Probes for INS

Introduction: Four randomized controlled trials studying fecal microbiota transplantation (FMT) in active ulcerative colitis (UC) patients showed variable success rates. The efficacy of FMT appears to be influenced by various factors including donor- and procedure-specific characteristics. Aim: We hypothesized that the outcome of FMT in patients with active UC could be improved by donor preselection on microbiota level, by using a strict anaerobic approach, and by repeated FMT administration. Methods: The RESTORE-UC trial (NCT03110289) was a national, multi-centric double-blind, sham-controlled randomized trial. Active UC patients (Total Mayo score 4-10 with endoscopic sub-score > or = 2) were randomly allocated (1:1) to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT by permutated blocks (2- 4) and stratified for weight, concomitant steroid use, and therapy refractoriness. S-FMTs were selected after a rigorous screening excluding samples with Bacteroides 2 enterotype, high abundances of Fusobacterium, Escherichia coli and Veillonella and the lowest microbial loads (Q1). A futility analysis after 66% (n=72) of inclusions was planned per protocol including a modified intention-to-treat (mITT) analysis using non-responder imputation (NRI) for patients receiving at least one FMT. The primary endpoint was steroid-free clinical remission (Total Mayo ≤ 2, with no subscore >1) at week 8. Secondary outcomes included steroid-free PRO-2 remission (Combined Mayo subscores of ≤1 for rectal bleeding plus stool frequency) and response (≥3 points or/and ≥50% reduction from baseline in combined Mayo subscores for rectal bleeding plus stool frequency) and steroid-free endoscopic remission (Mayo endoscopic subscore ≤1) and response (Mayo endoscopy subscore ≤1 and ≥1 point reduction from baseline). Results: Between March 2017-2021, 72 patients signed the ICF and 66 were randomly allocated to S-FMT (n=30) or A-FMT (N=36) and received at least one FMT. Both study arms were matched for baseline characteristics, yet a trend (p= 0,07) towards higher concomitant biological use in the S-FMT arm was observed. A remarkably high proportion of patients were previously exposed to biologicals (58.3% and 60.0% for the A-FMT and S-FMT group respectively). In the S-FMT and the A-FMT respectively 4 and 5 patients terminated the trial early due to worsening of colitis (4 in both arms) or FMT enema intolerance (1 A-FMT). They were included in the mITT analysis using NRI, showing after 66% of intended inclusions, the primary endpoint was reached in 3/30 (mITT with NRI 10.0%) S-FMT and 5/31 (13.9%) patients randomized to A-FMT (p=0.72). As the predefined minimum difference of 5% between both treatment arms was not attained, the study was stopped due to futility. Steroid-free PRO-2 remission was achieved in 7/30 (23,3%) patients on S-FMT and 10/36 (27,8%) on A-FMT (p= 0,78). Steroid-free PRO-2 response was attained by respectively 9/30 (30,0%) patients in the S-FMT arm and 12/36 (33,3%) patients in the A-FMT arm (p= 0,80). Steroid-free endoscopic response and remission were noted in 5/30 (16,7%) assigned to the S-FMT arm compared with 7/36 (19,4%) allocated to the A-FMT arm (p= 1.0). Of note, no patients on concomitant biologicals reached the primary endpoint, and there were 2 serious adverse events in the A-FMT arm: dysuria requiring hospitalization and worsening of UC requiring colectomy. Conclusions: In this double-blind sham-controlled trial comparing repeated administrations of anaerobic-prepared S-FMT with A-FMT in patients with active UC, no significant difference in steroid-free remission rates at week 8 were observed. The FMT procedure was generally well tolerated, and no new safety signals were observed.

Introduction: Four randomized controlled trials studying fecal microbiota transplantation (FMT) in active ulcerative colitis (UC) patients showed variable success rates. The efficacy of FMT appears to be influenced by various factors including donor- and procedure-specific characteristics. Aim: We hypothesized that the outcome of FMT in patients with active UC could be improved by donor preselection on microbiota level, by using a strict anaerobic approach, and by repeated FMT administration. Methods: The RESTORE-UC trial (NCT03110289) was a national, multi-centric double-blind, sham-controlled randomized trial. Active UC patients (Total Mayo score 4-10 with endoscopic sub-score > or = 2) were randomly allocated (1:1) to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT by permutated blocks (2- 4) and stratified for weight, concomitant steroid use, and therapy refractoriness. S-FMTs were selected after a rigorous screening excluding samples with Bacteroides 2 enterotype, high abundances of Fusobacterium, Escherichia coli and Veillonella and the lowest microbial loads (Q1). A futility analysis after 66% (n=72) of inclusions was planned per protocol including a modified intention-to-treat (mITT) analysis using non-responder imputation (NRI) for patients receiving at least one FMT. The primary endpoint was steroid-free clinical remission (Total Mayo ≤ 2, with no subscore >1) at week 8. Secondary outcomes included steroid-free PRO-2 remission (Combined Mayo subscores of ≤1 for rectal bleeding plus stool frequency) and response (≥3 points or/and ≥50% reduction from baseline in combined Mayo subscores for rectal bleeding plus stool frequency) and steroid-free endoscopic remission (Mayo endoscopic subscore ≤1) and response (Mayo endoscopy subscore ≤1 and ≥1 point reduction from baseline). Results: Between March 2017-2021, 72 patients signed the ICF and 66 were randomly allocated to S-FMT (n=30) or A-FMT (N=36) and received at least one FMT. Both study arms were matched for baseline characteristics, yet a trend (p= 0,07) towards higher concomitant biological use in the S-FMT arm was observed. A remarkably high proportion of patients were previously exposed to biologicals (58.3% and 60.0% for the A-FMT and S-FMT group respectively). In the S-FMT and the A-FMT respectively 4 and 5 patients terminated the trial early due to worsening of colitis (4 in both arms) or FMT enema intolerance (1 A-FMT). They were included in the mITT analysis using NRI, showing after 66% of intended inclusions, the primary endpoint was reached in 3/30 (mITT with NRI 10.0%) S-FMT and 5/31 (13.9%) patients randomized to A-FMT (p=0.72). As the predefined minimum difference of 5% between both treatment arms was not attained, the study was stopped due to futility. Steroid-free PRO-2 remission was achieved in 7/30 (23,3%) patients on S-FMT and 10/36 (27,8%) on A-FMT (p= 0,78). Steroid-free PRO-2 response was attained by respectively 9/30 (30,0%) patients in the S-FMT arm and 12/36 (33,3%) patients in the A-FMT arm (p= 0,80). Steroid-free endoscopic response and remission were noted in 5/30 (16,7%) assigned to the S-FMT arm compared with 7/36 (19,4%) allocated to the A-FMT arm (p= 1.0). Of note, no patients on concomitant biologicals reached the primary endpoint, and there were 2 serious adverse events in the A-FMT arm: dysuria requiring hospitalization and worsening of UC requiring colectomy. Conclusions: In this double-blind sham-controlled trial comparing repeated administrations of anaerobic-prepared S-FMT with A-FMT in patients with active UC, no significant difference in steroid-free remission rates at week 8 were observed. The FMT procedure was generally well tolerated, and no new safety signals were observed.

Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption1,2. These sensory signals modulate brain appetite circuits in a feed-forward manner3-5. Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway.