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Gut Microbiome and Modulation of CNS Function

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Abstract

Preclinical evidence strongly suggests a role for the gut microbiome in modulating the host central nervous system function and behavior. Several communication channels have been identified that enable microbial signals to reach the brain and that enable the brain to influence gut microbial composition and function. In rodent models, endocrine, neural, and inflammatory signals generated by gut microbes can alter brain structure and function, while autonomic nervous system activity can affect the microbiome by modulating the intestinal environment and by directly regulating microbial behavior. The amount of information that reaches the brain is dynamically regulated by the blood‐brain barrier and the intestinal barrier. In humans, associations between gut microbial composition and function and several brain disorders have been reported, and fecal microbial transplants from patient populations into gnotobiotic mice have resulted in the reproduction of homologous features in the recipient mice. However, in contrast to preclinical findings, there is little information about a causal role of the gut microbiome in modulating human central nervous system function and behavior. Longitudinal studies in large patient populations with therapeutic interventions are required to demonstrate such causality, which will provide the basis for future clinical trials. © 2020 American Physiological Society. Compr Physiol 10:57‐72, 2020.

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Figure 1. Figure 1. Systems biological model of brain‐gut‐microbiome interactions. The gut microbiota communicate with a network of interacting cell types in the gut that include neuronal, glial, endocrine, and immune cells 18 (see also Figure 4), and changes in gut function can modulate gut microbial behavior. This gut‐based system has been referred to as the gut connectome 18 in analogy to the brain connectome, the interconnected networks of the central nervous system 159. The brain connectome generates and regulates the influence of the ANS, which can alter the gut microbial composition and function indirectly by modulating the microbial environment in the gut. The gut microbiota can communicate to the brain indirectly via gut‐derived molecules acting on afferent vagal and/or spinal nerve endings or directly via microbe‐generated signals. Alterations in the gain of these bidirectional interactions in response to perturbations such as psychosocial or gut‐directed (e.g. diet, medication, infection) stress can alter the stability and behavior of the system, manifesting as brain‐gut disorders. The model predicts that both brain‐ and gut‐directed therapeutic approaches or a combination can be effective. Modified, with permission, from Fung TC, et al., 2017 50.
Figure 2. Figure 2. Interactions of gut microbial signals with the host via immune, neural, and endocrine mechanisms. Interactions between luminal signals, specialized cells in the gut wall, the enteric, and the central nervous system and luminal signals. Enteroendocrine cells (EECs), enterochromaffin cells (ECCs), and gut‐associated immune cells function as main transduction mechanisms between luminal signals (nutrients, gut microbial metabolites, toxins, and irritants) and the central nervous system. Nutrients can signal to the host directly or via gut microbial metabolites. Substances released from these transduction cells can reach the brain via the systemic circulation or via vagal and spinal afferent pathways. Modified, with permission, from Mayer, et al., 2017 153.
Figure 3. Figure 3. Bidirectional signaling within the BGM axis involving serotonin. Enterochromaffin cells (ECCs, shown in green) are the main storage site for the body's serotonin (5‐HT). The rate‐limiting enzyme for 5‐HT synthesis, tryptophan hydroxylase (TPH1) in ECCs is modulated by SCFAs and 2°BAs produced by spore‐forming Clostridiales. The microbial effect on 5‐HT synthesis is increased with increased dietary tryptophan availability. ECCs are closely linked to afferent nerve fibers through synapse‐like connections. In addition, the autonomic nervous system can stimulate ECCs to release 5‐HT into the gut lumen, where it can interact with gut microbes. Reproduced, with permission, from Martin CR, et al., 2018 102.
Figure 4. Figure 4. Putative temporal sequence of altered brain‐gut‐microbiome interactions in irritable bowel syndrome. Bidirectional interactions link the brain connectome (interacting brain networks) with the gut connectome (interacting regulatory systems in the gut). Alteration of brain networks by genetic and early life epigenetic influences alter perception of stress and stress reactivity, increasing the vulnerability for the later development of IBS. Altered autonomic nervous system output from the brain associated with increased stress reactivity can modify the environment for the gut microbes and modulate gut microbial behavior directly both tonically and acutely in response to psychosocial stress. Additional modulators of the gut microbiome include diet and gut infections, which are likely to interact with ANS influences. ANS‐induced alterations of gut microbial abundances and activity result in the generation of microbial neuroactive metabolites and immune mediators, which feedback to the brain, either systemically or via vagal afferents. This microbial modulation of brain networks may increase stress responsiveness, anxiety, and sensory perception.


Figure 1. Systems biological model of brain‐gut‐microbiome interactions. The gut microbiota communicate with a network of interacting cell types in the gut that include neuronal, glial, endocrine, and immune cells 18 (see also Figure 4), and changes in gut function can modulate gut microbial behavior. This gut‐based system has been referred to as the gut connectome 18 in analogy to the brain connectome, the interconnected networks of the central nervous system 159. The brain connectome generates and regulates the influence of the ANS, which can alter the gut microbial composition and function indirectly by modulating the microbial environment in the gut. The gut microbiota can communicate to the brain indirectly via gut‐derived molecules acting on afferent vagal and/or spinal nerve endings or directly via microbe‐generated signals. Alterations in the gain of these bidirectional interactions in response to perturbations such as psychosocial or gut‐directed (e.g. diet, medication, infection) stress can alter the stability and behavior of the system, manifesting as brain‐gut disorders. The model predicts that both brain‐ and gut‐directed therapeutic approaches or a combination can be effective. Modified, with permission, from Fung TC, et al., 2017 50.


Figure 2. Interactions of gut microbial signals with the host via immune, neural, and endocrine mechanisms. Interactions between luminal signals, specialized cells in the gut wall, the enteric, and the central nervous system and luminal signals. Enteroendocrine cells (EECs), enterochromaffin cells (ECCs), and gut‐associated immune cells function as main transduction mechanisms between luminal signals (nutrients, gut microbial metabolites, toxins, and irritants) and the central nervous system. Nutrients can signal to the host directly or via gut microbial metabolites. Substances released from these transduction cells can reach the brain via the systemic circulation or via vagal and spinal afferent pathways. Modified, with permission, from Mayer, et al., 2017 153.


Figure 3. Bidirectional signaling within the BGM axis involving serotonin. Enterochromaffin cells (ECCs, shown in green) are the main storage site for the body's serotonin (5‐HT). The rate‐limiting enzyme for 5‐HT synthesis, tryptophan hydroxylase (TPH1) in ECCs is modulated by SCFAs and 2°BAs produced by spore‐forming Clostridiales. The microbial effect on 5‐HT synthesis is increased with increased dietary tryptophan availability. ECCs are closely linked to afferent nerve fibers through synapse‐like connections. In addition, the autonomic nervous system can stimulate ECCs to release 5‐HT into the gut lumen, where it can interact with gut microbes. Reproduced, with permission, from Martin CR, et al., 2018 102.


Figure 4. Putative temporal sequence of altered brain‐gut‐microbiome interactions in irritable bowel syndrome. Bidirectional interactions link the brain connectome (interacting brain networks) with the gut connectome (interacting regulatory systems in the gut). Alteration of brain networks by genetic and early life epigenetic influences alter perception of stress and stress reactivity, increasing the vulnerability for the later development of IBS. Altered autonomic nervous system output from the brain associated with increased stress reactivity can modify the environment for the gut microbes and modulate gut microbial behavior directly both tonically and acutely in response to psychosocial stress. Additional modulators of the gut microbiome include diet and gut infections, which are likely to interact with ANS influences. ANS‐induced alterations of gut microbial abundances and activity result in the generation of microbial neuroactive metabolites and immune mediators, which feedback to the brain, either systemically or via vagal afferents. This microbial modulation of brain networks may increase stress responsiveness, anxiety, and sensory perception.
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Teaching Material

Vadim Osadchiy, Clair R. Martin, Emeran A. Mayer. Gut microbiome and modulation of CNS function. Compr Physiol 10: 2020, 57-72.

Didactic Synopsis

Major Teaching Points:

  1. The central nervous system and the gut microbiota interact with each other in a bidirectional way.
  2. Gut microbiota communicate with the host CNS through endocrine, immune, and neural pathways. This communication is programmed during the first 3 years of life and remains relatively stable throughout life despite perturbations.
  3. The CNS modulates the composition and function of the gut microbiota primarily through autonomic regulation of the gastrointestinal environment, as well as through direct modulation of gut microbial function by host signaling molecules, including norepinephrine.
  4. This bidirectional communication is regulated at critical barriers including the intestinal epithelium and blood brain barrier.
  5. A significant and growing body of evidence demonstrates differences in the gut microbiome between healthy controls and humans with CNS-related pathological conditions.
  6. Animal models indicate a potentiating or driving role of the gut microbiota in CNS disease-related phenotypes, but causality has not been convincingly demonstrated in human patient populations.
  7. Despite the promise of therapeutic potential, a limited understanding of the brain-gut-microbiome (BGM) network and dearth of clearly defined target mechanisms limits the translational impact.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

FIGURE 1. Teaching Points: Systems biological model of brain-gut-microbiome interactions.

The gut microbiota communicate with a network of interacting cell types in the gut that include neuronal, glial, endocrine, and immune cells (18)(see also Figure 4), and changes in gut function can modulate gut microbial behavior. This gut based systems has been referred to as the gut connectome (18) in analogy to the brain connectome, the interconnected networks of the central nervous system (159). The brain connectome generates and regulates the influence of the autonomic nervous system which can alter gut microbial composition and function indirectly by modulating the microbial environment in the gut. The gut microbiota can communicate to the brain indirectly via gut-derived molecules acting on afferent vagal and/or spinal nerve endings, or directly via microbe-generated signals. Alterations in the gain of these bidirectional interactions in response to perturbations such as psychosocial or gut-directed (e.g. diet, medication, infection) stress can alter the stability and behavior of the system, manifesting as brain-gut disorders. The model predicts that both brain and gut directed therapeutic approaches, or a combination can be effective. Modified from Fung et al (50), with permission.

FIGURE 2. Teaching Points: Interactions of gut microbial signals with the host via immune, neural and endocrine mechanisms.

Interactions between luminal signals, specialized cells in the gut wall, the enteric and the central nervous system and luminal signals. Enteroendocrine cells (EECs), enterochromaffin cells (ECCs) and gut associated immune cells function as main transduction mechanisms between luminal signals (nutrients, gut microbial metabolites, toxins and irritants) and the central nervous system. Nutrients can signal to the host directly, or via gut microbial metabolites. Substances released from these transduction cells can reach the brain via the systemic circulation, or via vagal and spinal afferent pathways (modified from Mayer et al (153), with permission)

FIGURE 3. Teaching Points: Bidirectional signaling within the BGM axis involving serotonin.

Enterochromaffin cells (ECCs, shown in green) are the main storage site for the body's serotonin (5-HT). The rate limiting enzyme for 5-HT synthesis, tryptophan hydroxylase (TPH1) in ECCs is modulated by SCFAs and 2BAs produced by spore-forming Clostridiales. The microbial effect on 5-HT synthesis is increased with increased dietary tryptophan availability. ECCs are closely linked to afferent nerve fibers through synapse-like connections. In addition, the autonomic nervous system can stimulate ECCs to release 5-HT into the gut lumen, where it can interact with gut microbes. Reproduced from Martin et al (102), with permission.

FIGURE 4. Teaching Points: Putative temporal sequence of altered brain-gut-microbiome interactions in Irritable Bowel Syndrome.

Bidirectional interactions link the brain connectome (interacting brain networks) with the gut connectome (interacting regulatory systems in the gut). Alteration of brain networks by genetic and early life epigenetic influences alter perception of stress and stress reactivity, increasing the vulnerability for the later development of IBS. Altered autonomic nervous system output from the brain associated with increased stress reactivity can modify the environment for the gut microbes and modulate gut microbial behavior directly both tonically and acutely in response to psychosocial stress. Additional modulators of the gut microbiome include diet and gut infections which are likely to interact with ANS influences. ANS-induced alterations of gut microbial abundances and activity result in the generation of microbial neuroactive metabolites and immune mediators which feed back to the brain, either systemically or via vagal afferents. This microbial modulation of brain networks may increase stress responsiveness, anxiety, and sensory perception.

 


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How to Cite

Vadim Osadchiy, Clair R. Martin, Emeran A. Mayer. Gut Microbiome and Modulation of CNS Function. Compr Physiol 2019, 10: 57-72. doi: 10.1002/cphy.c180031