Visceral hypersensitivity in female but not in male serotonin transporter knockout rats

Galligan, James J.; Patel, Bhavik Anil; Schneider, Stephen P.; Wang, H.; Zhao, Hong; Novotný, Martin; Bian, Xiaochun; Kabeer, Rana; Fried, David; Swain, Greg M.

doi:10.1111/nmo.12133

Cited by 27 publications

(36 citation statements)

References 48 publications

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“…Although the estrous cycle of female mice was not controlled in this study, it may be useful to examine its potential effects on expression of Htr4 and Slc6a4 in future studies. Given the importance of 5-HT transporter in human bowel disorders (22, 23), and the use of drugs targeting the 5-HT 4 receptor in GI disorders such as IBS, additional studies are warranted to understand the signaling pathways responsible for driving expression of the transcripts encoding these factors. Future studies will be needed to determine the cell type(s) and the mediators responsible for the observed correlation between Slc6a4 and Htr4 expression in the colon, and to determine if this correlation is limited to the colon or may be seen in other areas, such as the brain.…”

Section: Discussionmentioning

confidence: 99%

Correlated gene expression encoding serotonin (5‐HT) receptor 4 and 5‐HT transporter in proximal colonic segments of mice across different colonization states and sexes

Reigstad

Linden

Szurszewski

et al. 2016

Neurogastroenterology Motil

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The production and handling of serotonin (5-HT) is an important determinant of colonic motility and has been reported to be altered in gastrointestinal (GI) disorders such as irritable bowel syndrome (IBS). Recent studies suggest that the intestinal microbiota and sex of the host can influence expression of genes involved in 5-HT biosynthesis and signaling. While expression of genes in serotonergic pathways has been shown to be variable, it is unclear whether genes within this pathway are co-regulated. As a first step in that direction, we investigated potential correlations in relative mRNA expression of serotonergic genes, in the proximal colon isolated from male and female mice in different states of microbial association: germ-free (GF), humanized (ex-germ-free colonized with human gut microbiota, HM), and conventionally raised (CR) mice. Among the ten pairwise comparisons conducted between five serotonergic transcripts, Tph1, Chga, Maoa, Slc6a4 and Htr4, we found a strong, positive correlation between colonic expression of Slc6a4 and Htr4 across different colonization states and sexes. We also identified a positive correlation between the expression of Tph1 and Chga; however, there were no correlations observed between any other tested pair of 5-HT-related transcripts. These data suggest that correlated expression of Slc6a4 and Htr4 likely involves co-regulation of genes located on different chromosomes which modulate serotonergic activity in the gut. Further work will need to be done to understand the pathways and cell types responsible for this correlated expression, given the important role of 5-HT in gastrointestinal physiology.

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Section: Discussionmentioning

confidence: 99%

Correlated gene expression encoding serotonin (5‐HT) receptor 4 and 5‐HT transporter in proximal colonic segments of mice across different colonization states and sexes

Reigstad

Linden

Szurszewski

et al. 2016

Neurogastroenterology Motil

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“…20 So far, several studies have focused on sex-specific stress response and visceral hypersensitivity. [21][22][23][24][25][26] To our knowledge, the sex-related differences between all kinds of parameters have not been fully described in a single report. Therefore, we aimed to elucidate differences in colonic movement, mucosal mast cell counts, cytokine levels, and visceral sensitivities between the 2 sexes in a stress rat model.…”

Section: Introductionmentioning

confidence: 99%

Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin-1β Levels with Sex Differences in the Distal Colon of Wistar Rats

Lee

Kim

et al. 2016

J Neurogastroenterol Motil

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Background/AimsThis study was aimed at evaluating differences in the effects of repeated water avoidance stress (rWAS) on colonic movement, mucosal mast cell counts, cytokine levels, and visceromotor response (VMR) to colorectal distension (CRD) in rats of both sexes. MethodsWistar rats were divided into stress and no-stress groups. Rats in the stress group were exposed to rWAS (1 hr/day) for 10 days. Mucosal mast cells were immunohistochemically stained with anti-mast cell tryptase antibody and counted. The colonic mucosal cytokine levels were measured with enzyme-linked immunosorbent assay. The VMR to CRD (visceral analgesia) was assessed by using a barostat and noninvasive manometry. ResultsThe mean number of fecal pellets in the rWAS group increased significantly as compared with that in the no-stress group in both sexes. After adjustment for body weight, the female rats had a significantly higher pellet output than the male rats. The mucosal mast cell count of the female rWAS group was higher than that of the male rWAS group (13.0 ± 0.9 vs 8.8 ± 0.6; P < 0.001). The colonic mucosal interleukin-1β level was also higher only in the female rats of the rWAS group than in those of the no-stress group. On days 10 and 11, a decrease in VMR to CRD was observed at 40 and 60 mmHg in both sexes of the rWAS group, without a sex-based difference. ConclusionsThe colonic response to stress appeared to be more sensitive in the female rats than in the male rats. However, stress-induced visceral analgesia had no sex-related difference and the underlying mechanism needs to be further evaluated.

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“…Finally, experimental studies indicate that colonic 5‐HT3 receptor gene expression is increased in ovariectomized rats exposed to restraint stress and restored with hormone replacement after ovariectomy . Similarly, serotonin transporter gene knockout female rats, but not male, display an increased colonic extracellular serotonin associated with visceral hypersensitivity and hyperexcitability of colon sensory neurons …”

Section: Effect Of Stress and Sex On The Intestinal Immune System Andmentioning

confidence: 99%

The joint power of sex and stress to modulate brain–gut–microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome

Pigrau

Rodiño-Janeiro

Casado‐Bedmar

et al. 2015

Neurogastroenterology Motil

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Visceral hypersensitivity in female but not in male serotonin transporter knockout rats

Abstract: Increased colonic extracellular serotonin in female SERT KO rats is associated with visceral hypersensitivity and hyperexcitability of colon projecting sensory neurons. The SERT KO rat is a model for studying interactions between serotonin, sex and visceral sensation.

Cited by 27 publications

References 48 publications

Correlated gene expression encoding serotonin (5‐HT) receptor 4 and 5‐HT transporter in proximal colonic segments of mice across different colonization states and sexes

Correlated gene expression encoding serotonin (5‐HT) receptor 4 and 5‐HT transporter in proximal colonic segments of mice across different colonization states and sexes

Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin-1β Levels with Sex Differences in the Distal Colon of Wistar Rats

The joint power of sex and stress to modulate brain–gut–microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome

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