Nutrition and dietary guidelines in gastrointestinal disorders vary in scope, rigour and recommendations, contributing to variations in practice. This Comment identifies nutrition and dietary guidelines for gastrointestinal disorders, namely chronic constipation, irritable bowel syndrome and inflammatory bowel disease, and examines the methodologies used to develop them.

INTRODUCTION:Specific foods are associated with abdominal bloating, which can significantly affect quality of life. To identify responders to fiber-induced bloating and the mechanisms underpinning clinical and microbial responses. METHODS:Double-blind, placebo-controlled, randomized, 2-period, 2-challenge crossover trial in 41 individuals with functional bloating. Participants were randomized to 8 g/d of fructan or α-galacto-oligosaccharides (α-GOS) for 7 days with a 21-day washout. Clinical, nutritional, microbial (shotgun sequencing, metatranscriptomics), and fermentation (short-chain fatty acids, volatile organic compounds, breath hydrogen) profiles were characterized before each challenge to identify factors predicting response and after the challenge to elucidate mechanisms underpinning food-induced bloating. RESULTS:Thirty-nine participants completed both challenges (39 fructan, 40 α-GOS). Overall, 7 (7/39, 17.9%) participants were fructan responders and 8 (8/40, 20%) were α-GOS responders (experienced fiber-related symptom induction). Clinical metrics indicative of bloating distinguished responders and nonresponders to both challenges, including greater abdominal girth (fructan, P = 0.009; α-GOS, P = 0.030). α-GOS responders had higher breath hydrogen (H 2 ) prechallenge than α-GOS nonresponders ( P = 0.011). Trends were identified within metagenomic and metatranscriptomic gut microbial analyses, with higher carbohydrate active enzyme (CAZyme) diversity in fructan responders (prechallenge, adjusted P -value ( P adj) = 0.024; postchallenge, P adj = 0.042) and greater increase in gene expression for gamma-aminobutyric acid (GABA) degradation in α-GOS responders ( P adj = 0.041). DISCUSSION:A higher burden of GI symptoms predicts clinical response to fermentable fibers in functional bloating, while for α-GOS, higher repeated fasting breath H 2 is also a predictor. Gut microbiome function and fermentation is associated with functional bloating; however, further investigations are required to draw firm conclusions for the microbial influence in this interplay.

AIM:The aims of the study were to: (1) update a systematic review on the efficacy of transanal irrigation (TAI) in patients with chronic constipation (CC) and/or faecal incontinence (FI); (2) provide guidance on the position of TAI in the treatment pathway of CC and FI; and (3) discuss knowledge gaps and areas of future research. METHOD:A collaborative of 11 experts (gastroenterologists, colorectal surgeons, and clinical scientists) from eight European countries was established. The expert group was divided into three main groups, with each group leading a specific section (systematic review, treatment pathway, and knowledge gaps). A previously published systematic review on TAI was updated by conducting an additional search on 12 April 2025. Studies on TAI in specific subgroups (neurogenic bowel dysfunction, low anterior resection syndrome) were excluded. RESULTS:Sixteen studies involving 1567 (range 16-507) patients were included. Only one underpowered randomised trial was performed, which demonstrated that high-volume TAI may be more effective than low-volume TAI in patients with CC. Most other studies (observational) showed improvement in symptoms and/or quality of life to some extent, with a large variation in outcomes used. Treatment discontinuation was reported in 3-57% of patients. The position of TAI in the treatment pathway of CC and FI was proposed, and 13 knowledge gaps were provided. CONCLUSION:TAI may be an effective treatment in patients with CC and/or FI. There is a need for randomised controlled trials to study its efficacy and current knowledge gaps.

INTRODUCTION:The London classification provides standardization for characterization of disorders of anorectal function, although prevalences and clinical impact of these disorders are unclear. METHODS:An international research consortium was established, including 5 specialist centers. Prospective data were collected in consecutive adults referred for refractory chronic constipation (CC), fecal incontinence (FI), or coexistent CC/FI over 18 months. Patients completed a standardized clinical questionnaire and underwent anorectal physiology tests, which were performed and interpreted using uniform methodology. The prevalence of the London classification was compared between symptom groups (CC, FI, and coexistent CC/FI), equipment types, and sites. Clinical impact was assessed using Cleveland Clinic Constipation and St. Marks Incontinence Scores. RESULTS:Of 1,012 included patients (85.6% women), 30.5% had self-reported CC, 33.2% had FI, and 36.3% had coexistent CC/FI. Rectoanal areflexia was uncommon (3.1%). Disorders of anal tone/contractility (CC: 45.0%; FI: 68.5%; coexistent CC/FI: 63.8%; P < 0.0001) and disorders of rectal sensation (major findings: rectal hyposensitivity, CC: 10.0%; FI: 5.0%; coexistent CC/FI: 11.1%; P = 0.018; rectal hypersensitivity, CC: 3.8%; FI: 9.0%; coexistent CC/FI: 4.9%; P = 0.025) varied between the symptom groups and were associated with symptom severity. Most disorders of rectoanal coordination were found in similar proportions across the symptom groups and were not associated with the severity of CC (median Cleveland Clinic Constipation Score 10-14 in all groups). Prevalences of some disorders differed between equipment types (specifically balloon expulsion test). DISCUSSION:This prospective multicenter study provides information on the prevalence and clinical impact of the London classification and will guide refinement of the current London classification.

ABSTRACT Background Quantitative data on colon length in adult chronic constipation (CC) are lacking. This study aimed to measure the length of the colon in CC, in the undisturbed state and after an osmotic laxative challenge, using magnetic resonance imaging (MRI) as compared to healthy volunteers (HV) and IBS‐C patients. Methods Segmental and total colon length were measured by manual tracing on fasting MRI scans, retrieved retrospectively for 57 HV, 17 CC, and nine patients with irritable bowel syndrome with constipation (IBS‐C). In all CC patients and 22 HV, MRI scans were also performed after an oral osmotic laxative challenge. Participants' age range was 18–75 years. Key Results CC patients showed significantly longer colons (162 ± 6 cm) than HV (127 ± 2 cm; p < 0.01), with 10/17 being longer than the upper limit of normal. Colon length in IBS‐C (129 ± 6 cm) was similar to HV. The colon in HV was able to elongate from 133 ± 3 to 148 ± 4 cm ( p < 0.0001) to accommodate the macrogol challenge influx, while the CC colon could not do so (from total length at baseline 162 ± 6 to 168 ± 5 cm; p = 0.0768). Conclusion & Inferences The study provides normative values of colon length, to which CC and IBS‐C are compared. CC was associated with increased colon length and reduced capacity to elongate longitudinally, rather than radially, in response to a laxative challenge. Colon length in IBS‐C was similar to HV. These measurements can improve our understanding of gut disease pathophysiology and response to treatment.

BACKGROUND:Current clinical guidelines for chronic constipation offer limited dietary recommendations. The aim of this project was to develop the first comprehensive evidence-based dietary guidelines for the management of chronic constipation in adults. METHODS:Four systematic reviews and meta-analyses were performed to identify eligible randomised controlled trials (RCTs). The findings generated from the meta-analyses were then used to develop guideline statements using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach and a Delphi consensus survey among a multi-disciplinary expert Guideline Steering Committee. Recommendation statements were produced for treatment response, stool output, gut symptoms, adverse events, and quality of life, and only based on the findings where ≥ 2 RCTs contributed to the meta-analysis. The strength of recommendation was assessed using the GRADE approach. Consensus voting amongst the Guideline Steering Committee was performed using a modified Delphi survey approach. RESULTS:The four systematic reviews included a total of 75 RCTs. Fifty-nine dietary recommendation statements were generated and accepted through the Delphi survey. For dietary supplements, 15 recommendation statements relate to fibre supplements, 20 relate to probiotics, 2 to synbiotics, 5 to magnesium oxide, 2 to senna, and 3 to kiwifruit supplements. For foods, three recommendation statements related to kiwifruits, two to prunes, and two to rye bread. For drinks, five recommendation statements related to high mineral-containing water. No recommendations were made for whole diet approaches due to a lack of evidence. Twelve statements had a very low level of evidence, 39 had a low level of evidence, and 8 had moderate evidence. Twenty-seven statements were strong recommendations, and 32 were qualified recommendations. CONCLUSIONS:These are the first comprehensive evidence-based dietary guidelines for the management of constipation based upon a robust systematic review and GRADE processes. Recommendations were made for dietary supplements, foods and drinks that have never been previously included in clinical guidelines, and can now be rapidly implemented into clinical practice, thereby improving clinical care and patient outcomes.

Irritable bowel syndrome (IBS) is a very common condition worldwide. Treatment options for severe IBS are few. Sacral neuromodulation (SNM) for patients with IBS has been shown to reduce symptoms and improve quality of life in the medium term. This study aimed to evaluate the long-term effectiveness and safety of SNM in diarrhoea-predominant and mixed IBS. A prospective cohort of patients with IBS treated with SNM were evaluated 1, 3, 5, and 10 years after implantation. The primary end-point was a change in the Gastrointestinal Symptom Rating Scale–Irritable Bowel Syndrome version questionnaire (GSRS-IBS) from baseline to 10-year follow-up (FU). Secondary end-points were change in the GSRS-IBS score from baseline to 5-year FU and change in the Irritable Bowel Syndrome–Impact Scale questionnaire (IBS-IS) from baseline to 5- and 10-year FU. Adverse events following SNM were observed. Of 36 patients treated with SNM, 23 were eligible for 5-year FU and 13 for 10-year FU. The GSRS-IBS score was significantly reduced at both 5-year (p < 0.0001) and 10-year (p = 0.0007) FU. The IBS-IS score was also significantly improved at both 5 years (p < 0.0001) and 10 years (p = 0.0002). Fifty-six adverse events were registered. Five patients were explanted because of adverse events. SNM seems to offer an effective and safe treatment option for highly selected patients with diarrhoea-predominant and mixed IBS. The present study has not been registered. The latest founding study was registered at ClinicalTrials.gov, NCT01948973.

AIM:Sacral neuromodulation (SNM) is considered the first-line surgical treatment in adults with refractory faecal incontinence (FI). However, its clinical efficacy has not been rigorously tested in a trial setting. METHOD:Randomised, multicentre, double-blind crossover trial (two 16-week periods) of active stimulation versus sham, and open-label follow-up to 58 weeks. PARTICIPANTS:adults aged 18-80 with refractory FI. INTERVENTIONS:Active: subsensory sacral nerve stimulation with an implanted pulse generator; Sham: identical implant but turned off. PRIMARY OUTCOME:FI episodes per week (paper bowel diary) during final 4 weeks of crossover periods (allowing 12 weeks' washout). Randomised allocation (1:1) to arm 1 (SNM/sham) or arm 2 (sham/SNM). BLINDING:participants, surgeons, assessors; tamper-proof tape-masked stimulation settings. SAMPLE SIZE:80 patients to detect a 30% reduction in episodes. Groups compared using a paired t-test, and treatment effects summarised by mean differences. RESULTS:Trial delivery was severely affected by COVID-19. Thirty-nine patients of 220 screened (arm 1: N = 17; arm 2: N = 22) were recruited at 10 sites (February 2018-July 2022), of whom only 16 (arm 1: N = 9; arm 2: N = 7) had complete primary outcome data. Of the 39, 19 completed follow-up to 58 weeks. SNM conferred a non-significant reduction in mean FI episodes per week compared to sham (-0.795 [95% CI: -1.5 to 0.0], p = 0.06). Improvements were observed in FI symptoms at 58 weeks compared to baseline (FI episodes per week: 3.2 [SD 3.3] vs. 6.2 [SD 5.9]). CONCLUSIONS:The SUBSoNIC trial failed to find conclusive evidence of the experimental efficacy of SNM. Further demonstration of experimental efficacy remains important as SNM is a high-cost and invasive therapy.

Background/Objectives: Chronic nausea and vomiting (N/V) disorders are common in clinical practice. Our primary aim was to compare total and segmental gastrointestinal transit times as well as gastric contraction patterns in patients with chronic N/V syndrome to those of healthy volunteers (HVs). In the patient group, our secondary aim was to explore how symptoms and motility patterns were affected by a serotonin HT4 receptor agonist (Prucalopride). Methods: Patients with chronic N/V syndrome and HVs underwent baseline assessment of regional gastrointestinal (GI) motility/transit using the Motilis 3D-Transit system. Patients were then treated with Prucalopride 2 mg daily for 28 days, with the 3D-transit examination repeated within 10-20 days after treatment onset. Two self-administered questionnaires (the Gastrointestinal Symptom Rating Scale [GSRS] and Gastroparesis Cardinal Symptom Index [GCSI]) were used to assess patients' symptoms. Results: A total of 19 patients (13 F; median age 25 years (IQR 22-39) and 55 HVs (25 F; median age 28 (24-35) were included. At baseline, no differences in regional GI transit times were found between groups. However, patients had a significantly lower gastric contraction amplitude than HVs (9 mmHg (IQR 8-11) vs. 12 (10-15: p < 0.001). In response to Prucalopride treatment, gastric emptying time was reduced from a median of 3.1 h to 1.6 h (p < 0.005). Further, the GCSI was significantly reduced from GCSI 3.0 (IQR 2.3-3.7) at baseline to GCSI 1.9 (IQR 1.3-3.2) with Prucalopride. Conclusions: Patients with chronic N/V syndrome have significantly lower gastric contraction amplitude than HVs and may symptomatically benefit from prokinetics. They do not, however, have evidence of panenteric dysmotility.

BACKGROUND:Colonic motility in constipation can be assessed non-invasively using MRI. OBJECTIVE:To compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response. DESIGN:Part 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500-1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by 'tagging' were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation. RESULTS:Part 1: Total CVs median (range) were significantly greater in IBS-C (776 (595-1033)) and FC (802 (633-951)) vs HV (645 (467-780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03). CONCLUSION:An abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity. TRIAL REGISTRATION NUMBER:The study was preregistered on ClinicalTrials.gov, Reference: NCT03226145.

Trial design Randomised, multicentre, double-blind crossover trial (with 2 × 16-week periods) of active neurostimulation versus sham stimulation with subsequent open-label follow-up to 58 weeks. Embedded mechanistic sub-study using magnetoencephalography to study bidirectional functional connectivity between brain and anorectum. Methods Participants: adults aged 18–80 years, with chronic symptoms of faecal incontinence refractory to first-line treatments (and meeting national criteria for sacral neuromodulation). Interventions: active: chronic, subsensory (low amplitude) stimulation of a mixed sacral nerve (usually S3) using a commercially available surgically implanted pulse generator; sham: identical implant but turned off (or to 0.05 V). Patient-chosen sub- or supra-sensory open-label stimulation from week 32 to week 58. Primary objectives: (1) to determine whether sub-sensory sacral neuromodulation led to a reduction in total faecal incontinence episodes per week compared to sham stimulation; (2) to identify whether clinical responses to sub-sensory sacral neuromodulation were biologically related to changes in evoked and induced activity between the brain and anorectum. Primary outcome: total faecal incontinence episodes per week based on paper bowel diary performed in the final 4 weeks of each crossover period (allowing 12-week washout). Randomised allocation (1 : 1) to arm 1 (sacral neuromodulation/sham) or arm 2 (sham/sacral neuromodulation) at time of surgery was stratified by sex and centre. Blinding: participants, surgeons and assessors; tamper-proof tape masked stimulation settings. Statistical methods: Poisson regression models failed to converge for the count outcomes, hence paired t-tests were used, and treatment effects summarised by mean differences [with 95% confidence intervals (CIs)]. Sample size: a total of 90 patients (45 per group) were required to detect a 30% reduction in episodes, allowing for 10% loss to follow-up (alpha = 0.05; power 90%). Results Recruitment: a total of 39 patients of 220 screened and 65 pre-enrolled (arm 1: N = 17; arm 2: N = 22) were recruited to the crossover trial at nine sites from the United Kingdom and one site from Ireland between February 2018 and July 2022, of whom only 16 (arm 1: N = 9; arm 2: N = 7) had complete primary outcome data. Nineteen completed follow-up to 58 weeks. Trial delivery was severely affected and terminated early due to COVID-19. Main barriers were the inability to continue face-to-face patient visits, redeployment of research staff to COVID-19 facing clinical roles and cancelling of sacral neuromodulation procedures due to lack of priority for non-urgent surgery. A total of 25 patients underwent magnetoencephalography studies compared to 20 healthy volunteers. Primary outcome (N = 16): sacral neuromodulation conferred a non-significant reduction in mean faecal incontinence episodes per week compared to sham (−0.7, 95% CI −1.5 to 0.0; p = 0.06). Secondary outcomes: in participants who also used the e-event recorder to record the number of faecal incontinence episodes in both periods (n = 7), estimate of effect size was greater but less precise (−1.5, −3.5 to +0.5; p = 0.12). Data suggested successful allocation concealment. Improvements were observed in faecal incontinence symptoms in the follow-up cohort (at 58 weeks) compared to baseline (approx. 3 fewer faecal incontinence episodes per week). A small number of expected adverse events all resolved. Magnetoencephalography studies demonstrated bidirectional afferent evoked cortical and efferent induced anal activity that did not vary greatly from control subjects (n = 20) and appeared unchanged by sacral neuromodulation. Conclusions Due to under-recruitment it is important to interpret the findings on the experimental efficacy of sacral neuromodulation as exploratory. Effects on symptoms observed during double-blinded crossover point to some efficacy over sham, though not large in comparison with placebo responses. The magnitude of effect was highly dependent on method and interpretation of event recording. Study registration Current Controlled Trials ISRCTN98760715. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/144/08) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 19. See the NIHR Funding and Awards website for further award information. Plain language summary A treatment called sacral neuromodulation is commonly offered to adults experiencing bowel (faecal) incontinence. A battery powered unit is implanted into the lower back in the region of the sacrum (tailbone). This is connected to a specially developed lead with electrodes that rest on the nerves of the lower spine. This stimulator then continuously sends electrical impulses to the nerves and muscles that control the lower bowel (rectum and anus). The aim is to improve bowel control. Previous studies have reported a great benefit of sacral neuromodulation in some patients, but others have little or no response. The SUBsensory Sacral Neuromodulation for InContinence trial recruited 39 patients (of 90 intended) who met the current national criteria for sacral neuromodulation. It compared the effect on numbers of weekly faecal incontinence episodes with the device either on (active) or off (sham) using a special study design called a randomised crossover trial. All participants had the device on and off for 16 weeks in random order (crossing over in the middle). Using stimulation below the level that can be felt (subsensory), both the patients and the research team were unaware of whether the stimulator was on or off (called double blinding). Due to COVID-19, only 16 patients had complete data for analysis, which was much less than the intended number of 90. The results showed that patients experienced reductions in faecal incontinence episodes during both on and off periods (i.e. there was a strong placebo effect). However, slightly greater effects were seen during the on period suggesting a possible genuine biological effect of sacral neuromodulation. The study also showed that the way we record symptoms during research trials for example with paper bowel diaries needs improvement, as the bowel diaries were not fully completed by some participants. Although this is the first double-blind trial of its kind for sacral neuromodulation, all conclusions must bear in mind the poor recruitment and retention of patients. Scientific summary Background Faecal incontinence (FI), defined as the recurrent involuntary loss of faecal material leading to a social or hygienic problem, is a common and debilitating condition with profound effects on quality-of-life and high societal costs. Initial treatments including pharmacological and behavioural therapies (e.g. biofeedback) have variable outcomes and are poorly evidenced. Traditional surgical approaches focusing on anal sphincter reconstruction or augmentation are invasive, irreversible, and risk significant morbidity. A stoma is the final option. Chronic low-amplitude stimulation of the mixed sacral spinal nerves using an implanted electrode and pulse generator – sacral neuromodulation (SNM) is a less invasive alternative, now considered the first-line surgical treatment option for adults with FI in whom non-operative therapies have failed to alleviate symptoms. Current evidence for SNM is based on extensive observational data and few randomised trials that are heterogeneous in design and outcomes. Despite having widespread regulatory approval, SNM remains an expensive intervention with need for greater confidence in efficacy. A further concern regarding SNM therapy is the lack of evidence and understanding of the mechanism of any effect. Objectives Our primary aim was to determine the clinical efficacy of sub-sensory chronic low voltage electrical SNM using a commercially-available implantable device in adults with FI in whom conservative treatment has failed. We sought to determine whether SNM, compared to sham, led to a clinically important reduction in weekly FI episodes. The study also included mechanistic studies to examine whether clinical responses to sub-sensory SNM were biologically related to changes in the central pathway between the brain and anorectum. Methods Trial design SUBsensory Sacral Neuromodulation for InContinence (SUBSoNIC) was a multicentre, randomised double-blind crossover trial at nine UK sites and one site in Ireland in which SNM was compared to sham stimulation. We aimed to randomise 90 eligible participants (adults aged 18–80 years, where non-surgical approaches to National Institute for Health and Care Excellence (NICE) standard have failed and meeting minimum FI severity criterion) to two study arms after SNM implantation. Both arms had two intervention periods (ON-OFF or OFF-ON) of 16-week duration (T0–T16 and T16–T32). Efficacy outcomes were derived from assessments in the final 4 weeks of each cross-over period (T12–T16 and T28–T32) thus allowing for almost 3 months intervention before outcome assessments (and adequate washout for participants in the ON–OFF sequence). Mechanistic studies were performed in the final 2 weeks of the 4-week assessment periods in a subgroup of consecutively consenting participants from both arms until data saturation. After completing the crossover phase of the study, participants were followed up for a further 26 weeks. During this time, participants had either sub- or supra-sensory ‘open label’ stimulation based on preference as would have been normal for routine clinical practice. Further efficacy outcomes were recorded at T54–T58 to provide an indication of the short-term effectiveness of SNM within the rigor of a clinical trial unit (CTU)-monitored prospective study. Interventions Chronic low voltage stimulation of the third or fourth sacral root was achieved by surgical implantation of a commercially available Conformité Européenne-marked active implantable (class III) medical device [Medtronic InterStimTM (Medtronic, Minneapolis, MN, USA)] used in accord with the manufacturer’s instructions and local practice. For the active intervention (ON), the clinical team programmed the device using standard settings of a 14-Hz frequency and 210-µs pulse width. Optimal electrode configuration was determined by cumulatively increasing the amplitude of stimulation by 0.1 V from zero for each electrode until the sensory threshold was reached. The amplitude and site of stimulation were recorded for each electrode with the electrode configuration that achieved sensation in the anus or perineum at lowest amplitude being chosen for chronic stimulation. Sub-sensory chronic stimulation was initiated by reducing the amplitude to a level just below the habituated sensory threshold (for blinding). For the sham intervention (OFF), sensory thresholds were recorded identically; however, the level was then adjusted to zero volts or 0.05 V (the latter was required in some participants due to the new device handset limitations). Mechanistic studies were undertaken at the Institute of Health and Neurodevelopment (IHN) at Aston University in a subgroup of patients identified in the Midlands region (compared to 20 healthy volunteers without FI). A protocol including spatial registration (magnetic resonance imaging head) and a series of magnetoencephalographic (MEG) acquisitions measured induced and evoked cortical activity relevant to determining functional connectivity between the anus and brain (using anal electrical stimulation) and brain and anorectum (using volitional anal squeeze). Control paradigms (tibial nerve stimulation and fist clench) were used respectively. Outcomes The primary clinical outcome was reduction in FI events per week (recorded on paper bowel diaries over a 4-week period) in SNM versus sham phase of crossover (16 and 32 weeks). Secondary clinical outcomes including other bowel diary measures, e-event recording and a panel of summative questionnaires were recorded at 16, 32 and 58 weeks. Mechanistic outcomes included spatial localisation, relative cortical source signal strength and latencies of evoked and induced responses. Allocation and blinding Randomised allocation (1 : 1) to group 1 (SNM/sham) or group 2 (sham/SNM) was performed at the time of surgery using an online randomisation system managed by the Pragmatic Clinical Trials Unit at QMUL, with a randomisation list generated by an independent statistician to ensure allocation concealment. Randomisation was stratified by sex and centre with block sizes of four. Members of the research team, statisticians, surgeons who performed the surgical procedure, and participants were blinded to intervention status (SNM or sham). Participants were informed of the allocation ratio of 1 : 1 and that blinding prevented them from knowing in which group they were participating. Tamper-proof tape was used to mask stimulation settings. Sample size and statistics The study was designed to detect a mean 30% reduction between SNM and sham stimulation in FI event rate (ratio 0.7). At 90% power and 5% significance level with a cross-over design this required 90 participants (45 per group), allowing for 10% loss to follow-up. The pre-specified analysis for the primary outcome involved a mixed Poisson regression applied to the counts of FI events, with fixed effects of cross-over period and stratification factors, a random effect of individual, and a random effect of period within individual (the latter to allow for an over-dispersed Poisson distribution). When it came to the analysis, owing in part to the small numbers, the Poisson regression models did not converge for the count outcomes. Instead we applied a paired t-test to the FI rates in order to estimate the difference between SNM and sham with a 95% confidence interval and p-value. Results Clinical results The COVID-19 pandemic had a major effect on trial recruitment and patient retention. The trial was terminated on 24 July 2022 with just 39 patients randomised. Trial delivery was severely affected and terminated early due to COVID-19. Main barriers were the inability to continue face-to-face patient visits, redeployment of research staff to COVID-19 facing clinical roles and cancelling of SNM procedures due to lack of priority for non-urgent surgery. In total, 220 patients were screened for eligibility at nine sites from the UK and one site from Ireland between February 2018 and July 2022. Of these, 155 patients declined study participation or were ineligible due to study specific exclusion criteria. A total of 65 patients were pre-enrolled and consented to the study, of whom 26 did not meet the baseline minimum frequency criteria of FI episodes per week or did not receive an implant. The remaining 39 patients were randomised (arm 1: N = 17; arm 2: N = 22); however, only 16 completed the primary outcome during both cross-over periods (arm 1: N = 9; arm 2: N = 7). The remaining 23 participants withdrew from the study (N = 12), were excluded on the basis of problems of eligibility (N = 5) or did not complete the primary outcome data (N = 6: still included in the cohort follow-up phase). A total of 22 participants started the cohort follow-up phase, although 3 of these participants did not complete the final follow-up visit, leaving 19 participants for the 1-year effectiveness assessment. There were no major differences at baseline between allocated groups. As predicted, about 90% participants were female with mean age about 57 years. Almost all participants reported symptoms of urgency, combined with varying combinations of passive and urge FI. All participants reported previous conservative management for their FI symptoms (as per NICE guidance). Numbers of FI events at baseline were concordant with design assumptions (based on approx. seven events in a 1-week period). Median St Mark’s incontinence score was 19 in both groups, indicating severe symptoms (max score 24). E-event recordings were only undertaken by a minority (14/39) of participants. Test stimulation was performed using a tined lead in 68.6% participants. General anaesthesia was used in 70.6% of procedures and median operating time was 36 minutes (range 30–55 minutes). The lead was positioned in foramina S3 in most participants (91.4%) with some variations in fidelity of siting based on individual electrode responses (only 50% lead placements achieved the ideal published standard of motor or sensory responses for three electrodes < 1V). Primary outcome showed that compared to sham, SNM led to a non-significant mean difference of < 1 FI episode per week [−0.7, confidence interval (CI) −1.5 to 0.0; p = 0.06]. The estimated treatment effect was greater but less precise in the seven participants who had complete e-event data in both periods (−1.5, −3.5 to +0.5; p = 0.12). Secondary outcomes showed small (non-statistical and non-clinically significant) but directional changes favouring SNM versus sham. Adverse events were infrequent (n = 10), non-serious and expected; most resolved during the study. Blinding was successful in masking allocation based on contingencies of correct perception. Cohort study outcomes (from open-label sub- or supra-sensory stimulation) showed substantial benefit in terms of symptom reduction at 1 year in keeping with published observational studies. Mechanistic results A total of 30 patients recruited from the SUBSoNIC study consented to participate of whom only 12 completed the SUBSoNIC clinical study and nine made all three visits to the IHN. The remaining 18 participants contributed to baseline data. There were small statistically significant increases in electrical stimulus amplitude required for tibial evoked cortical responses between FI patients and healthy controls but no differences in latencies (although these were often numerically longer in patients). Anal electrical stimulation produced measurable evoked potentials in the primary somatosensory cortex near the vertex; however, these did not significantly differ between patients and controls in relative amplitude or latency. Induced motor MEG activity was demonstrated throughout the whole sensorimotor strips bilaterally during voluntary fist clenching and anal squeezing activity in both patients and controls at 14–30 Hz (beta band). Given the lack of difference between healthy and FI participants, it was difficult to interpret variations seen between SNM and sham periods in the trial. Conclusions Despite very important caveats of under-recruitment (39 of 90) and attrition (only 16 with complete data), SUBSoNIC is the first randomised study of SNM in a treatment naïve population with proven effective double blinding. Due to the under-recruitment it is important to interpret the findings as exploratory. The mean difference in effect between SNM and sham (−0.7 FI, 95% CI −1.5 to 0.0, episodes perweek) represents a mean percentage reduction of 23.3% (0.7/3.0) when expressed with reference to sham frequency. This effect is less than that sought by the predetermined sample size calculation (0.77 vs. 0.70) and much less than the placebo response (possible placebo effect) based on symptom frequency reductions of a 50% reduction between baseline and sham. Differences in reporting between the paper bowel diaries and the e-event recording re-emphasise the importance of how FI outcomes are measured and the frailties of current approaches. Future work Since the primary objective of the SUBSoNIC trial remains relevant and unanswered, future studies could seek to repeat SUBSoNIC in a post-COVID era. Attention should be paid to improving on current estimation of clinical effect by outcomes research and strict curation of source observations during trial delivery. Placebo ‘effects’ from SNM merit further clinical and mechanistic evaluation. Study registration Current Controlled Trials ISRCTN98760715. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/144/08) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 19. See the NIHR Funding and Awards website for further award information.