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Principles and clinical implications of the brain–gut–enteric microbiota axis


While bidirectional brain–gut interactions are well known mechanisms for the regulation of gut function in both healthy and diseased states, a role of the enteric flora—including both commensal and pathogenic organisms—in these interactions has only been recognized in the past few years. The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells). Communication from enteric microbiota to the host can occur via multiple mechanisms, including epithelial-cell, receptor-mediated signaling and, when intestinal permeability is increased, through direct stimulation of host cells in the lamina propria. Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system. Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions. Disruption of the bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic gastrointestinal disease states, including functional and inflammatory bowel disorders.

Key Points

  • Bidirectional brain–gut interactions have an important role in the modulation of gastrointestinal functions, such as motility, secretion, blood flow, intestinal permeability, mucosal immune activity, and visceral sensations, including pain

  • Evidence suggests that the enteric microbiota has an important role in the above interactions

  • Brain to gut signaling can affect host–bacteria interactions in the gastrointestinal tract indirectly by increasing permeability of the intestinal epithelium, modulating the mucosal immune response and effecting changes in gastrointestinal secretion

  • Evidence supports direct communication between epithelial cells and enteric bacteria via luminal release from neurons, immune cells, Paneth cells and enterochromaffin cells of signaling molecules that can modulate microbial virulence

  • Evidence supports a communication pathway between microbes in the gut lumen and the host's central nervous system via enteric microbiota–enterochromaffin cells–vagal afferent nerves signaling

  • Bidirectional interactions between brain and enteric microbes might have an important role in modulating gut function and may be involved in the modulation of emotions, pain perception and general well-being

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Figure 1: Schematic representation of the pattern of bidirectional brain–gut–microbe interactions.
Figure 2: Interface between the enteric microbiota, immune cells in the lamina propria and the ANS.
Figure 3: Schematic representation of the interkingdom, adrenergic signaling between host and enteric microbiota.
Figure 4: Schematic representation of endocrine cell-mediated signaling from enteric microbiota to host.
Figure 5: Enterochromaffin cells as bidirectional signal transducers between host and enteric microbiota.


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This work was supported in part by the National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases grants R01 DK 48,351, P50 DK64539 and R24 AT002681, RO1 DK47343, P01 DK 33,506, R01 DK072471, and RO1 DK060729. The authors thank Jennifer Drader for excellent editorial services.

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Correspondence to Emeran A. Mayer.

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E. A. Mayer declared association with the following companies: Eli Lilly and Company as consultant, GlaxoSmithKline as consultant and recipient of grant/research support, Groupe Danone as consultant and recipient of grant/research support, Johnson & Johnson as recipient of grant/research support, Nestlé and Prometheus Laboratories as consultant. C. Pothoulakis and S. H. Rhee declared no competing interests.

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Rhee, S., Pothoulakis, C. & Mayer, E. Principles and clinical implications of the brain–gut–enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6, 306–314 (2009).

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