Introduction

Motility disorders, such as gastroparesis and slow transit constipation (STC), are common gastrointestinal (GI) conditions affecting up to 5% of individuals worldwide. The symptoms of motility disorders can be debilitating, affecting quality of life and driving utilisation of healthcare systems. Diagnosis relies on evaluation of regional transit times, with delayed gastric and colonic transit indicated for gastroparesis and STC, respectively. The SmartPill GI Monitoring System (SmartPill), an FDA-cleared wireless motility capsule (WMC), has been used in the assessment of gastroparesis and STC since 2008 but has recently been discontinued, leaving a need for a like replacement. This study aimed to assess a new WMC, the Atmo Gas Capsule System (Atmo Capsule), against SmartPill for the assessment of regional transit times in these conditions.

Aims & Methods

Individuals with upper, lower, or overlapping GI symptoms were recruited in a prospective multi-centre study. Participants concomitantly ingested the Atmo Capsule and SmartPill in a randomized order. Regional transit times including Gastric Emptying Time (GET) and Colonic Transit Time (CTT) were measured and compared between the devices, where paired data were available. GET >5 hours and CTT >59 hours were defined as delayed.

Results

213 participants (median age 41 [range 20-77], 188 female) were recruited across 12 sites: 177 yielded paired GET results, and 147 for CTT. Pearson correlation coefficients for GET and CTT comparisons between Atmo Capsule and SmartPill were 0.86 (0.81-0.89) and 0.74 (0.66 – 0.81) respectively. GET demonstrated a positive predicted value (PPV) of 78.00% (SE: 5.86%), negative predictive value (NPV) of 85.83% (SE: 3.09%), and overall agreement (OA) of 83.62% (SE: 2.78%). For CTT, PPV was 67.35% (SE: 6.70%), NPV was 92.89% (SE: 2.60%), and OA was 84.35% (SE: 3.00%). No serious adverse device events were reported. 32.2% of the total GET evaluable cohort had delayed GET, 27.2% of the CTT evaluable cohort had delayed CTT. For the cohort that had measurements for all transit regions (n=142), 20% had delayed CTT only, 11% had delayed GET only and 18% had a delay in multiple GI regions as measured by the Atmo capsule.

Conclusion

The Atmo Capsule exhibited substantial agreement with SmartPill in measuring both GET and CTT, highlighting its utility as a potential replacement for the discontinued SmartPill for assessment of motility disorders. Nearly 1 in 5 patients studied had delayed upper and lower transit times highlighting the benefit of evaluating multiple regions of the GI tract with a single test.

Disclosure

Nothing

Introduction

Gastrointestinal (GI) transit abnormalities due to dysmotility often affect multiple regions of the GI tract rather than occur in isolation. Identifying regional GI transit delays may influence clinical management. Use of wireless motility capsules (WMC) enable regional and whole GI transit times to be objectively measured; the relationship between symptom profiles and regional transit times are explored here with a new capsule device, the Atmo Capsule.

Aims & Methods

The Atmo Capsule was administered to subjects with suspected upper and/or lower gastrointestinal dysmotility. This analysis utilized data from subjects where valid transit measurements via the Atmo Capsule were available for all regions of the GI tract, and no protocol deviations pertaining to the use of contraindicated medication or inclusion criteria violations were incurred. Regional transit times were considered delayed as follows: gastric emptying ≥ 5 h; small bowel transit, ≥ 6 h; colonic transit, ≥ 59 h. Delays affecting a single region (i.e., gastric, small bowel, or colon) were considered ‘isolated’, delays affecting multiple (> 1) regions were considered ‘generalized’. Symptom profiles were assessed using the Patient Assessment of Gastrointestinal Disorders - Symptoms (PAGI-SYM) and Patient Assessment of Constipation – Symptoms (PAC-SYM) questionnaires: all patients completed the PAGI-SYM while those with symptoms suggestive of lower GI dysmotility completed the PAC-SYM. Data were analyzed via Kruskal-Wallis test.

Results

The WMC was administered to 209 subjects (median age 41; 188 female), of whom 170 had data suitable for this analysis. Delayed GI transit was identified in 100 (59%) subjects: 65 were isolated and 35 were generalized. There were no differences in overall symptom scores in subjects with no delays (PAGI-SYM, median 1.5 [IQR: 1.1, 2.1]; PAC-SYM, 2.0 [1.5, 2.6]), isolated delays (1.5 [1.0, 2.1]; 1.9 [1.2, 2.6]) and generalized transit delays (1.8 [1.4, 2.3]; 2.1 [1.4, 2.8]) (p>0.05 for both) or symptom sub-scores (Table 1). Gastric transit was delayed in 46 subjects: 19 (41%) were isolated and 27 (59%) were generalized. Colonic transit was delayed in 60 subjects: 31 (52%) were isolated and 29 (48%) were generalized. GI symptom profiles were not different in subjects with isolated and generalized transit delays for either the stomach or colon (p>0.05 for all relevant subscales).

Table 1. Symptom profiles amongst patients with no transit delay, isolated transit delay (affecting a single region) and generalized transit delay (affecting multiple regions). Data presented as median (interquartile range) and analyzed via Kruskal-Wallis test.

Conclusion

WMC measurements of regional and whole GI transit using the Atmo Capsule revealed that delayed transit impacting multiple regions were common. However, symptom profiles were unable to distinguish between isolated vs. generalized transit delays, suggesting that symptoms are an unreliable predictor of abnormalities in GI transit as previously found via other transit modalities.

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

Gastric emptying is controlled by phasic gastric contractions which occur at a frequency of ~3 cycles per minute (cpm) in phase with gastric slow waves. Tests to measure slow waves cannot directly detect abnormal contractions. The Atmo Capsule possesses an accelerometer that measures changes in capsule orientation and can thus detect gastric contractions. We analyzed accelerometer data to define its capability to characterize gastric contraction frequency and amplitude in patients with suspected dysmotility, and to assess if frequency or amplitude vary in relation to transit delay.

Aims & Methods

Gut transit was measured by the Atmo Capsule in 209 subjects: 48 with predominant upper GI (UGI) symptoms alone (suspected gastroparesis), 21 with lower GI (LGI) symptoms (suspected slow colon transit) alone, and 140 with combined UGI+LGI symptoms. This analysis utilized data from subjects recording valid gastric emptying time (GET) measures and did not incur protocol deviations affecting gastric transit. Delays in GET were categorized as: normal, <5 h; delayed, 5-10 h; severely delayed, ≥10 h. Fast Fourier Transformation (FFT) of the accelerometer data allows for the identification and analysis of the dominant gastric frequency and amplitude using 10-minute windows and a cutoff frequency of 4.5 cpm. Variability of frequency and amplitude measures were estimated by calculating interquartile range (IQR) and range (max-min) values and were analyzed in relation to presenting symptoms and gastric emptying delays.

Results

Gastric data from 190 subjects were suitable for analysis: gastric contractions with dominant frequencies of 3.30 cpm (IQR 0.47, range 1.47) and amplitudes of 0.10 arbitrary units (au) (IQR 0.04, range 0.14) were detected in 185 (97%) of subjects. Mean contraction frequency tended to be higher in those with delayed GET compared with no delay (p=0.016) and severe delay (p=0.005) (Table 1). Frequency IQR (p=0.002) and range (p=0.002) were higher for GET delay vs. no delay, while range was higher in severe GET delay vs no delay (p<0.001). Mean amplitude was higher in subjects with severe GET delay compared with normal delay (p=0.008) and normal transit (p=0.001). Amplitude IQR and range were both higher in those with severe GET delay compared with normal delay (p=0.002; p=0.001) and no delay (p<0.001 for both). Frequency metrics were similar irrespective of predominant symptoms. Amplitude means (p=0.022), IQR (p=0.030) and range (p=0.0004) were higher for UGI vs. LGI symptoms.

Table 1. Dominant gastric frequencies and amplitudes in relation to gastric emptying delays. Data shown as median (interquartile range) and analyzed via Kruskal-Wallis test.

Conclusion

The Atmo Capsule accelerometer reliably characterizes 3 cpm gastric contraction frequency and amplitude in subjects with proposed delays in gut transit. Increased variabilities in contraction frequency and amplitude were defined in those with severely delayed gastric emptying and increased amplitude variability was found for predominant upper GI symptoms. We propose these higher variations identified by accelerometry may reflect hypomotility or contractile dropout, suggesting additional clinical utility of the Atmo Capsule in suspected gastroparesis.

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

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

Gastroparesis (GP) is a chronic motility disorder characterized by recurrent upper gastrointestinal (GI) symptoms, namely early satiety, nausea and vomiting, in the absence of a mechanical obstruction. Functional Lumen Imaging Probe (FLIP) is a potential game-changer in anatomical sphincter assessment. Recently, wide prospective trials[1] and a randomized sham-controlled study[2] implemented FLIP to predict response of pyloric-targeted treatments. This has prompted the need for a comprehensive analysis of available FLIP data in GP.

Aims & Methods

The aim of this systematic review was to investigate FLIP role in GP. Meta analysis of normative values and treatment comparative outcomes was also performed. A systematic search was performed until May 2024 on 4 major databases (Pubmed-MEDLINE, Embase, Web of Science, Cochrane). Studies on post-oncological/bariatric surgery gastroparesis were excluded. Pooled baseline mean of FLIP metrics and mean differences (MDs) pre vs post-treatment were calculated. In addition to estimate clinically meaningful normative values for GP, upper-limit reference ranges were estimated by pooled standard deviations (SDs) implementing the formula pooled mean ± 1.96 × pooled SD. Random effects meta-analysis with Knapp-Hartung correction for 95% confidence intervals (CIs) adjustment and I² statistics with subgroup analysis to address heterogeneity were performed.

Results

Twenty studies (N= 805 patients) were included. The majority focused on treatment response, particularly pyloromyotomy. The most assessed FLIP metrics were distensibility index (DI) and cross-sectional area (CSA). Three studies (on 7 total) reported a positive correlation between DI and CSA with specific symptoms (dyspepsia spectrum and nausea/vomiting) and their severity at baseline. Ten studies (on 15 total) studies showed an association between FLIP parameters with clinical response. Pooled mean DI ranged from 7.5 to 8.9 mm²/mmHg and CSA from 85.5 to 195.6 mm² at baseline. Minimum diameter (Dmin) ranged between 10.6 and 16.5 mm while Pressure (P) between 14.8 and 34.5 mmHg (table 1.). Upper-limit normative values for GP ranged from 173-317 mm² for CSA, 17-27 mm for Dmin, 32-64 mmHg for P (between 30-50 mL of fill volumes), while for DI at 50mL the reference limit attested at 21.5 mm²/mmHg. Comparing pre-and post-treatment response, MD of 2.5 mm²/mmHg (I² 24%) for DI at 50 mL, 46.7 mm² (I² 47%) and 68.8 mm² (I² 0%) for CSA at 40 and 50 mL respectively, were statistically significant.

Table 1. FLIP metrics pooled mean values at different fill volumes at baseline in gastroparesis patients

Conclusion

This is the first systematic effort in gathering evidence on FLIP in gastroparesis. CSA and DI significantly changed after pylorus-targeted treatments. Normative values displayed substantial heterogeneity and wide CIs. The cut-off of 10 mm²/mmHg for DI seems feasible to categorize patients to be addressed to pylorus-targeted treatments. Further studies to calculate prediction ability of this cut-off are warranted.

References

1. Jacques J, Pagnon L, Hure F, Legros R, Crepin S, Fauchais A-L, et al. Peroral endoscopic pyloromyotomy is efficacious and safe for refractory gastroparesis: prospective trial with assessment of pyloric function. Endoscopy. 2019;51(1):40-9.
2. Martinek J, Hustak R, Mares J, Vackova Z, Spicak J, Kieslichova E, et al. Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial. Gut. 2022;71(11):2170-8.

Disclosure

E.V. received speaker and/or consulting fees from Sanofi/Regeneron, Falk Pharma, Apollo Therapeutics, and Aurora Biofarma. AJB received research funding from BMS, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Uniquity, Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Uniquity, Reckitt, AlfaSigma and AstraZeneca. All other authors did not have any disclosures.

Introduction

STW5-II is a medicinal product composed by 6 herbal extracts that has been shown to relieve clinical symptoms in patients with dyspepsia. The mechanisms of action include selective effects on gastric tone, antro-pyloric activity
and visceral sensitivity. Patients with functional dyspepsia (FD) have a poor tolerance to gastric gas that has been related to a combination of several factors, including delayed gas transit and evacuation, visceral hypersensitivity and altered viscero-visceral reflexes.

Aims & Methods

The aim of the present study was to determine the effect of STW5-II on transit and tolerance of gastric gas in patients with FD. In 27 patients (26 female and 1 male, age range 22-70 years old) with FD and bloating (17 postprandial distress syndrome, 4 epigastric pain syndrome and 6 mixed type dyspepsia), a gas challenge test was performed after two weeks on STW5-II 20 drops t.i.d. or placebo, in a parallel, double blinded, controlled trial. The gas challenge test consisted in infusion of a mixture of gases into stomach through a nasogastric tube at 100 mL/min for 15 minutes (total volume infused 1500 mL) with concomitant gastric nutrient perfusion (Nutridrink 1.5 Kcal/ml, total 315 Kcal), mimicking a normal meal. Rectal gas evacuation, via a rectal tube connected to a barostat, and belching, by an esophageal multilumen impedance catheter, were continuously measured for 90 min from infusion start. Abdominal symptoms, using a 0-6 perception scale, and abdominal distension, using a tape measure, were quantified at 10-min intervals.

Results

Gastric gas infusion was followed by a progressive gas evacuation from the rectum, that was accelerated when patients were on STW5-II, compared to placebo. After 20 min from infusion start (when gas and nutrient perfusion was already finished) only 80±39 mL of gas had been expelled in studies on placebo, whereas 319±81 mL of gas were collected on STW5-II group (p=0.015). Thereafter, both groups continued to expel gas at similar rates, without differences between groups at the end of the study (837±180 mL and 1030±160 mL, saline and STW5-II, respectively; p=0.432). Gastric belches were exceptional in both groups (0.8±1.0 and 1.1±1.6 gastric belches in 90 min, saline and STW5, respectively; p=0.318).
Gastric gas infusion gas associated to a rapid rise in perception of abdominal symptoms, that was significantly lower in patients treated with STW5-II than those treated with placebo (score increment 3.0±0.4 vs 1.9±0.6, placebo and STW5-II, respectively; p=0.036). Following continuous rectal gas evacuation, perception decreased in both groups, however perception remained significantly greater at the end of the 90-min study period in patients on saline (score increment 1.4±0.6; p=0.018 vs infusion start), whereas it had returned to basal levels in patients treated with STW5-II (score increment -0.2±0.4; p=0.324 vs infusion start). There were no significant differences in abdominal girth increment between groups (max increment 16±2 mm and 13±2 mm placebo and STW5-II, respectively; p=0.224).

Conclusion

STW5-II is a medicinal product that improves tolerance to gastric gas in patients with functional dyspepsia, by acceleration of transit and rectal evacuation of gas, and reduction of the intensity of symptoms elicited by gas. Hence, this medicinal product could be beneficial for management of gas-related abdominal symptoms like bloating in patients with functional dyspepsia.
EudraCT: 2019-003976-38