Review

.2016 Nov 3;167(4):915-932.

doi: 10.1016/j.cell.2016.10.027.

The Central Nervous System and the Gut Microbiome

Gil Sharon¹, Timothy R Sampson², Daniel H Geschwind³, Sarkis K Mazmanian⁴

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: gsharon@caltech.edu.
² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Program in Neurobehavioral Genetics, Semel Institute, and Program in Neurogenetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Treatment and Research, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.

PMID:27814521
PMCID: PMC5127403
DOI: 10.1016/j.cell.2016.10.027

Review

The Central Nervous System and the Gut Microbiome

Gil Sharon et al. Cell.2016.

.2016 Nov 3;167(4):915-932.

doi: 10.1016/j.cell.2016.10.027.

Authors

Gil Sharon¹, Timothy R Sampson², Daniel H Geschwind³, Sarkis K Mazmanian⁴

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: gsharon@caltech.edu.
² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Program in Neurobehavioral Genetics, Semel Institute, and Program in Neurogenetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Treatment and Research, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.

PMID:27814521
PMCID: PMC5127403
DOI: 10.1016/j.cell.2016.10.027

Abstract

Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease.

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Figures

**Figure 1. Intersections of gut microorganisms and basic developmental processes**
Basic developmental processes driven directly or indirectly by gut microbes and their products. (A) Gut microorganisms relay messages to the brain via various direct and indirect mechanisms. (B) Basic neurodevelopmental processes are modulated as a result of colonization of GF animals or depletion of gut bacteria by antibiotics. Specifically, the following processes are modulates: blood-brain barrier (BBB) formation and integrity (Braniste et al., 2014), neurogenesis (Möhle et al., 2016; Ogbonnaya et al., 2015), microglia maturation and ramification (Erny et al., 2015; Matcovitch-Natan et al., 2016), myelination (Gacias et al., 2016; Hoban et al., 2016), and expression of neurotrophins (Bercik et al., 2011a, 2011b; Desbonnet et al., 2015), neurotransmitters (Bercik et al., 2011a; O’Mahony et al., 2015), and their respective receptors.

**Figure 2. Major events in mammalian brain development**
Developmental trajectories and key neurodevelopmental events in mice and humans (adapted from(Knuesel et al., 2014; Pressler and Auvin, 2013; Semple et al., 2013). E-embryonic age, P-postnatal age, GSW-gestational week. Bacterial taxa on the right panel are the dominant ones at each life stage (Bäckhed et al., 2015; Lloyd-Price et al., 2016b; Nuriel-Ohayon et al., 2016).

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The Central Nervous System and the Gut Microbiome

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