The serotonin precursor 5-hydroxytryptophan reinforces intestinal barrier function
D. Keszthelyi 1,2, F.J. Troost 1,2, H. van Eijk 3, E. Schaepkens 1,2, P. Lindsey 4, D. Jonkers 1,2, W.A.
Buurman 3, J. Dekker 1 and A.A.M. Masclee 1,2
1 Top
Institute Food and Nutrition, Wageningen, The Netherlands, 2Division of GastroenterologyHepatology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The
Netherlands, 3 Department of Surgery, Maastricht University Medical Centre+, Maastricht, The
Netherlands, 4 Deparment of Clinical Genomics, Maastricht University Medical Centre+, Maastricht,
The Netherlands
Tight junctions between intestinal epithelial cells form a selective barrier that contributes to
gut
homeostasis. Alterations in intestinal barrier function are considered to be early factors in the
pathogenesis of irritable bowel syndrome (IBS). Changes in serotonergic metabolism have also been
associated with IBS. The direct precursor of 5-HT, 5-hydroxytryptophan (5-HTP), is available as overthe-counter dietary supplement and is a potential substance to influence serotonin availability and
possibly also intestinal barrier function. Aim was to assess the effect of an oral bolus of 5-HTP on
intestinal barrier function and mucosal 5-HT metabolism.15 healthy volunteers participated in this
randomized double-blind placebo-controlled crossover study. Intestinal permeability was measured by
determining the plasma recovery of an orally ingested multi-sugar drink on two separate occasions.
Plasma samples were taken prior to, at 60, 90 and 120 min after intake of 100 mg 5-HTP or placebo.
At the end of each of both test days, a gastroduodenoscopy was performed to obtain mucosal
samples from the duodenum. Plasma concentrations of the sugars and mucosal concentrations of 5HTP, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA, the main metabolite of 5-HT) were determined by
HPLC-MS. In mucosal samples, the expression of tight junction proteins occludin and ZO-1 was
analyzed by qPCR and immunohistochemistry. Data are expressed as mean ± SEM. Intestinal
permeability as defined by the plasma recovery ratios of lactulose/rhamnose (L/R) and
sucralose/erythritol (S/E) was significantly reduced after 5-HTP (L/R 0.005±0.002 vs 0.006±0.002,
p<0.05, S/E 0.004±0.001 vs 0.005±0.001, p<0.05; 5-HTP vs placebo). The mRNA expression of ZO-1
was significantly increased after 5-HTP (1.27±0.24 vs 0.87±0.12; p<0.05), whereas the expression of
occludin was not altered by 5-HTP. Immunohistochemical staining for the ZO-1 and occludin proteins
showed that the proteins were located significantly closer to each other after 5-HTP. Administration of
5-HTP significantly increased mucosal 5-HTP levels (12.7±9.1 vs 1.6±1.5 pmol/mg; p=0.001), but did
not affect 5-HT levels (57±21 vs 47±18 pmol/mg; p=0.68), while 5-HIAA levels increased significantly
(7.1±1.7 vs 2.5±0.7 pmol/mg; p<0.05). Oral administration of 5-HTP reinforces small intestinal barrier
function by lowering intestinal sugar permeability, inducing the expression of the tight junction protein
ZO-1 and rearranging tight junction proteins. These changes are associated with 5-HTP-induced
alterations in mucosal serotonin metabolism. These data point to a role for serotonergic metabolism in
reinforcing intestinal barrier function.