The Microbiota-Gut-Brain Axis: From Motility to Mood

Abstract

The gut-brain axis plays an important role in maintaining homeostasis. Many intrinsic and extrinsic factors influence signaling along this axis, modulating the function of both the enteric and central nervous systems. More recently the role of the microbiome as an important factor in modulating gut-brain signaling has emerged and the concept of a microbiota-gut-brain axis has been established. In this review, we highlight the role of this axis in modulating enteric and central nervous system function and how this may impact disorders such as irritable bowel syndrome and disorders of mood and affect. We examine the overlapping biological constructs that underpin these disorders with a special emphasis on the neurotransmitter serotonin, which plays a key role in both the gastrointestinal tract and in the brain. Overall, it is clear that although animal studies have shown much promise, more progress is necessary before these findings can be translated for diagnostic and therapeutic benefit in patient populations.

Keywords: Brain Gut Axis; Irritable Bowel Syndrome; Microbiota-Gut-Brain Axis; Mood Disorders; Motility.

Figure 1:. Pathways of communication between microbiota & brain

A growing body of research is implicating different pathways of communication between the microbiome and brain in disorders of both mood and motility. Multiple direct and indirect (via systemic circulation) pathways exist through which the gut microbiota can modulate the gut-brain axis. They include endocrine (cortisol), immune (cytokines) and neural (vagus, enteric nervous system and spinal nerves) pathways. Several gut microbes are capable of synthesizing neurotransmitters (i.e., γ-amino butyric acid (GABA), noradrenaline, and dopamine) locally, which can act on target cells in the gut and act as an important avenue of communication. Neuroactive microbial metabolites can modulate brain and behavior through a number of ways that are still being elucidated. These include affecting epithelial cells to impact gut barrier function and enteroendocrine cells (EECs) to release GI hormones, as well as dendritic cells (DCs) to modulate immune function. Specialized structures on EECs and ECCs, known as neuropods have been shown to transduce sensory signals from the intestinal milieu to the brain through forming synapse-like connections to afferent nerves, including the vagus nerve. The enteric nervous system is perfectly poised to be an integral hub for microbial signals and can communicate with the brain via vagal and spinal pathways. However, the exact molecular signaling pathways of all these pathways involved remain to be defined.

Figure 2:. Serotonin (5-HT) as a critical regulator of gut-brain-microbiome axis signaling.

Gut bacteria in the intestinal microbiome produce short-chain fatty acids (SCFAs) that directly stimulate tryptophan hydroxylase 1 (TPH1), resulting in 5-HT synthesis in and secretion from intestinal enterochromaffin (ECC) cells. 5-HT released from the basal membrane of intestinal EC cells then interacts with receptors from neurons in the enteric nervous system to modulate motility and, during development, neuronal development and differentiation. Vagal afferents signal to the nucleus of the solitary tract (NTS) and the dorsal raphe nucleus (DRN), the latter of which houses the majority of the brain’s 5-HT neurons. These areas then interact with emotion-regulating brain networks that influence mood. Of note, SCFAs produced by gut bacteria can also directly stimulate free fatty acid receptors on multiple cell types, including epithelial cells, ECCs, immune cells, and nerve cells, including the vagus nerve and primary afferent neurons. This signaling can also modulate downstream regulation of motility, secretion, and gut-brain signaling. Abbreviations: Trp: tryptophan; SERT: serotonin reuptake transporter; MAO: monoamine oxidase.

Figure 3:. Challenges in Translational Research.

Schematic representation of research approaches aimed to identify a causal role of the gut microbiome in human brain and brain gut disorders. There is extensive evidence for cross sectional differences in the gut microbial composition between defined disease populations and healthy control populations (top row). A number of rodent models of human brain diseases have been developed that mimic certain disease aspects (second row from top). More recently, studies have been reported in which fecal microbial transplants from patients with certain brain diseases into germ free mice have resulted in altered mouse behaviors, mimicking some aspects of the human phenotype (middle row). Fecal microbial transplants from healthy human subjects into individuals with brain disorders have not resulted in consistent improvement in respective symptoms to date (second row from bottom). To date, there is limited evidence for the effectiveness of therapeutic interventions targeted at the microbiome (bottom row).