Introduction

In patients with chronic constipation, slow colonic transit is hypothesised to be associated with altered colonic fermentation profiles. Green kiwifruit is known to have laxative effects. This could be caused by the modulation of colonic microbiota, which has a role in regulating colonic transit¹. The wireless motility capsule measures gastrointestinal anatomical landmarks through changes in pH and temperature, while a novel gas-sensing capsule measures anatomical landmarks and colonic fermentation^2,3. In this study, both technologies were used to investigate the effects of green kiwifruit on gastrointestinal transit and colonic fermentation profiles in participants with constipation.

Aims & Methods

Participants with chronic constipation (N = 62) were randomised to consume two green kiwifruit (Actinidia deliciosa, ~150g per serving, ~90 kcal) or
calorie-matched maltodextrin (~90 kcal = 25g) daily for four weeks. A subset of the participants (N = 21) consumed a standardised breakfast and ingested the wireless motility capsule or both wireless motility devices (wireless motility capsule and gas-sensing capsule) at baseline and post-intervention. Participants fasted six hours post-ingestion and wore data receivers until device excretion.

Results

Preliminary blinded results show that the wireless motility capsule measured colonic transit time decreased in participants on intervention A (median decrease = 1.4 hours, interquartile range (IQR) (-32.00, 9.12)) and increased on intervention B (median increase = 15.8 hours, IQR (-46.89, 23.48)), the change in colonic transit time was not significant (p = 0.628). There was no significant difference between the median colonic H₂ and CO₂ (% concentration/hour) at baseline and post-intervention (H₂: p = 0.50; CO₂: p =0.138). The difference between interventions was not significant for median colonic H₂ and CO₂ concentrations (H₂: p = 0.200; CO₂: p =0.800).

Conclusion

The wireless motility capsule and the gas-sensing capsule technologies assessed the differences in colonic transit time after dietary intervention. The gas-sensing capsule measured the colonic gas profile accurately and safely. The gas-sensing capsule has the potential to be used as a tool for measuring colonic fermentation profile. Despite encouraging results, this study had several limitations, including a small sample size, unusable data due to data loss, and transit time beyond the battery life of the capsules. Further analyses will explore the relationship of colonic gas concentration with colonic transit time and faecal microbiota.

References

1. Bayer, S. B., Gearry, R. B., & Drummond, L. N. (2018). Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function. Crit Rev Food Sci Nutr, 58(14), 2432-2452. https://doi.org/10.1080/10408398.2017.1327841
2. So, D., Yao, C. K., Ardalan, Z. S., Thwaites, P. A., Kalantar-Zadeh, K., Gibson, P. R., & Muir, J. G. (2022). Supplementing Dietary Fibers With a Low FODMAP Diet in Irritable Bowel Syndrome: A Randomized Controlled Crossover Trial. Clinical Gastroenterology & Hepatology, 20(9), 2112-2120.e2117. https://doi.org/10.1016/j.cgh.2021.12.016
3. Thwaites, P. A., Yao, C. K., Maggo, J., John, J., Chrimes, A. F., Burgell, R. E., Muir, J. G., Parker, F. C., So, D., Kalantar-Zadeh, K., Gearry, R. B., Berean, K. J., & Gibson, P. R. (2022). Comparison of gastrointestinal landmarks using the gas-sensing capsule and wireless motility capsule. Alimentary Pharmacology & Therapeutics, 56(9), 1337-1348. https://doi.org/10.1111/apt.17216

Disclosure

Jasjot Maggo and Hwei Ng - Received research support from Atmo Biosciences.
Simone Bayer - Received funding for project, travel and conference from Zespri^™ International Ltd.
Nicole Roy - Received funding from Zespri^™ International Ltd.
Richard Gearry - Received research funding from Atmo Biosciences and Zespri^™ International Ltd. He is an advisory board member for Zespri^™ International Ltd. He has received support for travel or educational planning/attendance at conferences from Zespri^™ International Ltd.

Introduction

The Atmo Capsule is a wireless motility capsule that senses and telemetrically transmits measurements of hydrogen (H₂) and carbon dioxide (CO₂) along the gut. In the colon, luminal concentrations of H₂ and CO₂ represent the metabolic activity of the microbial community. We hypothesized that delayed colonic transit would lead to altered gas profiles due to earlier depletion of fermentable substrates relative to transit time and/or facilitation of contact between methanogens and hydrogen (Levitt et al. CGH 2006).

Aims & Methods

The Atmo Capsule was administered to subjects with suspected upper and/or lower gut dysmotility. Colonic transit times (CTT) ≥ 59 h were considered delayed. Luminal H₂ and CO₂ concentrations (as time-normalized, area-under-the-curve [TN-AUC], [%.h]/h) were evaluated across the entire colon. Regional colonic profiles were evaluated per quartile of relative colonic transit, with quartiles 1 and 4 indicative of the proximal and distal colon, respectively. Gas measures were included if ≥ 50% of data were available for the corresponding segment. Fermentation profiles were estimated by the ratio of quartile 1:4 values, and time to peak concentrations were evaluated relative to CTT. Data were analyzed via Mann-Whitney test.

Results

The Atmo Capsule was administered to 209 subjects (median age 41; 188 female) with 170 yielding valid data on both colonic transit and colonic gas concentrations. Delayed colonic transit was identified in 60/170 (35%) subjects. In subjects with delayed CTT, H₂ concentrations tended to be higher in the proximal colon and lower in the distal colon with no overall difference across the region compared with those with normal transit (Table 1). CO₂ concentrations were higher throughout the colon except in the distal colon in subjects with delayed CTT. Peak concentrations of colonic H₂ and CO₂ were higher (H2, 8.7 h vs 5.9 %.h/h, p<0.01; CO2, 37.4 vs 29.9 %.h/h, p<0.01) and tended to occur earlier (H₂, 35.9 vs 47.0 % of colonic transit p=0.14; CO₂, 49.1 vs 86.8 % colonic transit, p<0.01) in patients with delayed compared with normal CTT.

Table 1. Gas profiles in patients with delayed colonic transit and correlation with symptom profiles. Data shown as median (interquartile range) and analyzed via Mann-Whitney test.

Conclusion

Colonic gas profiles, as measured via the Atmo Capsule, differed in patients with delayed compared with normal CTT, with patterns suggesting progressive depletion of fermentable substrates and/or conversion of H2 to methane during transit in those with delayed transit.

References

Levitt MD, Furne JK, Kuskowski M, Ruddy J. Stability of human methanogenic flora over 35 years and a review of insights obtained from breath methane measurements. Clin Gastroenterol Hepatol. 2006 Feb;4(2):123-9. doi: 10.1016/j.cgh.2005.11.006. PMID: 16469670.

Disclosure

These authors disclose the following: Braden Kuo, Anthony J. Lembo, Eammon M.M. Quigley, Satish S.C. Rao, and William D. Chey serve on the Medical Advisory Board of Atmo Biosciences. Michael Cline and Baharak Moshiree served on the Medical Advisory Board of Atmo Biosciences. Braden Kuo has received funding from NIH, Vanda, Atmo Biosciences, and Takeda and has consulted for Evoke, Takeda, Ironwood, Novo Nordisk, Cindome, and Neurogastrx. Thomas Abell has received funding from Gastric Dysrhythmias, Neurogastrx, NIH GpCRC, and Vanda and has consulted for Enterra Medical, Novo Nordisk, Nuvaira, and Vanda. Anthony J. Lembo has received funding from Ardelyx, Biomerica, GSK, Ironwood, Takeda, and Vibrant and holds stock with Allurion, Bristol Myer Squibb, and J&J. Abigail Stocker has received funding from Cindome, Enterra Medical, and Vanda. William D. Chey has received funding from Atmo Biosciences, Commonwealth Diagnostics Intl, QOL Medical, and Salix; has consulted for AbbVie, Ardelyx, Biomerica, Comvita, Gemelli, Ironwood, Nestle, QOL Medical, Phathom, Redhill, Salix, Vibrant, and Takeda; has filed patents with My Nutrition Health, Digital Manometry, and Rectal Expulsion Device; and holds stock options with Coprata, Evinature, Food Marble, Kiwi Bioscience, and Modify Health. The remaining authors disclose no conflicts.

Introduction

Functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C) are highly frequent conditions characterized by chronic constipation (up to 24% in adults) (1). The initial management of chronic constipation typically involves dietary and lifestyle modifications, fiber supplementation, and laxative therapy. For patients who do not respond to these interventions, second-line therapies, such as medications with prokinetic effects, are recommended. Pyridostigmine, an anticholinesterase agent commonly used in the treatment of myasthenia gravis and paralytic ileus, might play a role in refractory chronic constipation, but evidence is still not available.

Aims & Methods

We carried out a retrospective observational study involving all patients diagnosed with functional constipation (constipation-predominant irritable bowel syndrome [IBS-C] or chronic idiopathic constipation) according to the Rome IV criteria, who met the criteria for severe chronic constipation (2) (defined as two or fewer spontaneous and complete bowel movements per week for a minimum of 6 months, associated with hard stools, sensation of incomplete evacuation, or straining during defecation in at least 25% of bowel movements), who were refractory to first-line treatments (dietary and lifestyle counseling, bulk-forming laxatives, osmotic laxative such as polyethylene glycol and stimulant laxative such as bisacodyl) and who were treated with pyridostigmine in our outpatient gastroenterology clinic from April 2021 to December 2024. Patients were included if they attended at least one follow-up visit within 12 weeks after treatment. We excluded all patients with organic gastrointestinal disorders. We evaluated the improvement in constipation at follow-up, defined as patients having three or more spontaneous, complete bowel movements per week during the follow-up period. (2) We also evaluated any improvement in other gastrointestinal symptoms and the safety profile of the treatment.

Results

Overall, 110 patients were included in the study, of whom 77 (70%) met the criteria for IBS-C and 33 for chronic idiopathic constipation (30%). Other gastrointestinal symptoms included bloating (n=88, 80%), abdominal pain (n=77, 70%), dyspepsia (n=17, 15%). Overall, 74 (67%) patients experienced an improvement in constipation. Additionally, 51(46%) patients exhibited improvements in other gastrointestinal symptoms: 38/77 (49%) patients experienced relief from abdominal pain, 35/88 from bloating (40%), and 10/17 (59%) from dyspepsia. Finally, Four (4%) patients have discontinued therapy due to pyridostigmine intolerance (2 patients experienced muscle fasciculation, 2 patients fatigue); no severe therapy-related adverse events were observed.

Conclusion

In our cohort, pyridostigmine was an effective and safe treatment for IBS-C and chronic idiopathic constipation in patients unresponsive to first-line treatments, providing benefits not only in alleviating constipation but also in ameliorating other gastrointestinal symptoms. Further prospective and randomized studies are warranted to confirm our findings.

References

1. Oh SJ, Fuller G, Patel D, et al. Chronic constipation in the United States: results from a population-based survey assessing healthcare seek- ing and use of pharmacotherapy. Am J Gastroenterol 2020;115:895- 905.
2. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med. 2008 May 29;358(22):2344-54. doi: 10.1056/NEJMoa0800670. PMID: 18509121.

Introduction

Chronic constipation leads to an increased risk of heart disease, stroke, and kidney disease¹⁾. Stimulant laxatives provide quick relief and are preferred by patients and pharmaceutical companies; “sennosides” and “bisacodyl,” are more popular compared with bulk-forming laxatives²⁾. However, with prolonged use, the human body becomes habituated to them. The laxatives induce prostaglandin production³⁾ through immune cell aggregation and local cytokine expression⁴⁾. Thus, prolonged use of stimulant laxatives leads to inflammation and damages the intestinal nervous plexus, leading to intestinal exhaustion⁵⁾.
Mesalazine can remove reactive oxygen and inhibit the biosynthesis of cytokines including interleukin (IL)-1β and leukotrieneB4, and hence, is used for treating inflammatory bowel disease⁶⁾. Concurrent intake of mesalazine and stimulant laxatives might suppress leukotriene and the subsequent adverse inflammatory responses, thus allowing the safe and long-term use of sennosides.
Herein, we observed stool characteristics of animal models and performed pathological analyses of their colon tissue to establish the stable use of mesalazine-adapted stimulant laxatives. Lamina propria mononuclear cells (LPMCs) of the colon were then collected for flow cytometry analysis (FACS) and real-time polymerase chain reaction (PCR).

Aims & Methods

Six-week-old BALB/cAJcl mice were assigned to one of the four groups: control, mesalazine (100 mg/kg), sennosides (4.8 mg/kg), or mesalazine and sennosides combination groups, (n = 8 for each group). Each drug was suspended in 0.5% carboxymethylcellulose (CMC). Doses were administered orally once daily for 21 days. Stool samples were collected on days 0, 7, 14, and 21; looseness and weight of each stool sample were measured. Feces were then freeze-dried and weighed to calculate the water content percentage.
Mice were euthanized after 21 days, and their colons were harvested. Inflammatory cell aggregation was detected on pathological evaluation, which was performed via H&E staining. Composition of the aggregated LPMCs was evaluated via FACS. Real-time PCR was performed to detect cytokine mRNA expression in LPMCs.

Results

No differences in food intake, water consumption, and body weight were observed among the groups during the experimental period. On day 21, the sennosides group exhibited significantly greater stool looseness compared with the control group. Stool looseness was similar in the sennosides and combination groups. Water content percentage in the stool was significantly higher in the sennosides group compared with in the control group, and this increase was not influenced by the addition of mesalazine. Inflammatory cell aggregation was detected in sennosides and combination groups. A drastic increase in the level of killer T cells was revealed in the sennosides group on FACS, and mesalazine administration resulted in restoration to normal composition. Regarding mRNA expression, IL-1β, IL-2, and IFN-γ levels were elevated in the sennosides group, which was alleviated by mesalazine co-administration.

Conclusion

Sennosides is predicted to provoke IL-2 and IFN-γ biosynthesis that induces killer T cell aggregation and subsequent IL-1β production. As the combination group did not show any inflammation, it is assumed that mesalazine prohibits the inflammatory process. These results provide further evidence to indicate that mesalazine can alleviate sennosides-induced inflammation without adversely affecting its efficacy. This finding may promote the effective use of laxatives in patients with chronic constipation.

References

1) Joseph Y Chang, et al. Am J Gastroenterol, 105: 822-832 (2010)
2) Barry L. Werth, et al. J. Clin. Med, 10, 143 (2021)
3) Teruyo Yagi, et al. J. Pharm. Pharmacol, 40: 27-30 (1988)
4) B A van Gorkom, et al. Aliment Pharmacol Ther, 13: 443-452 (1999)
5) John H. Cummings, et al. Gut, 15: 758-766 (1974)
6) Koichi Nakamaru, et al. Folia Pharmacol. Jpn, 104：447-457 (1994)

Introduction

Chronic constipation (CC) is a frequent gastrointestinal disorder which significantly affects patients' quality of life. International guidelines recommend the use of polyethylene glycol (PEG) as part of the first-line management of CC after the failure of diet and lifestyle modifications. However, limited data are available on how PEG is used in daily clinical practice. Therefore, a national survey among gastroenterologists (GEs) and general practitioners (GPs) was conducted to evaluate its use in the management of CC.

Aims & Methods

Members of Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO) and Italian Federation of General Practitioners (FIMMG) were invited to complete a 44-item online survey. The questionnaire was structured to explore several dimensions regarding the use of PEG (e.g. type of PEG used, formulations and dosages recommended, etc.).

Results

The survey was completed by 1188 physicians (317 GEs, 871 GPs). GEs were significantly younger (mean age 44.9 vs. 51.0 years, p<0.01) and more likely to have less than 10 years of experience compared to GPs.
PEG was prescribed as part of first-line treatment in addition to dietary and behavioral advice more frequently by GEs than GPs (92.4% vs. 82.9%, p<0.001). GPs preferred to prescribe PEG in the early morning or evening before bedtime compared to GEs (p<0.001), which preferred mid-morning or midafternoon (p<0.01). GPs more often recommended taking it away from other drugs and/or supplements compared to GEs (76.7% vs 61.5%, p<0.001).
GEs considered PEG products to be taken continuously more often than GPs (36.9% vs 18.6%, p<0.001) and were more inclined to avoid setting a fixed treatment duration (62.8% vs 38.2%, p<0.001), while GPs often recommend a short-term or an on-demand use. GEs also more often preferred to discontinue PEG gradually compared to GPs (74.8% vs. 63.0%, p<0.001)
PEG’s formulation choices varied: GEs favored the powder formulation less than GPs (58.7% vs 78.9%, p<0.001), and more often started therapy at higher dosages (Table 1). Moreover, GEs gave more importance on palatability compared to GPs (71.9% vs 60.4%, p<0.001).
Safety perceptions were similarly high across the groups, GEs were more likely to prescribe PEG than GPs to patients with comorbidities such as chronic kidney disease (75.7% vs 64.0%, p<0.001) and during pregnancy/lactation (71.3% vs 48.8%, p<0.001).

Table 1. Prescription of PEG as part of first line management of CC and PEG's initial dosage answers.

Conclusion

To the best of our knowledge, this is the first national survey to assess how PEG is prescribed by GEs and GPs in daily clinical practice. The survey highlighted a certain heterogeneity in prescription behaviors. GEs tended to adopt longer-term therapeutic strategy, starting with higher doses. Moreover, they paid greater attention to PEG palatability and were more confident on PEG safety in patients with chronic comorbidities. These findings underscored the need for shared knowledge and approaches to optimize constipation management across different care settings.