THE COLONIC BIOLOGICAL CLOCK AND PREDICTABILITY OF TIME OF BOWEL MOVEMENTS DURING TREATMENT WITH A VIBRATING CAPSULE (VIBRANT®) IN PATIENTS WITH SEVERE CHRONIC IDIOPATHIC CONSTIPATION

Background: The gastrointestinal (GI) disturbance is a frequent complication in patients with thoracolumbar vertebral fracture (TVF), especially in the postoperative period. Laxatives are sometimes of limited effect. Transcutaneous electrical acustimulation (TEA) has been reported to effectively treat functional or secondary constipation and accelerate postoperative gastrointestinal function recovery after abdominal surgery; however, it is unknown whether it has an ameliorating effect on GI disturbances in TVF patients after receiving posterior pedicle screw fixation surgery.
Objectives: This study was designed to investigate the effects of TEA on postoperative recovery and possible mechanisms involving autonomic functions.
Materials and Methods: A total of 81 TVF patients who underwent elective posterior pedicle screw fixation surgery were randomized to receive TEA or sham-TEA. After enrollment, electrocardiogram (ECG) was recorded for 30 min to assess autonomic function. TEA at ST36 or sham-TEA at non-acupoints was performed for one hour twice daily from 24 hours before surgery to postoperative day (POD) 3. Clinical symptoms were assessed in the form of diary. In the morning of POD1 and POD4, the ECG was recorded again for 30 min .
Results: 1) In comparison with sham-TEA, TEA enhanced postoperative recovery associated with lower GI motility (see Fig.1), including a reduction in time to defecation by 27.2% (P =0.002), time to first flatus by 17.2% (P = 0.027), an increase in the Bristol stool score (P = 0.014) and the number of spontaneous bowel movement (SBM,P =0.009). 2) TEA also improved other GI symptoms including abdominal bloating on POD1 and POD4 (P < 0.001 and P=0.001, respectively), straining during defecation (P<0.001) and sensation of anorectal blockage during defecation (P=0.02) in comparison with sham-TEA. 3) TEA reduced the visual analogue scale (VAS) wound pain score on POD1 (P=0.026), POD2 (P< 0.001) and POD3 (P< 0.001). 4) TEA but not sham-TEA increased vagal activity and decreased sympathetic activity (P < 0.001) on POD4 compared with POD1, assessed from the spectral analysis of heart rate variability derived from the ECG. The serum level of norepinephrine (NE) was significantly lower in the TEA group in comparison with the sham-TEA group on both POD1 (P=0.047) and POD4 (P=0.036). 5) The use of TEA was found to be an independent predictor of shortened time to first defecation.
Conclusions: Non-invasive TEA at ST36 is effective in promoting postoperative recovery in TVF patients by enhancing vagal and suppressing sympathetic activities.

Background: Spinal cord injury (SCI) can trigger GI complaints including constipation. The impact of the level of SCI on GI transit and motility needs to be better defined. Furthermore, the natural history of GI dysfunction in patients with SCI is unknown. We performed wireless motility capsule (WMC) studies in patients with SCI: (i) to determine the impact of the level of SCI (cervical [C1-C8] vs. thoracic [T1-T11]) on gastric, small bowel (SB), and colon transit and motility and (ii) to compare GI transit and motility in patients with SCI <10 vs. >10 years duration.
Methods: 25 patients (age 52±14 years, 76% male) with SCI (>1 year) above T12 with chronic constipation underwent WMC testing. Patients on opioids were excluded. Stimulant laxatives and GI motility drugs were stopped 48 hours before testing. Rescue suppository laxatives were permitted at day 7. WMC transit parameters included gastric emptying time (GET)(delayed >5 hours), SB transit time (SBTT)(delayed>6 hours), and colon transit time (CTT)(delayed>59 hours). Motility parameters included contractions per minute and motility index or MI (ln) 30 min prior to WMC pylorus passage (gastric), 30 min after pylorus passage (proximal SB), 30 min before ileocecal junction (ICJ) passage (distal SB), 30 min after ICJ passage (proximal colon), and 30 min before anal expulsion (distal colon).
Results: SCI level was cervical in 17 (68%) and thoracic in 8 (32%) patients; time since SCI was <10 years in 16 (64%) and >10 years in 9 (36%) patients. Transit delays in the stomach, SB, and colon were prevalent and were similar with cervical vs. thoracic SCI (Figure). Transit delays <10 vs. >10 years after SCI were not different for GET (18.8 vs. 44.4%, P=0.35), SBTT (37.5 vs. 44.0%, P=1.00), or CTT (50.0 vs. 33.3%, P=0.66). Proximal SB contraction frequency (P=0.02) and MI (P=0.03) were lower after cervical vs. thoracic SCI, but contraction parameters in other gut regions did not differ in relation to level of injury (Table). Contraction frequencies and MI were similar <10 vs. >10 years across all gut regions (data not shown).
Conclusion: Whole gut transit delays involving the stomach, small bowel, and colon are common after spinal injury. These delays were not secondary to medication effects as opioid use was excluded and drugs with motility actions were discontinued before testing. There was no relation of level of spinal injury to transit delay and minimal impact on small bowel contractility, reinforcing the importance of vigilant attention to bowel regimens in all patients. The stability of GI transit delays and contraction profiles over many years suggests such vigilance may need to be lifelong.

Background: Current classification of patients with constipation into IBS with constipation (IBS-C) and functional constipation (FC) is problematic as symptoms overlap extensively and do not identify distinct mechanisms which might respond to specific therapy . Our primary aim was to determine if we could develop a novel classification of constipation including objective measures of colonic function that predict an individual’s responsivenessto either secretagogues, prokinetics or other therapies. Methods: Healthy volunteers (HVs) and patients with constipation (meeting ROME IV criteria - confirmed by 14-day stool diary) were recruited in London and Nottingham. They completed PAC-SYM and HADS questionnaires at baseline, along with stool diaries documenting stool form (Bristol Stool Form Score - BSFS) and weekly complete spontaneous bowel movements (CSBM). Their pain scores and colonic volume, both baseline and at T=60 and T=120 minutes following dosing with 10ml/kg macrogol (500-1000mL) were assessed using established MRI methods.Transit was measured with a validated MRI marker method and high-resolution manometry performed (see separate abstract). Kmeans clustering using standardised values of the above parameters was used to group the participants with constipation into clusters. Participants with missing data were excluded from this analysis. Results: Table 1 shows the results with patients grouped by the ROME criteria. IBS-C and FC showed significantly larger colon volumes, greater pain and slower transit than HVs with the expected substantial overlap between the 2 patient groups. All patients had hard stools as assessed by BSFS and few CSBMs (Table 1). Cluster analysis of patients suggested an alternative 3-group model based on colon volumes, transit time, maximum pain scores and psychological distress (HADS) (Table 2). Group 1 had large colons, prolonged transit time, hypermotility, high pain and high anxiety scores. Group 2 had a normal colon size but prolonged transit with less pain but similar anxiety. Group 3 by contrast had large colons but faster transit times, overlapping that of HVs, with low pain and low anxiety scores (Table 2). Discussion: Patients labelled as either FC or IBS-C show overlap of both objective and subjective parameters. Our cluster analysis, based on underlying mechanisms, includes measures of both psychological distress and objective colonic function. It identifies a yet unrecognised cluster (Group 3). These individuals have normal transit yet produce hard infrequent stools. We hypothesise that in this group excessive absorption, rather than slow transit, may underly constipation. Such patients may respond better to a secretagogue while those with slow transit (Group 1 & 2) would be predicted to respond to prokinetics. Clinical trials of these contrasting approaches in our 3 clusters are now warranted.

Background and aim: Elevated rectal sensory thresholds are considered to be associated with chronic constipation (CC), especially in elderly patients. Bile acids (BAs) were previously shown to affect rectal sensory thresholds in healthy subjects, but whether the BA transporter inhibitor elobixibat affects rectal sensory thresholds in elderly patients with CC remains unknown. This study was performed to investigate the effects of elobixibat on rectal sensory thresholds and the numbers of spontaneous bowel movements (SBMs) and complete SBMs (CSBMs) in elderly patients with CC and to evaluate the clinical characteristics associated with the effectiveness of elobixibat for rectal sensory thresholds.
Patients and methods: This prospective, randomized, parallel-group, double-blind, placebo-controlled clinical trial involved 20 elderly patients (≥60 years old) with CC who met the Rome IV criteria. The patients were instructed to keep a defecation diary until the end of the study. After a 1-week observation period, the patients received placebo or 5 mg of elobixibat orally 2 tablets daily before meals for 1 week. The rectal sensory thresholds were measured by validated rapid barostat bag measurement before and after medications. Three well-established sensory thresholds were determined using simple ramp distension of the balloon with air at a rate of 2 mL/s: first constant sensation volume (FCSV), defecatory desire volume (DDV), and maximum tolerable volume (MTV). We also analyzed changes in the fecal concentration of BAs using fecal samples before and after medications.
Results: Elobixibat improved the numbers of SBMs and CSBMs per week without significant side effects. The total fecal BA concentrations increased from baseline, particularly secondary BAs (mean change from baseline, 5.53 ± 3.48 μmol/g). Elobixibat significantly decreased the threshold for DDV before and after medication (change from baseline, −15.2 ± 19.0 mL), while placebo showed no change (change from baseline, 0.8 ± 18.8 mL). There were differential trends between the two groups in the change in the threshold for DDV (P = 0.05) as shown in Figure 1. Elobixibat significantly decreased the threshold for FCSV before and after medication (change from baseline, −26.0 ± 16.9 mL), while placebo showed no change (change from baseline, 7.0 ± 24.1 mL). There were significant differences in the change in the threshold for FCSV between the two groups (P = 0.0018). No difference in MTV was observed between the two groups. Clinical characteristics associated with the efficacy of elobixibat for rectal sensory thresholds were older age, female sex, longer duration of CC, and history of CC treatment (Table 1).
Conclusions: Elobixibat improved rectal sensory thresholds in elderly patients with CC. The effect was more obvious in older women with a history of CC treatment.

Healthy subjects tend to defecate after activation of high amplitude propagating contractions (HAPC), mainly after waking and/or after a meal, a pattern attributed to the colonic biological clock regulated by circadian rhythms. However, the circadian rhythm and diurnal distribution of bowel movements have not been investigated in patients with Chronic Idiopathic Constipation (CIC). We previously demonstrated that a vibrating capsule (VC) significantly increases complete spontaneous bowel movements (CSBMs) compared to placebo in CIC. Aim: To examine the diurnal distribution of CSBMs in severe CIC patients who were treated with VC or placebo. Methods: We conducted a post-hoc analysis from the phase 3, multicenter, randomized, double-blind, placebo-controlled, 8-week trial of a VC (Vibrant ®, Yokneam, Israel) in CIC, of a subgroup with severe CIC, defined as 0 CSBMs reported on electronic diaries during the 2- to 3-week baseline period. Capsules were taken at 10 pm with activation of the VC programmed to occur 14 hours later. We evaluated the time of occurrence of CSBMs and CSBM responder rates (defined as the percentages of subjects with increases of at least 1 or 2 weekly CSBMs over baseline for 75% of treatment weeks). Results: The severe CIC subgroup comprised 175 (56%) of 312 subjects enrolled in the Phase III trial. CSBMs predominantly occurred in the latter half of the day in both groups with the cumulative average number of CSBMs for the 8-week treatment period being significantly higher for VC vs placebo during the hours of 18:00 to 22:00 (Figure). Stratification of the cumulative number of CSBMs occurring between 18:00 and 22:00 for the 8-week treatment period revealed significantly more CSBMs for VC vs placebo during this time period (Table). There was a significantly greater number of CSBM responders with severe CIC in the VC group compared to placebo. Similar patterns were observed for the entire phase 3 study population (results not shown). Conclusions: Individuals with severe chronic constipation tend to move their bowels later in the day suggesting alterations in their colonic biological clock. VC improved constipation by significantly increasing the number of CSBMs later in the day. Optimal treatment of patients with CIC requires awareness of this abnormal colonic diurnal rhythm in these patients.


Figure. Cumulative average number of CSBMs for VC vs placebo for subjects with severe CIC during the 8-week phase 3 clinical trial period. Time 0 hrs represents midnight. Time 23 hrs represents 23:00 (11:00 PM).

Table. Analysis of CSBMs for VC vs placebo occurring between 18:00 and 22:00 for subjects with severe CIC, stratified by numbers of CSBMs during the 8-week phase 3 clinical trial period. Nominal p values are presented. N, number of subjects; n, number of CSBMs.