Introduction

Fecal microbiota transplantation (FMT) is a highly effective and safe treatment for recurrent Clostridioides difficile infection (CDI) (1), but FMT centres are still underdiffused (2). Our centre has been providing a FMT program since 2013 (3) and has established itself as a worldwide leading hotspot for FMT, that coordinated several consensus initiatives on this topic (4-6).

Aims & Methods

Our aim is to evaluate efficacy and safety of FMT in patients with CDI at our center since the start of our FMT program.
We included all patients treated with FMT for CDI from June 2013 to January 2023. We collected demographical and baseline clinical data of patients, including: age, sex, severity of CDI (mild, severe, or fulminant), comorbidities assessed with the Charlson Comorbidity Index (CCI), risk factors for CDI, number of previous CDI recurrences.
Enrolled patients were followed up with visits and/or phone calls up to 90 days after the last FMT. The primary outcome was the clinical resolution of CDI (defined as resolution of diarrhea) at 8 weeks after FMT, while the secondary outcomes were the identification of risk factors for FMT failure and the safety of FMT.
Candidate stool donors were screened following international guidelines (4-6). FMT procedures were carried out by colonoscopy, after a 3-day pre-treatment with oral vancomycin and bowel cleansing, using a single-donor solution of at least 50 grams of fresh feces (before 2017) or frozen feces (after 2017).

Results

In the study period we performed 465 FMT procedures in 328 patients. Thirteen patients (all outpatients) did not attend follow-up visits nor replied to phone calls, and 315 patients were finally included in the analysis. The median age was 72 years (range 20 – 96 years), 202 patients were females (64%), 151 were inpatients (48%), and the mean CCI was 5.2. Seventy-one patients had severe CDI (22.5%), and 14 patients had fulminant CDI (4.4%). Eighty-six patients (27.3%) underwent to multiple FMT procedures (≥ 2).
At 8-week follow-up after FMT, cure of CDI was observed in overall 302 patients (96%).
Efficacy rates did not change over years (2013-2016: 94.8%; 2017-2019: 97.6%; 2020-2023: 94.6%).
Twenty-two patients (7%) died during the 90-day follow-up period. No death was attributable to FMT. Thirteen patients (59%) died within 30 days after FMT, while nine patients (41%) died between 31 and 90 days after FMT. Seven of the 22 patients (31.8%) did not respond to FMT and died for overwhelming CDI, while other patients died for other causes not related to CDI or FMT.
At multiple linear regression, enticement was significantly associated with FMT failure (p= 0.002) and death (p= 0.0001). Recent ICU admission (p= 0.0002) and severe CDI (p= 0.007) were significantly associated with death.
Serious adverse events occurred in 14 patients (4.4%), and 9 (2.9%) were potentially associated with FMT and/or failure to cure CDI, including bloodstream infection by enteric bacteria (n=6), severe diarrhea and delirium (n=1), severe hypoalbuminemia (n=1), diarrhea and self-limiting fever (n=1). All these events were transient and resolved in few days.

Conclusion

In the 10-year experience of our large-volume FMT center, FMT was highly effective in treating CDI, together with a high safety profile. In our cohort, enticement was significantly associated with increased risk of FMT failure. Severe CDI, enticement and recent ICU admission were significantly associated with increased risk of death after 12 weeks.

References

1. Ianiro G, Maida M, Burisch J, Simonelli C, et al. Efficacy of different faecal microbiota transplantation protocols for Clostridium difficile infection: A systematic review and meta-analysis. United European Gastroenterol J. 2018 Oct;6(8):1232-1244. doi: 10.1177/2050640618780762. Epub 2018 Jun 3. PMID: 30288286.
2. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015 May;41(9):835-43. doi: 10.1111/apt.13144. Epub 2015 Mar 1. PMID: 25728808.
3. Baunwall SMD, Terveer EM, Dahlerup JF, et al. The use of Faecal Microbiota Transplantation (FMT) in Europe: A Europe-wide survey. Lancet Reg Health Eur. 2021 Jul 19;9:100181. doi: 10.1016/j.lanepe.2021.100181. PMID: 34693388.
4. Ianiro G, Mullish BH, Kelly CR, et al. Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic. Gut. 2020 Sep;69(9):1555-1563. doi: 10.1136/gutjnl-2020-321829. Epub 2020 Jul 3. PMID: 32620549.
5. Cammarota G, Ianiro G, Kelly CR, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019 Dec;68(12):2111-2121. doi: 10.1136/gutjnl-2019-319548. Epub 2019 Sep 28. PMID: 31563878.
6. Cammarota G, Ianiro G, Tilg H, et al. European FMT Working Group. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017 Apr;66(4):569-580. doi: 10.1136/gutjnl-2016-313017. PMID: 28087657.

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Clinical Case Summary

A 21-year-old male, smoker, presented to the Emergency Room (ER) of our hospital due to rectal bleeding, causing severe anemia (Hemoglobin (Hb) 7g/dL), and referred to Proctology consultation.
Initial assessment revealed profuse bleeding, hemorrhoidal prolapse and low output symptoms. Proctologic examination showed congestive and tender left internal hemorrhoids. Instrumental therapy was postponed due to suspected perianal abscess, later ruled out post-endoanal endoscopy and pelvic MRI. Endoscopic studies did not identify other causes for anemia.
Polidocanol foam sclerotherapy provided significant symptom relief and improved quality of life. However, after 4 months, recurrent episodes of bleeding and symptomatic anemia (Hb 5.7g/dl) occurred, requiring transfusions and iron supplementation. Hemorrhoid artery ligation with recto-anal repair (HAL-RAR) was performed. Within 15 days, he recurred 3 times to ER for rectal bleeding, and in the last he had with syncope and Hb 6.4g/dL, leading to hospitalization for hemostasis review and surgical reintervention.
During hospitalization, another episode of profuse bleeding with a minimum Hb of 4g/dL required surgical reintervention. Following multidisciplinary consultation, despite no active bleeding on CT angiography, conventional angiography with superselective embolization of right upper rectal arteries was performed, resulting in symptom and anemia resolution, allowing discharge.
At 3-month follow-up, occasional rectal bleeding was described; proctologic examination revealed mucosal prolapse with defecation straining, mildly congestive internal hemorrhoids and distal rectal scarring. Blood analysis showed no anemia (Hb 15g/dL) or iron deficiency.
This case underscores the challenge of managing refractory hemorrhoidal disease in young patients and the need of a multidisciplinary approach. Indeed, this clinical scenario was only resolved by a minimally invasive strategy, essential in complex cases.

References

Endoscopic image, angiographic image and short video

Introduction

Many people with IBD experience fatigue, pain and faecal incontinence (FI), impacting quality of life (QoL). We developed an interactive digital online self-management intervention (IBD-BOOST) based on a theoretically informed logic model and cognitive behavioural techniques.

Aims & Methods

To evaluate IBD-BOOST we conducted a multi-centre two-arm parallel group randomised controlled trial (RCT) comparing IBD-BOOST with Care as Usual (CAU), recruiting patients from clinics and national registries who rated the impact of fatigue and/or pain and/or FI as ≥5/10. Those in the IBD-BOOST arm received 6 months access to the 12-session IBD-BOOST programme, a 30-minute telephone support call and weekly in-site email messages for 3 months. The UK Inflammatory Bowel Disease Questionnaire (UK-IBDQ) and global rating of symptom relief (GRSR) at 6 months were dual primary outcomes (alpha=0.025 was considered statistically significant with two primary outcomes). Other secondary outcomes, including individual symptoms, were measured at 6 and 12 months. Complier-averaged causal effects (CACE), sensitivity and pre-specified subgroup analyses were conducted.

Results

780 participants were randomised, 432 with Crohn’s disease; 520 (66.7%) were female, mean age 49 years. At 6 months, both UK-IBDQ and GRSR were similar between the BOOST and CAU arms, p=0.19 for IBDQ and p=0.39 for GRSR. Adverse events were similar between groups. FI score and EQ5D utility score (secondary outcomes) were in favour of IBD-BOOST at 6 months, but pain and fatigue were no different. 57% of the intervention group completed a pre-defined minimum “dose” of 4 sessions (i.e. compliers). The CACE analysis suggested that compliers were more likely to report better QoL (p=0.03). Subgroup analysis of those meeting criteria for irritable bowel syndrome (IBS) at baseline, showed that IBD-BOOST was more effective in improving IBDQ and GRSR at 6 months when compared with CAU for the IBD-IBS group (p_interaction=0.015 and 0.046, respectively).

Conclusion

This large RCT found that IBD-BOOST did not improve IBDQ and GRSR in patients with IBD and fatigue and/or pain and/or FI relative to CAU. Participants reported less FI at 6 and 12 months. Those with IBD-IBS improved more than those without.

Trial registration: ISRCTN71618461

Introduction

Recently, sub-classification of steatotic liver disease (SLD) has been updated by revising non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated steatotic liver disease (MASLD). In this new nomenclature, emphasis was on the etiology of SLD, primarily at factors of metabolic syndrome and alcohol intake. However, associations between MASLD and gastrointestinal tract cancers other than liver cancer in relation to alcohol intake still require further analysis.

Aims & Methods

We investigated the relationship between the incidence of three gastrointestinal tract cancers (esophageal, stomach, and colorectal) and MASLD or alcohol related-SLD in diabetic patients. Using a retrospective screening cohort of National Health Insurance Service, individuals with type 2 diabetes from 2009 to 2012 were enrolled with their disease status being monitored until 2021. Fatty liver index (FLI) score described by Bedogni et al. (2006) was used to stratify the probability of hepatic steatosis. No steatosis (NS), indeterminate steatosis (IS), and steatosis-probable (PS) group were defined as FLI score 0 to < 30, 30< to ≤60, and >60, respectively. SLD was assumed if FLI score ≥ 30, and MASLD was defined as having at least 1 adult criteria provided by the American Association for the Study of Liver Diseases (AASLD). 2,746,079 subjects were classified into following subgroups: group 1: no steatosis, group 2: MASLD alone, group 3: MASLD with other liver disease, group 4: MASLD with heavy alcohol intake (metALD, 30-60g/d for men and 20-50g/d for women), and group 5: alcoholic liver disease (alcohol intake ≥ 60g/d for men and ≥50g/d for women) with metabolic syndrome. Adjusted hazard ratios (aHR) for each gastrointestinal tract cancer were estimated by incorporating multivariate Cox proportional hazards model.

Results

Compared with group 1 (reference), group 2 showed increased risks of stomach and colorectal cancers (aHR [95% confidence interval (CI)]: 1.06 [1.04-1.09] and 1.17 [1.14-1.19] respectively), but a decreased risk of esophageal cancer (0.81 [0.74-0.88]). In all gastrointestinal tract cancers, the risk of developing cancer compared to group 1 tended to increase from group 3 to group 5 (aHRs in groups 3, 4, 5: 1.40, 1.74, 2.36 in esophageal cancer; 1.13, 1.20, 1.22 in stomach cancer; 1.24, 1.33, 1.34 in colorectal cancer, respectively; all p for trend < 0.0001). Subgroup analysis by probability of steatosis in non-drinkers showed that stomach and colorectal cancer risk was positively correlated with higher likelihood of liver steatosis (aHR for NS, IS, PS: 1.00, 1.05, 1.11 for stomach cancer and 1.00, 1.15, 1.27 for colorectal cancer, respectively, p for trend < 0.05). However, this correlation was not demonstrated in esophageal cancer (aHR for NS, IS, PS:1.00, 0.95, 1.08 for esophageal cancer).

Conclusion

In patients with diabetes, MASLD itself is associated with an increased risk of stomach and colorectal cancers but is likely associated with a reduced risk of esophageal cancer. Hepatic steatosis may be associated with higher risk of stomach and colorectal cancers, but not esophageal cancer. Amount of alcohol consumption is confirmed to increase the risk of these cancers regardless of the presence of SLD.

References

1. Rinella, Mary E. "Examining the Nomenclature Change From NAFLD and NASH to MASLD and MASH." Gastroenterology & Hepatology 19.11 (2023): 697.
2. Bedogni, Giorgio, et al. "The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population." BMC gastroenterology 6 (2006): 1-7.
3. Dabo, Bashir, et al. "The association between diabetes and gastric cancer: results from the Stomach Cancer Pooling Project Consortium." European Journal of Cancer Prevention 31.3 (2022): 260-269.
4. Lee, Hokyou, et al. "Metabolic Dysfunction–Associated Fatty Liver Disease Increases Colon Cancer Risk: A Nationwide Cohort Study." Clinical and translational gastroenterology 13.1 (2022): e00435.