Effects of in utero exposure to fluoxetine on the gastrointestinal tract of rat offspring.

Perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) has been shown to disrupt the development of serotonergic signaling pathways in the brain and enteric nervous system. Serotonin (5-hydroxytryptamine; 5-HT) signaling is critical for gastrointestinal homeostasis; changes in 5-HT expression and regulation have been associated with gastrointestinal diseases of motility and inflammation. We tested the hypothesis that perinatal exposure to the SSRI fluoxetine can influence the development of the gastrointestinal tract in exposed offspring. Female nulliparous Wistar rats were given fluoxetine (10 mg/kg) or vehicle control from 2 wk before mating until weaning; small and large intestines of female and male offspring were collected at postnatal days 1, 21 (P1, P21, respectively), and 6 mo of age. In histological preparations, the proportion of serotonergic neurons significantly increased in the colons of both female and male fluoxetine-exposed compared with control offspring at P21, a time point that signifies maximal exposure to fluoxetine. At 6 mo of age, male but not female fluoxetine-exposed offspring had a significant increase in circulating 5-HT, with a significant decrease in transcripts encoding the 5-HT2A receptor and monoamine oxidase as compared with control offspring. Measurement of spatiotemporal mapping of contractile activity of the small and large intestine at 6 mo of age revealed no changes in motility in the small bowel of fluoxetine-exposed offspring but revealed a significant increase in the frequency of colonic contractions in the female fluoxetine-exposed compared with control animals. Susceptibility to inflammation was examined at 6 mo using the dextran sulfate sodium model of acute colitis. In utero exposure to fluoxetine was not found to exacerbate colitis severity. These findings suggest that fluoxetine exposure during fetal and early postnatal development can lead to changes in serotonergic neurons at the peak of exposure with sex-specific changes in 5-HT signaling and colonic motility in adulthood.NEW & NOTEWORTHY There is increasing recognition of the relevance of in utero and early postnatal exposures in the developmental programming of the gastrointestinal tract. Perinatal exposure to selective serotonin reuptake inhibitors and antidepressant medications is of particular relevance as they are commonly prescribed during pregnancy, and serotonergic pathways play key roles during gastrointestinal development and in postnatal homeostasis. Here, we provide a comprehensive evaluation of clinically relevant outcomes of gastrointestinal motility and susceptibility to colitis in fluoxetine-exposed offspring and highlight changes in colonic serotonergic neurons at the peak of perinatal fluoxetine exposure with sex-dependent changes in serotonin signaling and colonic motility in adulthood.

Cell-specific effects of nitric oxide on the efficiency and frequency of long distance contractions in murine colon.

BACKGROUND: Nitric oxide (NO) mediates inhibitory neurotransmission and is a critical component of neuronal programs that generate propulsive contractions. NO acts via its receptor NO-sensitive guanylyl cyclase (NO-GC) which is expressed in smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Organ bath studies with colonic rings from NO-GC knockout mice (GCKO) have indicated NO-GC to modulate spontaneous contractions. The cell-specific effects of NO-GC on the dominant pan-colonic propulsive contraction, the long distance contractions (LDCs), of whole colon preparations have not yet been described. METHODS: Contractions of whole colon preparations from wild type (WT), global, and cell-specific GCKO were recorded. After transformation into spatiotemporal maps, motility patterns were analyzed. Simultaneous perfusion of the colon enabled the correlation of outflow with LDCs to analyze contraction efficiency. KEY RESULTS: Deletion of NO-GC in both ICC and SMC (ie, in GCKO and SMC/ICC-GCKO) caused loss of typical LDC activity and instead generated high-frequency LDC-like contractions with inefficient propulsive activity. Frequency was also increased in WT, SMC-GCKO, and ICC-GCKO colon in the presence of L-NAME to block neuronal NO synthase. LDC efficiency was dependent on NO-GC in SMC as it was reduced in GCKO, SMC-GCKO, and ICC/SMC-GCKO colon; LDC efficiency was decreased in all genotypes in the presence of L-NAME. CONCLUSIONS AND INFERENCES: NO/cGMP signaling is critical for normal peristaltic movements; as NO-GC in both SMC and ICC is essential, both cell types appear to work in synchrony. The efficiency of contractions to expel fluid is particularly influenced by NO-GC in SMC.

Characterization of Simultaneous Pressure Waves as Biomarkers for Colonic Motility Assessed by High-Resolution Colonic Manometry.

Simultaneous pressure waves (SPWs) in manometry recordings of the human colon have been associated with gas expulsion. Our hypothesis was that the SPW might be a critical component of most colonic motor functions, and hence might act as a biomarker for healthy colon motility. To that end, we performed high-resolution colonic manometry (HRCM), for the first time using an 84-sensor (1 cm spaced) water-perfused catheter, in 17 healthy volunteers. Intraluminal pressure patterns were recorded during baseline, proximal and rectal balloon distention, after a meal and following proximal and rectal luminal bisacodyl administration. Quantification was performed using software, based on Image J, developed during this study. Gas expulsion was always associated with SPWs, furthermore, SPWs were associated with water or balloon expulsion. SPWs were prominently emerging at the termination of proximal high amplitude propagating pressure waves (HAPWs); we termed this motor pattern HAPW-SPWs; hence, SPWs were often not a pan-colonic event. SPWs and HAPW-SPWs were observed at baseline with SPW amplitudes of 12.0 ± 8.5 mmHg and 20.2 ± 7.2 mmHg respectively. The SPW occurrence and amplitude significantly increased in response to meal, balloon distention and luminal bisacodyl, associated with 50.3% anal sphincter relaxation at baseline, which significantly increased to 59.0% after a meal, and 69.1% after bisacodyl. Often, full relaxation was achieved. The SPWs associated with gas expulsion had a significantly higher amplitude compared to SPWs without gas expulsion. SPWs could be seen to consist of clusters of high frequency pressure waves, likely associated with a cluster of fast propagating, circular muscle contractions. SPWs were occasionally observed in a highly rhythmic pattern at 1.8 ± 1.2 cycles/min. Unlike HAPWs, the SPWs did not obliterate haustral boundaries thereby explaining how gas can be expelled while solid content can remain restrained by the haustral boundaries. In conclusion, the SPW may become a biomarker for normal gas transit, the gastrocolonic reflex and extrinsic neural reflexes. The SPW assessment reveals coordination of activities in the colon, rectum and anal sphincters. SPWs may become of diagnostic value in patients with colonic dysmotility.

Abnormal absorptive colonic motor activity in germ-free mice is rectified by butyrate, an effect possibly mediated by mucosal serotonin.

The role of short-chain fatty acids (SCFAs) in the control of colonic motility is controversial. Germ-free (GF) mice are unable to produce these metabolites and serve as a model to study how their absence affects colonic motility. GF transit is slower than controls, and colonization of these mice improves transit and serotonin [5-hydroxytryptamine (5-HT)] levels. Our aim was to determine the role SCFAs play in improving transit and whether this is dependent on mucosal 5-HT signaling. Motility was assessed in GF mice via spatiotemporal mapping. First, motor patterns in the whole colon were measured ex vivo with or without luminal SCFA, and outflow from the colon was recorded to quantify outflow caused by individual propulsive contractions. Second, artificial fecal pellet propulsion was measured. Motility was then assessed in tryptophan hydroxylase-1 (TPH1) knockout (KO) mice, devoid of mucosal 5-HT, with phosphate buffer, butyrate, or propionate intraluminal perfusion. GF mice exhibited a lower proportion of propulsive contractions, lower volume of outflow/contraction, slower velocity of contractions, and slower propulsion of fecal pellets compared with controls. SCFAs changed motility patterns to that of controls in all parameters. Butyrate administration increased the proportion of propulsive contractions in controls yet failed to in TPH1 KO mice. Propionate inhibited propulsive contractions in all mice. Our results reveal significant abnormalities in the propulsive nature of colonic motor patterns in GF mice, explaining the decreased transit time in in vivo studies. We show that butyrate but not propionate activates propulsive motility and that this may require mucosal 5-HT. NEW & NOTEWORTHY Understanding the role that the microbiota play in governing the physiology of colonic motility is lacking. Here, we offer for the first time, to our knowledge, a detailed analysis of colonic motor patterns and pellet propulsion using spatiotemporal mapping in the absence of microbiota. We show a striking difference in germ-free and control phenotypes and attribute this to a lack of fermentation-produced short-chain fatty acid. We then show that butyrate but not propionate can restore motility and that the butyrate effect likely requires mucosal 5-hydroxytryptamine.

Risk Factors for Subsidence of a Modular Tapered Femoral Stem Used for Revision Total Hip Arthroplasty.

The purpose of this study was to determine the incidence, and the clinical and radiographic risk factors for significant subsidence of a cementless, modular tapered revision femoral stem. Femoral stem subsidence of at least 10 mm or subsidence requiring revision was considered significant subsidence. Ninety-seven patients (99 hips) were included with minimum radiographic follow-up of one year (mean 34 months; range, 12-91 months). The mean stem subsidence was 4.5 mm (range, 0-44 mm). Fourteen out of 99 (14.1%) stems had significant subsidence and 6 (6.1%) stems required revision due to subsidence. Patient weight greater than 80 kg (P=0.04) and femoral stem press-fit distance of less than 2 cm (P<0.01) were both independent risk factors for significant stem subsidence.