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 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 autonomic nervous system, 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 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 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 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 feedback to the brain, either systemically or via vagal afferents. This microbial modulation of brain networks may increase stress responsiveness, anxiety, and sensory perception.