Tryptophan Metabolism and the Microbiome-Gut-Brain Axis

The capacity of the gut microbiome to influence communication along the gut-brain axis relies in part on the microbial influence on neurotransmitter systems. Recent years have seen increasing surveillance of tryptophan in this regard, an essential amino acid and building block for a number of host-produced and microbial-derived bioactives. An appreciation of the important role for tryptophan in supporting microbiome-gut-brain axis signaling requires a reframing of what is currently known about this important precursor to integrate with newer concepts around the gut microbiota. The fate, distribution, metabolism, absorption, and distal availability of tryptophan for these pathways following dietary consumption is heavily influenced by the action of the gastrointestinal microbiota. This in turn has implications for local gastrointestinal enteric circuits and the neurobiology of a range of central nervous system and gastrointestinal disorders in which compositional and functional microbiota alterations have now been reported. Further research is required to bridge the knowledge gaps surrounding microbial regulation of tryptophan metabolism and availability. Mechanistic advances in our understanding of these important aspects of host–microbe dialogue offer the possibility of therapeutic targeting of the gut microbiome to fine-tune tryptophan metabolism in multiple pathways that contribute to symptom expression in disorders associated with the microbiome-gut-brain axis.

Posttraumatic Stress Disorder and the Gut Microbiome

Posttraumatic stress disorder (PTSD) is a trauma- and stressor-related disorder that is often associated with the dysregulation of multiple physiological systems, including autonomic nervous system functioning, glucocorticoid signaling, and chronic low-grade inflammation. Recent evidence suggests that persons with a diagnosis of PTSD also exhibit alterations in the composition of gut microbiomes compared to people who are trauma-exposed but do not develop PTSD. The bidirectional communication between the gut microbiome, the gut, and the brain, deemed the microbiome-gut-brain (MGB) axis, is composed of neural, neuroendocrine, and immune processes that both impact and respond to the structure of the gut microbiome. This chapter aims to outline (1) the ways in which trauma and stressor exposure may impact the gut microbiome; (2) the ways in which gut microbiome composition may influence brain function, including anxiety, and fear responses; and (3) how the bidirectional MGB axis, through interactions with several physiological circuits, may determine individual variability in resilience versus vulnerability to development of PTSD after trauma exposure.

Psychobiotics

For centuries, individuals have consumed probiotics as a means of improving quality of life and preventing disease. The gut microbiota refers to the collection of microorganisms residing within the gut. Psychiatric disorders show profound alterations of gut microbiota composition along with a lack of bacterial diversity. Specific subtypes of probiotics and prebiotics (fibers that promote the growth of beneficial bacteria) are referred to as psychobiotics, which impact the gut-brain axis and result in modifications of mood, anxiety, and cognitive function. It is essential for psychiatrists to improve their understanding of psychobiotic mechanisms and the evidence that supports their use in practice. In recent years, interventional studies have assessed the effects of psychobiotics for several symptom clusters, including depression and anxiety. However, some significant determinants, including duration of treatment, dosage of psychobiotics, and interactions with concomitant therapies, deserve more detailed investigation, and specific treatment guidelines for psychobiotics have not yet been established. The capacity of pre- and probiotics to modify psychological symptoms, while significant, is likely to be modest. In addition, this psychobiotic ability varies among probiotic strains—not all psychobiotics are right for all diseases. As psychobiotics are generally considered safe, this may justify their use as an add-on-therapy for some psychiatric indications. This chapter reviews the role of psychobiotics for mental health, their definition, their characteristics, and their mechanisms of action. Against the background of recent research, the chapter outlines a “psychobiotic prescription” to justify a condition-specific rationale for the use of psychobiotics based on recommendations in the current literature.

Gut Hormones and Neuropeptides as Mediators of Microbiome–Brain Communication

The gut microbiota interacts with the brain through multiple communication lines in which gut peptide hormones and neuropeptides play important messenger roles. These peptides are secondary chemical signals whose operation is controlled by the gut microbiota via a myriad of microbial metabolites, secondary bile acids, and structural components. We first outline a number of gut hormones (e.g., peptide YY, glucagon-like peptide, ghrelin, cholecystokinin) which communicate with the brain either via the circulation or via vagal afferent neurons. Several neuropeptides in the brain are likewise under the influence of gut microbes and mediate their impact on various aspects of brain function and behavior. These neuropeptides include neuropeptide Y, corticotropin-releasing factor, brain-derived neurotrophic factor, and several other peptides which act as neurotransmitters or trophic factors. Food intake, energy homeostasis, emotional-affective behavior, cognitive performance, stress resilience, and neurogenesis are among the processes which the gut microbiota regulates via the action of gut hormones and neuropeptides.

Gut Microbiome and Depression

Gut microbial diversity has been strongly associated with mood-related behaviors, including major depressive disorder (MDD), with an emerging potential to revolutionize both the diagnosis and treatment of depression. This article reviews the communication systems between the gut and the brain and the association between gut inflammatory conditions and depression. It further reviews the role of the gut microbiota in the treatment of depression, from pharmacological treatment to the use of probiotics and dietary treatments.

The Gut Microbiome in Neurodegenerative Disorders

For some time, the concept of the gut-brain axis has served as a useful paradigm to explain the many interactions between the “big brain” (the central nervous system [CNS]) and the “little brain” (the enteric nervous system). Recently, the gut microbiome has been added to the equation and the proposition that gut microbes could influence brain structure and function and vice versa has emerged. Research in this field has been facilitated by dramatic progress in technologies that permit the delineation of the microbial constituents of the gut and their function in health and disease. Studies in a variety of animal models have amply supported the concept of a microbiota-gut-brain-axis and demonstrated that interventions that modulate the microbiome can influence animal behavior and CNS physiology. Understandably, studies of the impact of the microbiome on human brain structure and function are less numerous, but sufficient evidence does exist to indicate that this axis is operating in humans. In terms of neurodegenerative disorders, here again animal data dominate, but a sufficient body of evidence has accumulated to justify further explorations of the role of gut microbiota in Parkinson’s disease and Alzheimer’s disease, as well as in the aging process per se—“inflammaging.” Many confounding factors complicate the interpretation of human studies of the microbiome, and large, longitudinal studies that attempt to account for such confounders are needed. A number of interventions can be entertained—most notably, diet, probiotics, and prebiotics. To date, studies of any such interventions in neurodegenerative disease in humans are scanty.