Increasing carbohydrate availability in the hindgut promotes hypothalamic neurotransmitter synthesis: aromatic amino acids linking the microbiota–brain axis

Abstract

The gut microbiota is increasingly recognized to modulate brain function by recent studies demonstrating the central effects of various gut microbial manipulation strategies. Our previous study demonstrated that antibiotic-induced alterations of hindgut microbiota are associated with changes in aromatic amino acid (AAA) metabolism and hypothalamic neurochemistry, while the underlying mechanistic insight is limited. Given that the microbial AAA metabolism can be affected by luminal carbohydrate availability, here we hypothesize that increasing hindgut carbohydrate availability affects the expression of neurotransmitters in the porcine hypothalamus. A hindgut microbiota-targeted strategy was adopted by increasing hindgut carbohydrate availability in a cecal-cannulated piglet model. Mechanistic involvement of AAAs along the gut microbiotaÀbrain axis was further investigated in mice and neuronal cells. Increasing carbohydrate availability by cecal starch infusion led to a decrease in hindgut AAA metabolism, and an increase in systemic AAA availability, central AAA-derived neurotransmitters (5-HT, dopamine), and neurotrophin BDNF in piglets, indicating that hindgut microbiota affect hypothalamic neurochemistry in an AAA-dependent manner. Single AAA i.p. injection in mice revealed that an increase in circulating tryptophan and tyrosine elevated their concentrations in brain and finally promoted the expressions of 5-HT, dopamine, and BDNF in a time-dependent manner. Neuronal cells treated with single AAAs in vitro further demonstrated that tryptophan and tyrosine enhanced 5-HT and dopamine synthesis, respectively, and promoted BDNF expression partly through the 5-HT1A/DRD1-CREB pathway. Our study reveals that increasing hindgut carbohydrate availability promotes hypothalamic neurotransmitter synthesis and that AAAs act as potential mediators between hindgut microbiota and brain neurochemistry.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

“…The gut microbiota digests the host’s dietary components to meet its own nutritional needs while simultaneously providing energy and nutrients for the host. However, the gut microbiota also produces some neuroactive metabolites such as neurotransmitters or their precursors, which can affect the concentrations of either related neurotransmitters, their precursors, or both, in the brain [ 22 , 23 , 24 , 25 ]. This suggests that the neurotransmitter synthesis pathway in the intestine might directly or indirectly affect the neuronal activity and cognitive functions of the brain [ 12 , 26 , 27 ].…”

Anhedonia induced by high-fat diet in mice depends on gut microbiota and leptin

“…that antibiotics reduce aromatic amino acid levels in the feces and blood and diminish the concentrations of aromatic amino acids and neurotransmitters derived from aromatic amino acids in the hypothalamus of piglets [33]. Since the availability of carbohydrates in the hindgut of piglets also influences hypothalamic neurotransmitter synthesis [34], the effect of the gut microbiome on carbohydrate and aromatic amino acid levels in the hindgut warrants further study as a link between microbiome and behavior. The change in the intestinal metabolome is likely to have an impact on several of the metabolic and behavioral alterations caused by ABT.…”

Gut-Brain Axis: Probiotic,Bacillus subtilis, Prevents Aggression via the Modification of the Central Serotonergic System

“…Consequently, gut microbiota influences and regulates hosts' health and mood statue including aggression by integrating metabolic, immune, endocrine, and neural reactions through the bidirectional communication of the gut-brain axis (Figure 1) [7, 33,[79][80][81][82][83]. Gut microbiota in hosts, for example, regulates brain neurotransmitters [84][85][86][87] such as serotonin (5-HT) through releasing its precursor, tryptophan, an essential amino acid [75,[88][89][90]. Serotonin is a key neurotransmitter within the brain, contributing to the development of the central nervous system (CNS)…”