Alessio Fasano - Gut Feelings: The Microbiome and Our Health

List of Figures

Food pyramid based on the Mediterranean diet and lifestyle. Adapted from https://oldwayspt.org.

Prenatal, perinatal, and postnatal factors influence microbiome composition and function. Adapted from V. J. Martin, M. M. Leonard, L. Fiechtner, and A. Fasano, Transitioning from Descriptive to Mechanistic Understanding of the Microbiome: The Need for a Prospective Longitudinal Approach to Predicting Disease, Journal of Pediatrics 179 (December 1, 2016): 240248, https://doi.org/10.1016/j.jpeds.2016.08.049.

Factors and lifestyle during the first one thousand days of life (from conception to two years of age) influence microbiome engraftment and function toward adulthood and adult health outcomes.

Hierarchy of the classification of the bacterial domain.

Gut dysbiosis causes switching from controlled antigen trafficking to zonulin-dependent increased antigen trafficking that is secondary to changes in tight junctionrelated gene expression. These changes lead to T-cell activation, production of proinflammatory cytokines, and onset of -cell autoimmunity. Blocking the zonulin pathway will ameliorate inflammation by blocking antigen trafficking, with subsequent preservation of residual cells.

Diet affects the composition of the intestinal microflora. A hydrolyzed casein (gluten-free) diet reduces the number of Bacteroides species within the microflora, while the diabetogenic (gluten-containing) diet favors a high titer of Bacteroides [1]. Colonization of the gut with an imbalanced microflora in which the Bacteroides species is favored over other species, such as Bifidobacterium and Lactobacillus, activates the zonulin pathway [2]. In parallel, gliadin, a component of the grain protein gluten, binds to the chemokine receptor CXCR3 (expressed on intestinal epithelial cells) and induces MyD88-dependent activation of the zonulin pathway [3]. A hydrolyzed casein diet prevents activation of the CXCR3-zonulin pathway [4]. Activation of the zonulin pathway leads to increased zonulin release [5]. The released zonulin binds to zonulin receptors on the surface of the intestinal epithelium and causes disassembly of tight junctions by causing changes in tight-junction dynamics, including phosphorylation of occludin and ZO-1, changes in occludin-ZO-1 and ZO-1-myosin IB protein-protein interaction, and actin polymerization [6]. The disassembly of tight junctions leads to the impairment of the barrier function, leading to increased passage of luminal antigens into the lamina propria, where they are taken up and processed by mucosal antigen-presenting cells and presented to T cells [7]. The cascade of immune events eventually leads to autoimmune disease [8].

Effect of gut microbiota on neurofunctions. Signals from gut microbes are required for neuroinflammatory responses as well as hallmark gastrointestinal and -synuclein-dependent motor deficits in a model of Parkinsons disease. Adapted from T. R. Sampson, J. W. Debelius, T. Thron, S. Janssen, G. G. Shastri, Z. E. Ilhan, C. Challis, et al., Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinsons Disease, Cell 167, no. 6 (December 1, 2016): 14691480, https://doi.org/10.1016/j.cell.2016.11.018.

How the microbiome changes with age and environmental factors. Adapted from M. Levy, A. Kolodziejczyk, C. A. Thaiss, and E. Elinav, Dysbiosis and the Immune System, Nature Reviews Immunology 17, no. 4 (March 2017): 219232, https://doi.org/10.1038/nri.2017.7.

Key milestones in microbiome science from its inception in 1683 to future projections of its potential exploitation for personalized medicine and disease intervention. (Adapted from N. Pariente, Milestones in Human Microbiota Research, Milestones, June 18, 2019, https://www.nature.com/immersive/d42859-019-00041-z/index.html, accessed February 2, 2020.)

List of Tables

Protective immunological factors found in human milk mitigate characteristics of immature innate immunity

Chronic inflammatory diseases to which zonulin has been linked as a biomarker of gut permeability

Next-generation probiotics, their main therapeutic effects, and their main mechanism of action