-initiated multicenter trials highlighted doxycycline and dapsone as valuable medications in the treatment of bullous pemphigoid.Non peer reviewe

Additional file 14: Table S11. of Improved detection of gene-microbe interactions in the mouse skin microbiota using high-resolution QTL mapping of 16S rRNA transcripts

Full details of pathway and biological process enrichment analyses for candidate regions. (XLSX 71 kb

Additional file 4: Table S3. of Improved detection of gene-microbe interactions in the mouse skin microbiota using high-resolution QTL mapping of 16S rRNA transcripts

Summary statistics of CMM OTUs and alpha diversity indices as profiled based on DNA. Means, standard deviations (STD), minimum (Min), maximum (Max), and coefficient of variation (CV) values of relative abundances in population G15 (n = 270). Un: unclassified. (XLSX 12 kb

Additional file 11: Figure S2. of Improved detection of gene-microbe interactions in the mouse skin microbiota using high-resolution QTL mapping of 16S rRNA transcripts

Manhattan plot of Neisseria_OTU1320 QTL mapping. Significant thresholds (p ≤ 0.05) are shown in a continuous line; suggestive thresholds (p ≤ 0.10) are shown in a discontinuous line. Chr: chromosome. (TIF 219 kb

Genome-wide mapping of gene-microbe interactions in the murine lung microbiota based on quantitative microbial profiling

Abstract Background Mammalian lungs comprise a complex microbial ecosystem that interacts with host physiology. Previous research demonstrates that the environment significantly contributes to bacterial community structure in the upper and lower respiratory tract. However, the influence of host genetics on the makeup of lung microbiota remains ambiguous, largely due to technical difficulties related to sampling, as well as challenges inherent to investigating low biomass communities. Thus, innovative approaches are warranted to clarify host-microbe interactions in the mammalian lung. Results Here, we aimed to characterize host genomic regions associated with lung bacterial traits in an advanced intercross mouse line (AIL). By performing quantitative microbial profiling (QMP) using the highly precise method of droplet digital PCR (ddPCR), we refined 16S rRNA gene amplicon-based traits to identify and map candidate lung-resident taxa using a QTL mapping approach. In addition, the two abundant core taxa Lactobacillus and Pelomonas were chosen for independent microbial phenotyping using genus-specific primers. In total, this revealed seven significant loci involving eight bacterial traits. The narrow confidence intervals afforded by the AIL population allowed us to identify several promising candidate genes related to immune and inflammatory responses, cell apoptosis, DNA repair, and lung functioning and disease susceptibility. Interestingly, one genomic region associated with Lactobacillus abundance contains the well-known anti-inflammatory cytokine Il10, which we confirmed through the analysis of Il10 knockout mice. Conclusions Our study provides the first evidence for a role of host genetic variation contributing to variation in the lung microbiota. This was in large part made possible through the careful curation of 16S rRNA gene amplicon data and the incorporation of a QMP-based methods. This approach to evaluating the low biomass lung environment opens new avenues for advancing lung microbiome research using animal models. Graphical Abstrac

Pathometagenomics reveals susceptibility to intestinal infection by Morganella to be mediated by the blood group-related B4galnt2 gene in wild mice

ABSTRACTInfectious disease is widely considered to be a major driver of evolution. A preponderance of signatures of balancing selection at blood group-related genes is thought to be driven by inherent trade-offs in susceptibility to disease. B4galnt2 is subject to long-term balancing selection in house mice, where two divergent allele classes direct alternative tissue-specific expression of a glycosyltransferase in the intestine versus blood vessels. The blood vessel allele class leads to prolonged bleeding times similar to von Willebrand disease in humans, yet has been maintained for millions of years. Based on in vivo functional studies in inbred lab strains, it is hypothesized that the cost of prolonged bleeding times may be offset by an evolutionary trade-off involving susceptibility to a yet unknown pathogen(s). To identify candidate pathogens for which resistance could be mediated by B4galnt2 genotype, we here employed a novel “pathometagenomic” approach in a wild mouse population, which combines bacterial 16S rRNA gene-based community profiling with histopathology of gut tissue. Through subsequent isolation, genome sequencing and controlled experiments in lab mice, we show that the presence of the blood vessel allele is associated with resistance to a newly identified subspecies of Morganella morganii, a clinically important opportunistic pathogen. Given the increasing importance of zoonotic events, the approach outlined here may find useful application in the detection of emerging diseases in wild animal populations

Additional file 1: Figure S1. of Dissecting genetics of cutaneous miRNA in a mouse model of an autoimmune blistering disease

Flowchart describing the workflow of analysis. The flowchart provides an overview of the analysis performed for understanding regulation of miRNAs and their contribution to the disease phenotype. Figure S2 Interaction network accessed via IPA software for epistasis of miR-501. The graph depicts the interacting genes identified from epistasis scan of miRNA miR-501 in chromosome 1 and chromosome 2. The graph shows all known gene interactions between the two loci where genes colored in yellow are from locus on chromosome 2 and green are from locus on chromosome 1. The red line shows the possible pathway for the regulation of miR-501. Figure S3 qRT-PCR validation of miR-223 expression in EBA and normal murine skin. (ZIP 637 kb