# Tryptophan and Membrane Mobility as Conditioners and Brokers of Gut-Brain Axis in Depression
###### Abstract
In particular, recent studies have shown how and to what extent the intestinal microbiota is involved in the regulation of functional aspects of the brain and behavior, with particular regard to alterations in tryptophan metabolism and the serotonergic system. Research has been focused on the bidirectional communication between the brain and gut, looking at 5-HT as a molecular signaling factor in both the brain and the enteric nervous system, where 5-HT regulates functions such as secretion, vasodilation, peristalsis, and the perception of pain. The gut microbiota is a critical element of this axis and performs its function not only locally but on several levels. Alterations of 5-HT occur in disorders of the microbiota-gut-brain axis and in communication between the districts [8; 46]. This axis explains the mood alterations in irritable bowel syndrome (IBS) and suggests that IBS pathogenesis is partly related to the dysfunctional control of 5-HT production by the gut microbiota. Furthermore, the development of IBS has been shown to be connected to tryptophan depletion. Mechanisms supporting the influence of the microbiota on the availability of tryptophan and therefore of 5-HT are possible through the enzymatic activities responsible for the degradation of tryptophan along the kinurenine pathway [47]. This pathway is involved in a reduction in the kinurenine/tryptophan ratio in germ-free mice (mice born and raised in the absence of microbiota). Furthermore, the alterations of IDO/tryptophan 2,3-dioxygenase (TDO) activity seem to have relevant clinical implications in various pathological conditions [48]. Figure 2: Tryptophan pathway from gut to brain. On the left, a schematic description of the metabolic pathway of tryptophan from enterochromaffin cells to platelets is shown under normal conditions. To the right, the same hypothetical pathway is modified in conditions of intestinal inflammation or dysbiosis (loss of stability of gut microbiota) and under an alteration in the fluidity of the membrane due to the excessive presence of arachidonic acid. In this case, 5-HT would not be captured by platelets and would remain free, thus contributing to possible cardiovascular and bone damage. In addition, the enzymes IDO and TDO metabolize tryptophan to kinurenine and, furthermore, stop tryptophan from entering the brain. AAAD, aromatic L-amino acid decarboxylase; AANAT, N-acetyl transferase; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; 5-HT, 5-hydroxytryptamine, serotonin; TPH1, tryptophan hydroxylase 1. Interestingly, the conversion of tryptophan to 5-HT occurs predominantly in the intestine, in the enterochromaffin cells of the intestinal mucosa. As previously mentioned, the vast majority of 5-HT is not found in the CNS but in the gastrointestinal tract [49]. The levels of 5-HT vary depending on plasma tryptophan levels and on the current availability of tryptophan from nutrition [50]. Several species of enteric microorganisms, such as _Lactobacillus_, _Bifidobacterium_, _Escherichia_, _Bacillus_, and _Saccharomyces_, are able to produce neurotransmitters, including 5-HT. Unlike 5-HT, tryptophan produced by gut microbiota is permeable with respect to the blood-brain barrier and produces positive effects on mood through an increase in 5-HT levels in the brain [51]. In addition, gut microbiota can use tryptophan directly. Preclinical studies have reported direct and indirect mechanisms by which the gut microbiota is able to regulate tryptophan availability for kynure pathway metabolism, with downstream effects on CNS function [52]. Finally, impaired rapid eye movement (REM) sleep in depression is partially caused by the hyperactivation of REM-on cholinergic neurons. This is supported by the discovery that cholinergic stimulation leads to a more severe REM sleep inhibition in depressed patients compared to healthy controls [53]. Sleep disturbances are common in depressed subjects and also in subjects with dysbiosis and intestinal inflammation [54].