Recent research has identified the gut-brain axis as a key mechanistic pathway and potential therapeutic target in depression. In this paper, the potential role of gut hormones as potential treatments or predictors of response in depression is examined, with specific reference to the peptide hormone motilin. This possibility is explored through two methods: (1) a conceptual review of the possible links between motilin and depression, including evidence from animal and human research as well as clinical trials, based on a literature search of three scientific databases, and (2) an analysis of the relationship between a functional polymorphism (rs2281820) of the motilin (MLN) gene and cross-national variations in the prevalence of depression based on allele frequency data after correction for potential confounders. It was observed that (1) there are several plausible mechanisms, including interactions with diet, monoamine, and neuroendocrine pathways, to suggest that motilin may be relevant to the pathophysiology and treatment of depression, and (2) there was a significant correlation between rs2281820 allele frequencies and the prevalence of depression after correcting for multiple confounding factors. These results suggest that further evaluation of the utility of motilin and related gut peptides as markers of antidepressant response is required and that these molecular pathways represent potential future mechanisms for antidepressant drug development.

BACKGROUND: Infants\' healthy growth and development are predicated, in part, on regular functioning of the gastrointestinal (GI) tract. In the first 6 months of life, infants typically double their birth weights. During this period of intense growth, the GI tract needs to be highly active and to function optimally. Identifying modifiable causes of GI tract dysregulation is important for understanding the pathophysiologic processes of such dysregulation, for identifying effective and efficient interventions, and for developing early prevention and health promotion strategies. One such modifiable cause seems to be maternal smoking, both during and after pregnancy. Purpose. This article brings together information that strongly suggests that infants\' exposure to tobacco smoke is linked to elevated blood motilin levels, which in turn are linked to an increased risk of GI dysregulation, including colic and acid reflux. We base this hypothesis on evidence supporting a link between maternal smoking and infantile colic (IC) and on additional evidence proposing increased motilin release, attributable to exposure to tobacco smoke and its metabolites, as a physiologic mechanism linking maternal smoking with infantile GI dysregulation.
METHODS: We critically review and synthesize epidemiologic, physiologic, and biological evidence pertaining to smoking and colic, smoking and motilin levels, and motilin and colic.
RESULTS: Six studies have investigated the link between maternal smoking and IC, but IC was defined according to Wessel\'s rule of threes (crying for > or =3 hours per day, > or =3 days per week, for > or =3 weeks) in only 1 of these studies. The remaining studies used definitions that ranged from less-stringent variations of Wessel\'s criteria to definitions that would suggest excessive crying but not necessarily colic. Results from 5 of these studies suggest that there is an independent association between maternal smoking and excessive crying, as well as IC. Recent studies of the GI system provide strong, but indirect, corroborating evidence suggesting physiologic pathways through which maternal smoking can be linked to IC. This physiologic evidence can be outlined as follows: (1) smoking is linked to increased plasma and intestinal motilin levels and (2) higher-than-average levels of motilin are linked to elevated risks of IC. Although these findings from disparate fields suggest a physiologic mechanism linking maternal smoking with IC, the entire chain of events has not been examined in a single cohort. A prospective study, begun in pregnancy and continuing through the first 4 months of life, could provide definitive evidence linking these disparate lines of research. Key points for such a study are considered.
CONCLUSIONS: New epidemiologic evidence suggests that exposure to cigarette smoke and its metabolites may be linked to IC. Moreover, studies of the GI system provide corroborating evidence that suggests that (1) smoking is linked to increased plasma and intestinal motilin levels and (2) higher-than-average intestinal motilin levels are linked to elevated risks of IC. In the United States, nearly one-half of all women smokers continue to smoke during their pregnancies. This amounts to approximately 12% of all women who give birth. Moreover, it is estimated that 50% to 80% of employed adults have regular exposure to environmental tobacco smoke and that >30% of nonsmokers live with smokers. If, as we suspect, exposure to cigarette smoke increases the risk of colic, then this would provide additional incentives to parents to abstain from smoking. Decreased exposure to tobacco smoke can be expected to provide widespread and long-term health benefits to maternal and child populations.