The gut-brain axis (GBA) is a bilateral communication network between the gastrointestinal (GI) tract and the central nervous system. The essential amino acid tryptophan contributes to the normal growth and health of both animals and humans and, importantly, exerts modulatory functions at multiple levels of the GBA. Tryptophan is the sole precursor of serotonin, which is a key monoamine neurotransmitter participating in the modulation of central neurotransmission and enteric physiological function. In addition, tryptophan can be metabolized into kynurenine, tryptamine, and indole, thereby modulating neuroendocrine and intestinal immune responses. The gut microbial influence on tryptophan metabolism emerges as an important driving force in modulating tryptophan metabolism. Here, we focus on the potential role of tryptophan metabolism in the modulation of brain function by the gut microbiota. We start by outlining existing knowledge on tryptophan metabolism, including serotonin synthesis and degradation pathways of the host, and summarize recent advances in demonstrating the influence of the gut microbiota on tryptophan metabolism. The latest evidence revealing those mechanisms by which the gut microbiota modulates tryptophan metabolism, with subsequent effects on brain function, is reviewed. Finally, the potential modulation of intestinal tryptophan metabolism as a therapeutic option for brain and GI functional disorders is also discussed.

Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and brain ultrastructure and antibiotics may act directly on the brain. We hypothesized that the concerns related to antibiotic-induced gut dysbiosis can only adequately be addressed if the effect of intragastric treatment of adult mice with multiple antibiotics on (i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior is systematically investigated. Of the antibiotics used (ampicillin, bacitracin, meropenem, neomycin, vancomycin), ampicillin had some oral bioavailability but did not enter the brain. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics revealed that gut dysbiosis was associated with depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Importantly, novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. We conclude that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut dysbiosis.

The gut-brain axis refers to the bidirectional communication between the gut and the brain. Four information carriers (vagal and spinal afferent neurons, immune mediators such as cytokines, gut hormones and gut microbiota-derived signalling molecules) transmit information from the gut to the brain, while autonomic neurons and neuroendocrine factors carry outputs from the brain to the gut. The members of the neuropeptide Y (NPY) family of biologically active peptides, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are expressed by cell systems at distinct levels of the gut-brain axis. PYY and PP are exclusively expressed by endocrine cells of the digestive system, whereas NPY is found at all levels of the gut-brain and brain-gut axis. The major systems expressing NPY comprise enteric neurons, primary afferent neurons, several neuronal pathways throughout the brain and sympathetic neurons. In the digestive tract, NPY and PYY inhibit gastrointestinal motility and electrolyte secretion and in this way modify the input to the brain. PYY is also influenced by the intestinal microbiota, and NPY exerts, via stimulation of Y1 receptors, a proinflammatory action. Furthermore, the NPY system protects against distinct behavioural disturbances caused by peripheral immune challenge, ameliorating the acute sickness response and preventing long-term depression. At the level of the afferent system, NPY inhibits nociceptive input from the periphery to the spinal cord and brainstem. In the brain, NPY and its receptors (Y1, Y2, Y4, Y5) play important roles in regulating food intake, energy homeostasis, anxiety, mood and stress resilience. In addition, PP and PYY signal to the brain to attenuate food intake, anxiety and depression-related behaviour. These findings underscore the important role of the NPY-Y receptor system at several levels of the gut-brain axis in which NPY, PYY and PP operate both as neural and endocrine messengers.

The microbial ecosystem that inhabits the gastrointestinal tract of all mammals—the gut microbiota—has been in a symbiotic relationship with its hosts over many millennia. Thanks to modern technology, the myriad of functions that are controlled or modulated by the gut microbiota are beginning to unfold. One of the systems that is emerging to closely interact with the gut microbiota is the body’s major neuroendocrine system that controls various body processes in response to stress, the hypothalamic–pituitary–adrenal (HPA) axis. This interaction is of pivotal importance; as various disorders of the microbiota–gut–brain axis are associated with dysregulation of the HPA axis. The present contribution describes the bidirectional communication between the gut microbiota and the HPA axis and delineates the potential underlying mechanisms. In this regard, it is important to note that the communication between the gut microbiota and the HPA axis is closely interrelated with other systems, such as the immune system, the intestinal barrier and blood–brain barrier, microbial metabolites, and gut hormones, as well as the sensory and autonomic nervous systems. These communication pathways will be exemplified through preclinical models of early life stress, beneficial roles of probiotics and prebiotics, evidence from germ-free mice, and antibiotic-induced modulation of the gut microbiota.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.