Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.
OBJECTIVE
Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans.


METHODS
We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping.


RESULTS
Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001).


CONCLUSIONS
These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.
Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. sfukudo@mail.tains.tohoku.ac.jp
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S
Fukudo
M
M
Kanazawa
T
T
Mizuno
T
T
Hamaguchi
M
M
Kano
S
S
Watanabe
Y
Y
Sagami
T
T
Shoji
Y
Y
Endo
M
M
Hongo
Y
Y
Itoyama
K
K
Yanai
M
M
Tashiro
M
M
Aoki
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000502:physiology*; D001931:Brain Mapping; D002560:Cerebrovascular Circulation / Q000502:physiology; D003106:Colon / Q000294:innervation*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008365:Manometry; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins