Mood disorders and constipation are often comorbid yet their shared etiologies have
rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous
system and enteric nervous system (ENS) development and long-term functions, including
gastrointestinal (GI) motility and mood. Defects in neuron production of 5-HT might
therefore result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2)
is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes
the R441H substitution (TPH2-R441H) was identified in individuals with severe depression.
We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%–80%
decrease in levels of 5-HT in central nervous system and behaviors associated with
depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to
TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces
depressive-like behaviors. We compared the effects of feeding chow, with or without
5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control
mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice and
immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons,
and 5-HT–dependent subsets of neurons. We performed calcium imaging experiments to
evaluate responses of enteric neurons to tryptamineevoked release of endogenous 5-HT.
In live mice we measured total GI transit, gastric emptying, small intestinal transit,
and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs),
we isolated colons and constructed spatiotemporal maps along the proximo-distal length
to quantify the frequency, velocity, and length of CMMCs. We measured villus height,
crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells
in small intestinal tissue. Levels of 5-HT were significantly lower in enteric neurons
from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in
ENS development and ENS-mediated GI functions, including reduced motility and intestinal
epithelial growth. Total GI transit and propulsive colorectal motility were slower
in TPH2-R439H mice than controls and CMMCs were slower and less frequent. Villus height
and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H
mice, compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice
restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H
mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit,
and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs
and enteric epithelial growth In studies of TPH2-R439H mice, we found evidence for
reduced release of 5-HT from enteric neurons that results in defects in ENS development
and GI motility. Our findings indicate that neuron production of 5-HT links constipation
with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS
and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be
used to treat patients with intestinal dysfunction associated with low levels of 5-HT.