Neonatology

Infectious Diseases

Developmental Biology

Neurology

Cross-Disciplinary Pathway

Clinical Research Pathway

Microbial Metabolites Associated With Immunity and Central Nervous System Health in Early Life: Opportunities for Biomarker Discovery and Therapeutics

Chair(s)

• 

  Mohan Pammi, MD, PhD, MRCPCH

  Associate Professor
  Baylor College of Medicine
  Houston, Texas, United States
• 

  Josef Neu, MD

  Professor
  Pediatrics/Neonatology
  University of Florida
  Gainesvilled, Florida, United States

The human microbiome and their metabolic processes play a vital role in human pathophysiology. Advancing technology including metabolomics and next generation sequencing have provided a better and holistic understanding of disease pathophysiology as it relates to the human microbiome. In this proposed symposium, we will discuss the influence of microbial metabolites and products on mucosal immunology and health of the central nervous system. We will also explore the role of microbial metabolites as opportunities for discovery of biomarkers and novel therapeutics.

The Microbiome in Early Life: The fetus and newborn undergoes major transitions in relation to microbial exposures before, during and shortly after the birthing process. The relatively naïve neonatal microbiome along with the interaction between microbial components and metabolites and the hosts’ responses mature and evolve rapidly. Prior to birth, emerging evidence supports that the maternal and fetal ecosystems play a role in timing of delivery. At birth, vaginal versus cesarean delivery and the events surrounding these processes, as well as feeding and feeding composition, antibiotic exposure and the environment influence the developing neonatal microbiome. During the neonatal period, microbial dysbiosis has been implicated in neonatal diseases such as necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia. Dysbiosis of the intestinal microbiome has been implicated in immune dysregulation (allergic and autoimmune disorders). A genetic predisposition, along with an altered microbiome and environmental triggers have been associated with a “perfect storm” for the pathogenesis of Type 1 diabetes and other autoimmune diseases.

Metabolomics is the latest of the ‘omics’ technology and identifies distinct patterns of small molecules generated during both host and microbial cellular metabolism. These biomarkers may help in disease diagnosis, prediction or prognostication. Microbial metabolite pattern may be useful in diseases associated with dysbiosis. Metabolite patterns are dynamic, changing with gestational age, chronological age or disease process and gives us a snapshot of the metabolic milieu of the organism. Nuclear magnetic resonance spectroscopy and mass spectrometry are the ones most common techniques employed. The metabolites produced by microbes and/or the host may regulate transcriptional and translational events that can be evaluated using transcriptomics and proteomics.

Microbiota, metabolites and CNS health: The intestinal microbiota and the brain communicate in many ways via the immune system, metabolites, the vagus nerve and the enteric nervous system (ENS). Microbial metabolites including those of tryptophan metabolism, short-chain fatty acids, branched chain amino acids, and peptidoglycans may act as signaling molecules that have direct or indirect effects on the CNS and the ENS. Gut microbiota have been shown to influence developmental processes including neurogenesis, myelination, glial cell function, synaptic pruning and blood‐brain barrier permeability and in adult animals, microglial activation and neuroinflammation. It is possible that there may be a critical period or window in early life when the gut microbial composition is crucial and perturbation of the gut microbiota during this period causes long‐lasting effects on the development of the CNS and the ENS. The intestinal microbiome (gut)-brain axis has been implicated in neurodevelopmental disorders such as autism spectrum disorders, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Most of the studies have shown associations without strong support for causality. Although animal and cell culture models can be helpful to better delineate mechanisms and causality, translational research with multi-omic approaches can provide evidence of causality.

Microbiota, metabolites and mucosal immunology: The commensal microbiome in the intestine regulates the maturation of the mucosal immune system, while the pathogenic microbiome causes immune dysfunction, resulting in inflammation and disease. The gut mucosal immune system, which consists of lymph nodes, lamina propria and epithelial cells, constitutes a protective barrier for the integrity of the intestinal tract. The composition of the gut microbiota is under the surveillance of the normal mucosal immune system. Inflammation, which is caused by abnormal immune responses, influences the balance of the gut microbiome, resulting in intestinal diseases. Microbiota as well as their cell components and their metabolites act as environmental triggers that influence mammalian gene expression as well as innate and adaptive immune responses. Recognition of commensal-derived PAMPs, such as lipopolysaccharides (LPS) by the intestinal epithelial cells (IEC) induce secretion of the antimicrobial peptide RegIIIg, which mediates colonization resistance in the gut. Microbiota-derived signals, butyrate, propionate and acetate (short chain fatty acids, SCFAs), induce IL-18 production from the IEC through activation of NOD-like family, receptors (NLRs) . Acetate produced by Bifidobacteria promotes epithelial cell barrier function by inducing an anti-apoptotic response in the IEC. The tryptophan/serotonin metabolic pathway, crucial in regulation of numerous neural responses rely on microbial production.

Microbial metabolites for diagnostics and therapeutics: Since presence of microbial dysbiosis may represent a disease phenotype, the intestinal microbiota and their metabolites have become effective targets for the development of new diagnostic methods. These diagnostic method may target markers of intestinal inflammation/ injury or those of systemic inflammation. Biomarkers include testing the blood (e.g. cytokines, CRP, procalcitonin, intestinal fatty acid binding protein, I-FABP) or non-invasive from stools (e.g. calprotectin, volatile organic acids) or from urine (I-FABP in urine, serum amyloid A in the urine). If dysbiosis is associated with disease, then optimizing the gut microbiome will likely represent an effective treatment for intestinal or other inflammatory diseases (fecal microbial transplant therapy).

Presentations:

• 9:00 AM - 9:10 AM US CT

  Introduction and objectives
  

  Presenter: Josef Neu, MD – University of Florida
• 9:10 AM - 9:30 AM US CT

  Microbiome and metabolites
  

  Presenter: Mohan Pammi, MD, PhD, MRCPCH – Baylor College of Medicine
• 9:30 AM - 10:00 AM US CT

  Microbial metabolites in CNS health and disease
  

  Presenter: Barbara Warner, MD, M.Sci – Washington University in St Louis
• 10:00 AM - 10:30 AM US CT

  Microbial metabolites in mucosal immunology and immunity
  

  Presenter: Emily Hollister, PhD – Diversigen, Inc
• 10:30 AM - 11:00 AM US CT

  Microbial metabolites as diagnostics, therapeutics, implications for the future
  

  Presenter: Josef Neu, MD – University of Florida
• 11:00 AM - 11:30 AM US CT

  Break
  

  Presenter: Belinda Thomas
• 11:30 AM - 12:00 PM US CT

  Click for Live Q&A: Microbial Metabolites Associated With Immunity and Central Nervous System Health in Early Life: Opportunities for Biomarker Discovery and Therapeutics
  

  Presenter: Belinda Thomas