Evaluation of gastrointestinal transit times and pH in healthy cats using a continuous pH monitoring system

Objectives The aim of this study was to characterize gastrointestinal (GI) transit times and pH in healthy cats. Methods GI transit times and pH were measured in six healthy, colony-housed, purpose-bred spayed female cats using a continuous, non-invasive pH monitoring system in a sequential order design. For the first period (‘pre-feeding’), food was withheld for 20 h, followed by oral administration of a pH capsule. Five hours post-capsule administration, cats were meal-fed by offering them their daily allowance of food for 1 h. For the second period (‘post-feeding’), food was withheld for 24 h and cats were fed for 1 h, after which a pH capsule was orally administered. Studies in both periods were repeated three times. GI transit times and pH were compared between the two periods. Results The median transit times for the pre- and post-feeding periods, respectively, were: gastric –94 mins (range 1–4101) and 1068 mins (range 484–5521); intestinal –1350 mins (range 929–2961) and 1534 mins (range 442–2538); and GI –1732 mins (range 1105–5451) and 2795 mins (range 926–6563). The median GI pH values for the first and second periods, respectively, were: esophageal –7.0 (range 3.5–7.8) and 4.5 (range 2.9–6.4); gastric –2.7 (range 1.7–6.2) and 2.0 (range 1.1–3.3); intestinal –8.2 (range 7.6–8.7) and 7.8 (range 6.7–8.5); first-hour small intestinal –8.2 (range 7.4–8.7) and 8.3 (range 7.9–8.6); and last-hour large intestinal –8.5 (range 7.0–8.9) and 7.8 (range 6.3–8.7). Gastric ( P <0.0020) and intestinal pH ( P <0.0059) were significantly increased in the pre-feeding period compared with the post-feeding period. Conclusions and relevance Gastric and intestinal pH differed significantly when the capsule was administered 5 h prior to feeding compared with 1 h after feeding. Transit times for both periods showed high degrees of intra- and inter-individual variability.

Assessment of whole gut motility in adolescents using the wireless motility capsule test

Functional gastrointestinal (GI) disorders are often associated with intestinal dysmotility representing a diagnostic challenge. A relatively new method is the wireless motility capsule (WMC) test, which continuously measures pH, pressure, temperature and regional transit times as it passes through the GI tract. In adults, the WMC test was approved for use in the diagnosis of gastroparesis and constipation by assessing GI transit and contractility. We performed the WMC test in nine adolescent patients aged 12–17 years with functional GI symptoms from July 2017 until February 2019. Abnormal transit times were detected in four patients. Three patients showed abnormal transit times of the upper GI tract: in two cases, contractility analysis revealed prolonged gastric retention, and in one patient, abnormal colonic transit was detected.Conclusion: The WMC test is a minimally invasive procedure with potential to expand future diagnostic opportunities for paediatric patients with functional GI disorders and suspected motility disturbances. What is Known:• The assessment of GI transit and contractility of the whole gut is possible with the WMC test which is approved for use in the diagnosis of gastroparesis and constipation in adults. What is New:• The WMC test is a non-invasive diagnostic tool with the potential to expand diagnostic opportunities in paediatric patients by assessing regional and whole gut motility.• In paediatric patients with functional GI disorders, the WMC test could help to make an adequate diagnosis and initiate appropriate therapy.

Impact of oral galenic formulations of Lactobacillus salivarius on probiotic survival and interactions with microbiota in human in vitro gut models

Health benefits of probiotics in humans essentially depend on their ability to survive during gastrointestinal (GI) transit and to modulate gut microbiota. To date, there is few data on the impact of galenic formulations of probiotics on these parameters. Even if clinical studies remain the gold standard to evaluate the efficacy of galenic forms, they stay hampered by technical, ethical and cost reasons. As an alternative approach, we used two complementary in vitro models of the human gut, the TNO gastrointestinal (TIM-1) model and the Artificial Colon (ARCOL), to study the effect of three oral formulations of a Lactobacillus salivarius strain (powder, capsule and sustained-release tablet) on its viability and interactions with gut microbiota. In the TIM-1 stomach, no or low numbers of bacteria were respectively released from the capsule and tablet, confirming their gastro-resistance. The capsule was disintegrated in the jejunum on average 76 min after administration while the core of sustained-release tablet was still intact at the end of digestion. Viability in TIM-1 was significantly influenced by the galenic form with survival percentages of 0.003±0.004%, 2.8±0.6% and 17.0±1.8% (n=3) for powder, capsule and tablet, respectively. In the ARCOL, the survival of the strain tended to be higher in the post-treatment phase with the tablet compared to capsule, but gut microbiota composition and activity were not differently modulated by the two formulations. In conclusion, the sustained-release tablet emerged as the formulation that most effectively preserved viability of the tested strain during GI passage. This study highlights the usefulness of in vitro gut models for the pre-screening of probiotic pharmaceutical forms. Their use could also easily be extended to the evaluation of the effects of food matrices and age on probiotic survival and activity during GI transit.

The Nonsteroidal Anti-Inflammatory Drug Ketorolac Alters the Small Intestinal Microbiota and Bile Acids Without Inducing Intestinal Damage or Delaying Peristalsis in the Rat

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce significant damage to the small intestine, which is accompanied by changes in intestinal bacteria (dysbiosis) and bile acids. However, it is still a question of debate whether besides mucosal inflammation also other factors, such as direct antibacterial effects or delayed peristalsis, contribute to NSAID-induced dysbiosis. Here we aimed to assess whether ketorolac, an NSAID lacking direct effects on gut bacteria, has any significant impact on intestinal microbiota and bile acids in the absence of mucosal inflammation. We also addressed the possibility that ketorolac-induced bacterial and bile acid alterations are due to a delay in gastrointestinal (GI) transit.Methods: Vehicle or ketorolac (1, 3 and 10 mg/kg) were given to rats by oral gavage once daily for four weeks, and the severity of mucosal inflammation was evaluated macroscopically, histologically, and by measuring the levels of inflammatory proteins and claudin-1 in the distal jejunal tissue. The luminal amount of bile acids was measured by liquid chromatography-tandem mass spectrometry, whereas the composition of microbiota by sequencing of bacterial 16S rRNA. GI transit was assessed by the charcoal meal method.Results: Ketorolac up to 3 mg/kg did not cause any signs of mucosal damage to the small intestine. However, 3 mg/kg of ketorolac induced dysbiosis, which was characterized by a loss of families belonging to Firmicutes (Paenibacillaceae, Clostridiales Family XIII, Christensenellaceae) and bloom of Enterobacteriaceae. Ketorolac also changed the composition of small intestinal bile by decreasing the concentration of conjugated bile acids and by increasing the amount of hyodeoxycholic acid (HDCA). The level of conjugated bile acids correlated negatively with the abundance of Erysipelotrichaceae, Ruminococcaceae, Clostridiaceae 1, Muribaculaceae, Bacteroidaceae, Burkholderiaceae and Bifidobacteriaceae. Ketorolac, under the present experimental conditions, did not change the GI transit.Conclusion: This is the first demonstration that low-dose ketorolac disturbed the delicate balance between small intestinal bacteria and bile acids, despite having no significant effect on intestinal mucosal integrity and peristalsis. Other, yet unidentified, factors may contribute to ketorolac-induced dysbiosis and bile dysmetabolism.

Effects of Cisapride, Buprenorphine, and Their Combination on Gastrointestinal Transit in New Zealand White Rabbits

Due to their effective analgesic properties, opioids are worthy of consideration for pain management in rabbits. However, this class of drugs causes undesirable effects including reduced gastrointestinal (GI) motility, reduced fecal output, and delays GI transit times and thus increases the risk of GI stasis. The risk of stasis discourages the use of opioids in rabbits, which could affect animal welfare. Gastroprokinetic agents such as cisapride are effective in promoting gastric emptying in many species, but whether this effect occurs in rabbits is unknown. This study assessed the efficacy of cisapride when administered as a single agent and in combination with buprenorphine in rabbits; efficacy was assessed by measuring GI transit times, fecal output, body weight, and food and water intake. Female New Zealand White rabbits (n = 10) were studied in a crossover, randomized design and received either vehicle and buprenorphine, cisapride and saline, cisapride and buprenorphine, or vehicle and saline (control) every 8 h for 2 d. Rabbits were anesthetized and administered radio-opaque, barium-filled spheres via orogastric tube. Feces was assessed via radiography for detection of the barium-spheres to determine GI transit time. GI transit time was significantly longer in buprenorphine groups than in control groups, regardless of the use of cisapride. Fecal output and food and water intake were lower for buprenorphine groups than control groups. Cisapride did not significantly alter GI transit, fecal output, or food and water intake. In addition, treatment group did not significantly affect body weight. In conclusion, buprenorphine treatment (0.03 mg/kg TID) prolonged GI transit time and reduced fecal output and food and water consumption in rabbits. Coadministration of buprenorphine and cisapride (0.5 mg/kg) did not ameliorate these effects, and the administration of cisapride at this dose did not appear to affect GI motility in female rabbits.

An easy and low-cost biomagnetic methodology to study regional gastrointestinal transit in rats

The identification of gastrointestinal (GI) motility disorders requires the evaluation of regional GI transit, and the development of alternative methodologies in animals has a significant impact on translational approaches. Therefore, the purpose of this study was to validate an easy and low-cost methodology (alternate current biosusceptometry – ACB) for the assessment of regional GI transit in rats through images. Rats were fed a test meal containing magnetic tracer and phenol red, and GI segments (stomach, proximal, medial and distal small intestine, and cecum) were collected to assess tracer’s retention at distinct times after ingestion (0, 60, 120, 240, and 360 min). Images were obtained by scanning the segments, and phenol red concentration was determined by the sample’s absorbance. The temporal retention profile, geometric center, gastric emptying, and cecum arrival were evaluated. The correlation coefficient between methods was 0.802, and the temporal retention of each segment was successfully assessed. GI parameters yielded comparable results between methods, and ACB images presented advantages as the possibility to visualize intrasegmental tracer distribution and the automated scan of the segments. The imaging approach provided a reliable assessment of several parameters simultaneously and may serve as an accurate and sensitive approach for regional GI research in rats.

Assessment of postoperative gastrointestinal motility in colorectal surgery: a study with the Motilis 3D-transit system

PurposePostoperative recovery following colorectal surgery remains impaired by severe complications including postoperative ileus (POI). Human studies of POI have been limited by a lack of safe and easy-to-use objective methods. Motilis 3D-transit is a completely ambulatory, minimally invasive system whereby electromagnetic capsules are followed by external sensors during their passage of the gastrointestinal (GI) tract. The aim of this study was to evaluate the applicability of the 3D-transit system in a surgical setting.MethodWe included 12 patients as a substudy of the randomised double blind controlled Stimulation of the Autonomic Nervous System In Colorectal Surgery by perioperative nutrition (SANICS)-II trial undergoing elective segmental colonic resection with primary anastomosis at Aarhus University Hospital and Randers Regional Hospital, Denmark. To study region-specific motility, three electromagnetic capsules were administered. One was taken 3 hours before surgery, the next was taken 1 hour before surgery, while the third was placed distal to the anastomosis during surgery. Total and regional GI transit times as well as time until first propulsive colonic contraction were determined.ResultsAll patients tolerated the setup well with no adverse events related to the 3D-transit system. Large variations were found in total GI transit time (26.7–127.6 hours), gastric emptying (0.07–>106.9 hours), small intestinal (1.2–58.4 hours) and colorectal transit time (14.3–>118.1 hours). Time from end of surgery to first propulsive movement in the colon varied from 3.9 to 85 hours. No correlation was found between parameters of GI motility and tolerance of an oral diet or recovery of bowel function.ConclusionThe 3D-transit system allows safe assessment of GI motility in patients operated with segmental colonic resections and primary anastomosis for colorectal cancer. Postsurgical motility varies significantly between patients.

A Close Relationship Between Networks of Interstitial Cells of Cajal and Gastrointestinal Transit In Vivo

The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are located in the same area as the myenteric plexus. ICC-MP networks are linked to the generation of electrical pacemaker activity that causes spontaneous gastrointestinal (GI) contractions; however, its role in GI transit is not clear. The aim of this study was to comprehensively investigate the effect of ICC-MP disruption on GI transit in vivo using W/Wv mice, partially ICC-deficient model mice. In this study, we measured GI transit using a 13C-octanoic acid breath test, an orally administered dye and a bead expulsion assay. ICC were detected by immunohistochemical staining for c-Kit, a specific marker for ICC. Interestingly, we found that gastric emptying in W/Wv mice was normal. We also found that the ability of small intestinal and colonic transit was significantly reduced in W/Wv mice. Immunohistochemical staining using whole-mount muscularis samples revealed that c-Kit-positive ICC-MP networks were formed in wild-type mice. In contrast, ICC-MP networks in W/Wv mice were maintained only in the gastric antrum and were significantly reduced in the ileum and colon. No significant changes were observed in the nerve structures of the myenteric plexus in W/Wv mice. These findings suggest that ICC-MP contribute to GI transit as a powerful driving function in vivo.

A118 GUT MICROBIOTA TRANSPLANTATION FROM A PATIENT WITH SEVERE CONSTIPATION INDUCED CHANGES IN COLONIC FUNCTION AND STRUCTUR OF GNOTOBIOTIC MICE

Background Increasing evidence suggests that gut microbiota play a key role in gastrointestinal (GI) tract function. We have previously shown that fecal microbiota transplantation diarrhea predominant IBS patients into germ-free mice induces faster GI transit, increased permeability and innate immune activation. However, it is unknown whether gut dysfunction is induced by microbiota from patients with chronic constipation. Aims Here, we investigated the role of the intestinal microbiota in the expression of severe slow transit constipation in a patient with previous C difficile infection and extensive antibiotic exposure. Methods Germ-free (GF) mice (14 weeks old) were gavaged with diluted fecal content from the patient with constipation (PA) or a sex and age-matched healthy control (HC). 12 weeks later, we assessed gut motility and GI transit using videofluoroscopy and a bead expulsion test.. We then investigated intestinal and colonic smooth muscle isometric contraction in vitro using electric field stimulation (EFS), and acetylcholine (Ach) release was assessed by superfusion using [3H] choline. Histological changes were evaluated by H&E and immunohistochemistry. Results Mice with PA microbiota had faster whole GI transit (score 18.9 ± 0.9 (N=9) than mice with HC microbiota (15.4 ± 1.0, N=10, p=0.032), with markers located mainly in the distal small bowel and cecum. However, bead expulsion from the colon was significantly longer in PA mice (420.8 s ± 124.6 s, N=9) than in HC mice (82.6 s ± 20.0 s, N=10, p=0.026). This delayed colonic transit was likely due to colonic retroperistalsis visualized videofluoroscopically by retrograde flow of barium in the right colon of PA mice. There was no difference between the two groups in small intestinal or colonic tissues in Ach release or contractility induced by carbachol or KCl,. EFS caused transient biphasic relaxation and contraction in small intestine and colon, with the colonic contraction being stronger in the PA group. Microscopic tissue analysis showed disruption of the interstitial cells of Cajal (ICC) network and increased lymphocyte infiltration in colonic mucosa and submucosa in PA mice. Conclusions These results indicate that the microbiota is a driver of delayed colonic transit in a patient whose constipation started following extensive antibiotic exposure for C. difficile infection. The observed dysmotility pattern was not due to lower muscle contractility but likely caused by immune mediated changes in the ICC network. Funding Agencies CIHR

Clinical Management of the Microbiome in Irritable Bowel Syndrome

Background A growing body of evidence suggests that dysbiosis contributes to the onset and symptomatology of irritable bowel syndrome (IBS) and other functional bowel disorders. Changes to the gastrointestinal microbiome may contribute to the underlying pathophysiology of IBS. Methods The present review summarizes the potential effects of microbiome changes on GI transit, intestinal barrier function, immune dysregulation and inflammation, gut–brain interactions and neuropsychiatric function. Results A multimodal approach to IBS management is recommended in accordance with current Canadian guidelines. Pharmacologic treatments are advised to target the presumed underlying pathophysiological mechanism, such as dysregulation of GI transit, peristalsis, intestinal barrier function and pain signalling. The management plan for IBS may also include treatments directed at dysbiosis, including dietary modification and use of probiotics, which may promote the growth of beneficial bacteria, affect intestinal gas production and modulate the immune response; and the administration of periodic short courses of a nonsystemic antibiotic such as rifaximin, which may re-establish microbiota diversity and improve IBS symptoms. Conclusion Dysregulated host–microbiome interactions are complex and the use of microbiome-directed therapies will necessarily be empiric in individual patients. A management algorithm comprising microbiome- and nonmicrobiome-directed therapies is proposed.