Introduction

Recent years have seen a significant increase in randomized controlled trials (RCT) published on the efficacy of probiotics on irritable bowel syndrome (IBS), which several reviews have tried to comprehensively review. Two recent trials, Yang et al. 2024¹ and Chen et al. 2023² report the safety and efficacy of probiotics for IBS, which seems to reflect prevailing favorable view of this therapeutic option by most reviews conducted. Yet, despite efforts in this field, major organizations have not changed their stance in this and make no assertive recommendation for probiotics in afflicted patients^3,4. While further investigations are required, two challenges are faced: (1) repeated reviews have been undertaken in this field, resulting in a "multiplicity problem", (2) traditional meta-analytic techniques may also fail to provide a conclusive answer on the sufficiency of evidence, particularly when the data are sparse, and the risk of type I and type II errors is significant. This indicates a need for.

Aims & Methods

This study aims to evaluate the efficacy of probiotics in alleviating symptoms of IBS and improve quality of life through a timely implemented trial sequential analysis (TSA) and rigorously evaluate the evidence for recommendations on future studies. Medline, Embase, Web of Science, and Cochrane were screened for randomized controlled trials (RCTs) comparing probiotics to placebo in adult patients with IBS. Primary outcomes included IBS Symptom Severity Score (IBS-SSS) and IBS Quality of Life (IBS-QOL) scores comparing probiotics and placebo groups. Traditional pairwise meta-analysis conducted in restricted maximum likelihood was conducted, with subsequent TSA . Study quality was graded according to risk-of-bias 2 (ROB-2) and certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Results

42 studies were included. Overall, probiotics demonstrated non-significant improvements in IBS-SSS (MD: -27.64; 95% CI: -56.90 to 1.63; p=0.06) and IBS-QOL (MD: 1.33; 95% CI: -3.65 to 6.30; p=0.59). TSA was conducted on IBS-SSS demonstrated current evidence has not reached the required information size. The representative cumulative Z-curve demonstrated neither futility, benefit nor detrimental effect, indicating the need for further trials. Assessment with ROB-2 indicates high quality amongst most trials included in this study. GRADE evaluation of the evidence demonstrated low certainty of existing evidence.

Table 1: GRADE Evaluation

No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Probiotics	Placebo	Relative (95% CI)	Absolute (95% CI)	Certainty
Probiotics effectively reduces a patient's IBS-SSS score
24	randomised trials	not seriousa	very seriousb	not serious	very seriousc	publication bias strongly suspectedd	2237	1599	-	MD 27.64 lower (56.9 lower to 1.63 higher)	⨁◯◯◯ Very lowa,b,c,d
Probiotics effectively reduces a patient's IBS-QOL score
24	randomised trials	not seriousa	very seriousb	not serious	not seriouse	publication bias strongly suspectedd	2292	1712	-	MD 1.33 higher (3.65 lower to 6.3 higher)	⨁◯◯◯ Very lowa,b,d,e

CI: confidence interval; MD: mean difference

Two contributing factors to the low certainty of current evidence include: (1) Inconsistency of existing trials – there exists high level of heterogeneity as detected by statistical analysis through I² and Cochran Q amongst studies; (2) Suspected publication bias through inspection of a funnel plot, though Egger’s regression did not demonstrate statistical significance.

Conclusion

Existing evidence is insufficient to make conclusive recommendations regarding the role probiotics should play in the management of IBS in symptoms and QOL. Given the persistent heterogeneity and potential publication bias, future research should focus on standardizing probiotic interventions and clarifying their clinical utility to truly advance the field.

References

1. Yang R, Jiang J, Ouyang J, Zhao Y, Xi B. Efficacy and safety of probiotics in irritable bowel syndrome: a systematic review and meta-analysis. Clinical Nutrition ESPEN. 2024;
2. Chen M, Yuan L, Xie C-R, et al. Probiotics for the management of irritable bowel syndrome: a systematic review and three-level meta-analysis. International Journal of Surgery. 2023;109(11):3631-3647.
3. Su GL, Ko CW, Bercik P, et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020;159(2):697-705. doi:10.1053/j.gastro.2020.05.059
4. McKenzie Y, Thompson J, Gulia P, Lomer M. British Dietetic Association systematic review of systematic reviews and evidence‐based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). Journal of Human Nutrition and Dietetics. 2016;29(5):576-592.
5. Lacy BE, Pimentel M, Brenner DM, et al. ACG clinical guideline: management of irritable bowel syndrome. Official journal of the American College of Gastroenterology| ACG. 2021;116(1):17-44.

Disclosure

All authors of the manuscript do not have a conflict of interest to declare.

Introduction

Although Endoscopic Retrograde Cholangiopancreatography (ERCP) has played an important role in the diagnosis and treatment of biliary and pancreatic diseases since its inception, the gallbladder is still considered a “blind spot” or inaccessible area for ERCP.

Aims & Methods

This study was intended to evaluate the technical success rate, safety, and clinical application value of per-oral cholangioscopy-guided transpapillary cystic duct approach for Gb-NOEES, and to explore the feasibility of Natural Orifice Endoluminal Endoscopic Surgery (NOEES) in the diagnosis and treatment of gallbladder diseases.
Patients with gallbladder diseases who received Gb-NOEES treatment from January 2023 to November 2024 were retrospectively included in a single-center study. Inclusion criteria: Patients are preoperatively diagnosed with gallstones, gallstones combined with common bile duct stones, gallstones combined with intrahepatic stones, acute cholecystitis, and gallbladder polyps. Exclusion criteria: patients with asymptomatic gallstones, patients with gallbladder cancer, and patients at risk of gallbladder cancer. All procedures were performed by experts with ≥10 years of experience in digestive endoscopy, and postoperative follow-up period ranged from 2 to 26 months.

Results

A total of 100 patients were included (58 males and 42 females, with an average age of 47±15.1). The disease distribution is shown in Table 1. The technical success rate of Gb-NOEES was 99% (99/100), and the average operative time was 130±59 minutes. The complication rate was 4%: 3 cases of gallbladder perforation (1 case of successful conservative treatment, and 2 cases of conversion to laparoscopic surgery), and 1 case of postoperative bleeding (successful conservative treatment). No severe pancreatitis or death occurred. Treatment outcomes: Gallstone clearance rate was 98% (78/80), with the largest stone measuring 4.0 cm, and up to 52 stones removed in a single operation. Complete excision rate of gallbladder polyps was achieved in 100% (15/15), with long diameter of polyps ranging from 4 mm to 15 mm, and up to 8 polyps excised in a single operation. Drainage success rate for acute cholecystitis was 100% (4/4). One case of early-stage gallbladder cancer was incidentally detected. During the follow-up period, the recurrence rate of stones was 2.5% (2/80), and there was no recurrence of polyps.

Conclusion

Gb-NOEES demonstrated favorable safety profile (complication rate was 4%) and high efficacy (overall success rate was 98%) in the diagnosis and treatment of gallbladder diseases. This technique has advantages of both lesion removal and organ preservation, offering a new minimally-invasive treatment option for gallbladder diseases. However, its clinical application value requires further validation through multi-center studies.

Table 1. Disease Distribution of Patients

Disclosure

There is no conflict of interest.

Introduction

Immune checkpoint inhibitors (CPI) have revolutionised cancer outcomes, but frequently trigger immune related adverse effects, including life-threatening colitis. Tissue resident memory (TRM) T cells are key cells involved in the pathogenesis of CPI-induced colitis (CPI-C), but the mediators they produce to facilitate disease are poorly defined.

Aims & Methods

We utilised our previously published in vivo pre-clinical model of CPI-C, which occurs when mice are given combination anti-CTLA4 and anti-PD1 and a proinflammatory microbiota mix, to define the role of the Granzyme A/B cytotoxicity pathway in disease. Disease was induced in wildtype (WT) and Granzyme A/B double knockout (GzmAB^-/-) mice. Clinical outcomes (colon and spleen mass, histology and infiltrating neutrophils) from these mice were assessed to measure the severity in disease. T cell populations were also analysed using flow cytometry.

Results

GzmAB^-/-mice showed a significant reduction in disease features compared to WT mice, with reduced colon mass, reduction in infiltrating neutrophils and fewer inflammatory monocytes. Flow cytometry analysis of the T cell compartment revealed a significant reduction in both bulk CD4 and CD8 T cells and also CD4 and CD8 tissue resident memory T cells in both the cLP and IEL in GzmAB^-/-mice treated with CPI-C in comparison to WT mice treated with CPI-C. GzmAB^-/-mice treated with CPI-C also had a reduction in IFNγ and TNFα production from both CD4 T cells and CD8 T cells. These data highlight the importance of granzymes in inducing the disease phenotype in CPI-C. In order to investigate whether CD4 T cells or CD8 T cells were more important, we depleted these cells in vivo in WT mice treated with CPI-C at both 1 and 3 weeks. Here, we found that WT mice with CD4 T cells depleted got significantly worse disease with colon masses increasing and there being increased infiltrating neutrophils. There was an increase in cytotoxic cytokines being produced by CD8 T cells when CD4 T cells were depleted. However, when CD8 T cells were depleted, there was no change in any clinical features or cytokine production from CD4 T cells.

Conclusion

Using GzmAB^-/- mice we have demonstrated that CPI-colitis is at least partially dependent on the granzyme cytotoxicity pathway. Targeting the cells that produce granzyme in the colon of patients with CPI-colitis might offer an attractive novel treatment option for patients with CPI-colitis.

References

1. Lo, J.W., Cozzetto, D., Alexander, J.L. et al. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis. Nat Commun 14, 6719 (2023). https://doi.org/10.1038/s41467-023-41798-2
2. Luoma A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655-671.e22 (2020).
3. Sasson, S. C. et al. Interferon-gamma-producing CD8(+) tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology 161, 1229–1244.e1229 (2021).
4. Gupta T, Antanaviciute A, Hyun-Jung Lee C, et al. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell. 2024 May 13;42(5):797-814.e15. doi: 10.1016/j.ccell.2024.04.010. PMID: 38744246.

Introduction

Restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) is one of the surgical options for patients with medically refractory ulcerative colitis (UC). It does, however, have long term complications, such as chronic idiopathic pouchitis, which develops in 10%–15% of patients with acute pouchitis.
Chronic inflammatory pouch conditions often require biologic treatment. Anti-tumour necrosis factor (anti-TNF) medications are commonly prescribed as first line biologic treatment for chronic inflammatory pouch conditions. However, their use in these conditions is based on studies of relatively small numbers of patients that lack long term follow up.

Aims & Methods

We aimed to describe the long term outcomes of first line anti-TNF therapy in a large, multi-centre multi-national cohort of patients with chronic inflammatory pouch conditions.
This was an observational retrospective study.
We included patients with chronic inflammatory pouch conditions initially treated with anti-TNF drugs infliximab (IFX) or Adalimumab (ADA), who had a follow up of at least 1 year.
The primary outcome was anti-TNF treatment persistence, defined as continuation of anti-TNF throughout the study period. Secondary outcome was pouch failure, defined by the need for a defunctioning ileostomy or pouch excision.

Results

We recruited 87 patients initially treated with anti-TNFs.
Average follow up length was 101 months.
The most common indication for biologic treatment was chronic pouchitis with concomitant pre-pouch ileitis (62/87 patients, 71.3%). Chronic pouchitis without pre-pouch ileitis was the treatment indication in 19 patients (21.8%). Pre-pouch ileitis, without concomitant pouchitis, was seen in 7 patients (6.9%).
IFX was the most common first line anti-TNF treatment (55/87 patients, 63.2%), while 32 patients (36.8%) were treated with first line ADA.
Anti-TNF was administered as monotherapy in 46 patients, while 27 patients received it in combination with an immunomodulator.
Second line treatments included IFX (6 patients), ADA (15 patients), Vedolizumab (16 patients), Ustekinumab (12 patients) and Upadacitinib (one patient).
At the end of the study period only 13/87 patients (14.9%) were still on first line anti-TNF treatment.
The median time to anti-TNF discontinuation was 12.2 months.
The most common cause for anti-TNF discontinuation was lack of efficacy despite adequate serum drug levels and absence of anti-drug antibody formation (28 patients, 32.2%). Loss of response due to anti-drug antibody formation was the cause in 18 patients (20.7%), while 12 patients (13.8%) stopped treatment because of side effects/safety concerns.
Compared to patients receiving ADA, patients receiving IFX had an HR of 2.0 for treatment discontinuation (p=0.016).
Compared to patients receiving combination therapy of anti TNFs with immunomodulators, patients receiving anti-TNF monotherapy had similar rates of treatment discontinuation (p=0.155).
Out of the 74 patients who discontinued first line anti-TNF treatment, 42 (48.3%) are currently treated with a different medical therapy, and 32 (36.8%) developed pouch failure.
The median time to pouch failure was 38.6 months.
Patients receiving IFX were not at increased risk of pouch failure compared to those receiving ADA (p=0.2).

Conclusion

First line anti-TNF therapy for chronic pouch inflammatory conditions is associated with low long term persistence rates.
A significant proportion of patients initially treated with anti-TNF therapy develop pouch failure.

These patients should be counselled about the high risk of pouch failure.