Introduction

Necrotizing enterocolitis and sepsis are two of the most prevalent life-threatening disorders for preterm neonates. Both of these disorders occur significantly less frequently in breastfed neonates (1). A beneficial role has been identified of tryptophan related factors in mother’s milk but the involvement of its bacterial-derived metabolites, which also act as Aryl hydrocarbon receptor (AhR) activator ligands, remains poorly understood.

Aims & Methods

In this study, we aim to investigate the presence of AhR-ligands in mother milk and in neonatal feces and assess their potential effects on neonatal epithelial cells.

Results

First, we assessed the ability of human milk and formula to activate AhR using an AhR-reporter cell system. Mother milk (n=10) (unlike formula; (n=6)) triggered AhR and increased significantly AhR-activity. In order to identify the composition and levels of AhR-ligands in milk and feces from neonates, targeted liquid chromatography coupled with high resolution mass spectrometry was performed on mother milk (n=40), formula milk (n=3) and feces from preterm (n=50) and full-term (n=10) Dutch neonates at birth. Indole-acetic-acid (IAA) and indole-3-sulfate (I3S) were significantly more abundant in mother milk (IAA [pmol/mL] = 43, IQR 32-57, I3S = 221, IQR 181-291) compared to formula (IAA [pmol/mL] = 5.40, I3S = 33, IQR 31-78). At birth, preterm neonates showed significantly lower fecal levels of indole-lactic-acid (ILA) compared to full-term neonates (preterm [pmol/mL] = 7, IQR 0-18, term = 10, IQR 0-252). Using our AhR-reporter system we confirmed the ability of milk IAA and I3S, and fecal ILA to activate AhR, suggesting that the levels of milk and fecal AhR-agonists are relevant for activating neonatal intestinal AhR.
Finally, to assess the role of milk AhR-ligands on epithelial barrier function, intestinal crypts were isolated from fetuses (16-20 weeks of gestation), grown into organoids and stimulated for 24h with AhR-agonists (physiological concentrations; 0.175-1 nmol/mL) and challenged with TNFα for 4h. The activation of Nf-kB and consequent production of IL-8 was significantly reduced by both IAA and ILA (One-way ANOVA, p<0.01 and p<0.0001) but not by I3S in human fetal derived organoids (p<0.58). In addition, the barrier function was assessed through TEER measurement. All three of the indoles restored barrier integrity damaged by TNFα after 72h (One-way ANOVA, IAA = p<0.001, I3S = p<0.01, ILA = p<0.001).

Conclusion

To conclude, our results suggest that 1) Feces of preterm neonates generate lower levels of ILA compared to full term neonates; 2) Mother milk contains AhR-ligands able to activate AhR in neonatal intestine; 3) Mother milk and neonatal feces-derived AhR-ligands reduce epithelial Nf-kB activation in fetal intestinal organoids; 4) IAA, I3S and ILA could restore intestinal barrier integrity.
All of these results suggest a possible beneficial mechanism of mother milk through intestinal AhR-activation.

References

¹ Herrmann K., et al. Breastfeed. Med. 2014;9:184–190. doi: 10.1089/bfm.2013.0121.

Introduction

Acute pancreatitis (AP) is an inflammatory disorder that causes a considerable economic health burden. While the majority of AP shows a mild clinical course, about 10% of patients have moderate or severe disease with major local and systemic complications and a prolonged hospital stay. Still there is a lack of early biomarkers of severity while multiple complicated scoring systems fail to predict the course of disease. Here, we aim to investigate the role of the microbiome to predict the course of AP at admission.

Aims & Methods

In 16 European centers buccal and rectal swabs were collected from 450 AP patients within the first 72h of hospital admission. All samples were sequenced with Oxford Nanopore Technologies. Primary endpoints are the association of orointestinal microbiome with revised Atlanta classification and severity. Secondary endpoints are the association with mortality and length of hospital stay.

Results

In total, 832 samples from 424 patients were sequenced, 26 patients met exclusion criteria. After normalization of microbial data 409 buccal samples and 391 rectal samples remained for subsequent analysis. Significant differences were observed in beta diversities for rev. Atlanta classification (Bray Curtis, p-value 0.009**), severity (Bray Curtis, p-value 0.008**), mortality (Bray Curtis, p-value 0.006**) and length of hospital stay (Bray Curtis, p-value 0.043*) in rectal but not buccal swabs. Notably, these results remain significant after factoring in 74 potential confounding variables such as alcohol consumption, smoking status, and antibiotics. No differences were observed in alpha-diversity. Classifier for severity was built with different abundant taxa achieving an AUROC of 80%.

Conclusion

The rectal but not oral microbiome has the ability to predict the course of acute pancreatitis at admission of the patient.

Introduction

Tumour necrosis factor-like ligand 1A (TL1A) is a novel therapeutic target for inflammatory bowel disease. Patients (pts) with moderately to severely active ulcerative colitis (UC) treated with the anti-TL1A antibody, RO7790121 (formerly PF-06480605 and RVT-3101), showed significant endoscopic improvement and adequate safety in the phase 2a TUSCANY trial.¹ Here, we report data from the global, randomised, double-blind, placebo-controlled, dose-ranging phase 2b TUSCANY-2 (NCT04090411) trial evaluating the efficacy and safety of subcutaneous (SQ) doses of RO7790121 in adult pts with moderately to severely active UC (total Mayo Score [tMS] ≥6, endoscopic subscore ≥2) who had previously failed conventional/advanced therapy.

Aims & Methods

Pts were randomised to receive RO7790121 SQ 50mg, 150mg, 450mg or placebo (PBO) monthly during the 12-week induction period and RO7790121 SQ 50mg, 150mg or 450mg monthly during the treat-through 40-week maintenance period. Efficacy endpoints were assessed at weeks 14 and 56 in the induction and maintenance intent-to-treat analysis sets, respectively. The primary efficacy endpoint was clinical remission at week 14 by tMS. Safety was assessed throughout the induction and maintenance periods. The secondary endpoint of clinical remission using modified Mayo Score (mMS) is aligned to updated FDA guidance. Other secondary endpoints included clinical remission (by tMS and mMS) at week 56 and endoscopic improvement at weeks 14 and 56. Efficacy analysis by pre-defined biomarker subgroups was also performed.

Results

Overall, 245 pts were randomised and treated; 228 completed the induction and 224 entered the maintenance period of the study. At week 14, 25.5%, 23.3% and 23.9% of pts in the RO7790121 50mg, 150mg, 450mg arms, respectively vs 11.6% in PBO experienced clinical remission by tMS (p>0.05 [Table]). The proportion of pts achieving clinical remission using mMS at week 14 was 29.8%, 35.0% and 31.8% in the RO7790121 50mg, 150mg, 450mg arms, respectively vs 11.6% in PBO (nominal p<0.05). Improvements in clinical remission were sustained throughout the maintenance period (Table). A greater proportion of pts demonstrated endoscopic improvement across all doses of RO7790121 vs PBO at week 14 and week 56. Numerically greater treatment effects were observed in biomarker-positive pts relative to all-comer pts. During the induction period, 47.8% (117/245) of pts reported ≥1 treatment-emergent adverse event (TEAE). The most common TEAEs (occurring in ≥5% pts overall) were anaemia (5.3%) and headache (5.3%). In the induction period, 10 pts experienced serious TEAEs (PBO=4; 50mg=3; 450mg=3); 2 treatment-related (PBO=1; 450mg=1). No pts discontinued the study due to TEAEs. A generally similar safety profile was observed during the maintenance period.

Conclusion

Data from the phase 2b TUSCANY-2 dose-ranging study suggests that RO7790121 has a favourable benefit/risk profile with clinically meaningful improvements in pts with moderately to severely active UC. A phase 3 study will be conducted to confirm these results.

Table. Summary of efficacy outcomes at week 14 and week 56

References

1. Danese S, et al. Clin Gastroenterol Hepatol 2021;19:2324–32.e6.

Disclosure

This study was sponsored by Pfizer Inc and Roivant Sciences Ltd. Medical writing support, under the direction of the authors, was provided by Margarita Gkrava, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
SD, consultancy/advisory role/board: AbbVie, Alimentiv, Allergan, Amgen, AMT, AstraZeneca, Athos Therapeutics, Biogen, Boehringer, BMS, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, J&J, Lilly, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc, TiGenix, UCB, Vial, Vifor. Lecture fees: Abbvie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda.
JRA, consulting/advisory role/board: Abbvie, Adiso, BMS, Ferring, Finch Therapeutics, GSK, Janssen, Merck, Pfizer, Roivant, Seres Therapeutics. Speakers’ bureau: Abbvie, BMS, Janssen. Research funding: Janssen, Merck, Pfizer.
SS, consulting/advisory role/board: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen, Lilly, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma, and Ventyx Biosciences.
LP-B, consulting/advisory role/board : Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, AMT, Arena, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, Hac Pharma, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia. Speakers’ Bureau: Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, Vifor. Research funding: Celltrion, Fresenius Kabi, Takeda. Support travel: Abbvie, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, Tillots.
VJ, employment: Western University, London Health Sciences Centre, Alimentiv. Consulting or advisory role/board : AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei, Asieris, AstraZeneca, Avoro Capital, BMS, Celltrion, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion. Speakers’ bureau: AbbVie, Ferring, BMS, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi.
GRD, consulting/advisory role/board: Alimentiv, Abbvie, BMS, Boehringer, Celltrion, GSK, Immunic, Index, J&J, Lilly, Polpharm, Takeda, Tillotts, Ventyx, Pfizer. Speakers’ bureau: Lilly, Pfizer, Takeda. Research funding: Cellitron, Lilly, Pfizer, Takeda.
JK, no COI.
RWL, consulting/advisory role/board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus, Takeda. Research funding: Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant, McKusker Charitable Foundation.
AJY, consulting/advisory role/board: Abbvie, Takeda, Celltrion, BMS, J&J, Abivax.
JMM, employment/stock/other ownership interests: Roche/Genentech.
DB, employment: F. Hoffmann-La Roche.
KL, employment: Roche/Genentech.
CS, employment/stock/other ownership interests: Roche/Genentech.
KEH, employment/stock/other ownership: Pfizer.
BGF, stock/other ownership interests: Connect Biopharm, EnGene. Honoraria/consulting/advisory role/board: AbbVie, Abivax, Adiso, Agomab, Allianthera, Amgen, AnaptysBio, Arena Pharma, Avoro Capital, Atomwise, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Equillium, Ermium, First Wave, Forbion, Galapagos, Galen Atlantica, Roche/Genentech, Gilead, Gossamer, GSK, Hinge Bio, Index Pharma, Imhotex, Immunic Therapeutics, Intercept, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Klick Health, Landos Biopharma, Lenczner Slaght, LifeSci Capital, Lilly, Lument, Mage Biologics, Mestag, Millennium, MiroBio, Monte Rosa, Morgan Lewis, Morphic Therapeutics, Mylan, Nexys Therapeutics, Nimbus Therapeutics, OM Pharma, OrbiMed, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Roivant/Televant, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Sobi, Spyre Therapeutics, Surrozen, Synedgen, Takeda, Teva, Thelium, Tigenix, Tillotts, Triastek, Ventyx Biosciences, Zagbio, Zealand Pharma. Speakers’ Bureau: Takeda, Janssen, Abbvie.

Introduction

Postoperative recurrence is a major concern in Crohn's disease. The Kono-S anastomosis has been described to reduce the rate of recurrence. However, the level of evidence for its effectiveness remains low. The KoCoRICCO study aimed to compare outcomes between Kono-S anastomosis and conventional anastomosis in two nationwide prospective cohorts.

Aims & Methods

Adult patients with Crohn's disease who underwent ileocolonic resection with Kono-S anastomosis were prospectively included in seven referral centers between 2020 and 2022. Patients with conventional side-to-side anastomosis were enrolled from a previously published cohort. Postoperative morbidity was compared between the two groups in the overall population, and a propensity score analysis was performed to compare recurrence at first endoscopy in a matched 1:2 ratio population.

Results

A total of 432 patients with ileocolonic anastomosis were enrolled, of whom 155 had a Kono-S anastomosis. Before matching, both groups were unbalanced for preoperative, intraoperative, and postoperative characteristics. Severe surgical morbidity was lower in the Kono-S group (4.6%) than in the conventional side-to-side group (7.6%) (p<0.0001). After matching patients with available endoscopic follow-up, endoscopic recurrence ≥i2 was found in 47.5% of the Kono-S group and 44.3% of the conventional side-to-side group (p=0.6745).

Conclusion

The KoCoRICCO study suggests that Kono-S anastomosis may be associated with reduced severe morbidity in Crohn's disease compared to conventional side-to-side anastomosis. However, we did not find evidence that Kono-S anastomosis reduces the risk of endoscopic recurrence. Further research with a longer follow-up is necessary to determine whether there is a potential benefit on surgical recurrence.