Introduction

The phase 2b GALAXI 1 and phase 3 GALAXI 2&3 studies evaluated guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in participants (pts) with moderately to severely active CD.¹ Pts treated with ustekinumab (UST) who met inadequate response criteria during the long-term extension (LTE) could cross over to GUS 200 mg SC q4w. Here, we present efficacy and safety results in pts who received GUS after experiencing an inadequate response to UST in the pooled GALAXI LTE.

Aims & Methods

Individuals with prior inadequate response or intolerance to UST were excluded from GALAXI; however, during the LTE, pts treated with UST 90 mg SC q8w who met inadequate treatment response criteria (not in clinical response [≥100-point reduction in CDAI score from baseline or CDAI<150] and CDAI ≥220) between Wks 52-80 of LTE were eligible for a treatment switch to GUS 200 mg SC q4w, without IV induction. Clinical response and clinical remission (CDAI<150) were both assessed 16 weeks after treatment switch. Endoscopic response (≥50% improvement from baseline SES-CD or SES-CD≤2) and endoscopic remission (SES-CD≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual component) were assessed at Wk 96. Safety was assessed through Wk 96.

Results

In total, 80 pts treated with UST underwent treatment switch to GUS 200 mg SC q4w maintenance therapy due to meeting inadequate treatment response criteria between Wks 52-80 of the LTE. Of these 80 pts, 75 were included in the efficacy analyses (baseline mean age, 35.2yrs; male, 64.0%; mean CD disease duration, 8.21yrs; mean CDAI, 291.5; mean SES-CD, 12.8; history of inadequate response/intolerance to biologics [BIO-IR], 60.0%).
The proportions of pts achieving clinical response and clinical remission 16 weeks after treatment switch from UST to GUS 200 mg SC q4w were 61.3% and 52.0%, respectively. These results were comparable to the proportions of pts treated with GUS 200 mg IV q4w induction in the BIO-IR subgroup of the total LTE population who achieved clinical response and clinical remission at Wk 12 (61.7% and 46.7%, respectively).
The proportions of pts achieving endoscopic response and endoscopic remission at Wk 96 (ie, ~1 year after treatment switch from UST to GUS 200 mg SC q4w) were 49.3% and 30.7%, respectively. These results were similar to the proportions of pts in the BIO-IR subgroup receiving GUS 200 mg SC q4w maintenance who achieved endoscopic response and endoscopic remission at Wk 48 (57.2% and 35.5%, respectively).
Safety results are summarized in the Table.

Table. Safety Summary From Treatment Switch Through Week 96

Conclusion

Among pts who experienced inadequate response to UST in the LTE, more than half achieved clinical remission 16 weeks after treatment switch to GUS 200 mg SC q4w, and approximately 50% were in endoscopic response ~1 year after treatment switch. These data suggest pts with an inadequate treatment response to UST may benefit from GUS treatment. Results should be interpreted considering that pts received GUS SC maintenance therapy directly without IV induction. Key safety event rates were consistent with the known safety profile of GUS in approved indications.

References

1) Sachen K, Hammaker D, Sarabia I, et al. Frontiers in Immunology. 2025; doi:10.3389/fimmu.2025.1532852.

Disclosure

AA reports potential conflicts of interest with AbbVie, Bristol Myers Squibb/Celgene, DiaSorin, Eli Lilly, Gilead, IBD Horizons, Janssen, Pfizer, Takeda, and TLL Pharmaceuticals
DW reports consulting fees from AbbVie, Bristol Myers Squibb, Janssen, Lilly, Pfizer, Takeda
RL reports having received advisory board fees from AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, and Takeda; received research grants from Celltrion, Shire, Janssen, Takeda, Joanna Tiddy grant from University of Sydney, McCusker Charitable Trust, Gastroenterological Society of Australia, NHMRC, Gutsy Group, and Pfizer
RVR, WvD, and CB are employees of Johnson & Johnson and own company stock/stock options.
TH received grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd., consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Nichi-Iko Pharmaceutical Co. Ltd., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and lecture fee from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc. Kissei Pharmaceutical Co. Ltd.
JP reports consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman, and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.

Introduction

Microscopic colitis (MC) refers to two pathologies – Collagenous colitis (CC) and Lymphocytic colitis (LC) that cause chronic watery diarrhoea, urgency, incontinence leading to significantly decreased quality of life¹. It is thought that MC develops due to a pathological immune response to intestinal luminal antigens in genetically predisposed individuals, with microbiota playing an important role^{2, 3}. However, the pathogenesis of MC is still unclear.

Aims & Methods

The aim of this study was to identify and characterize changes in bacterial composition of MC patients in terminal ileum and different colonic segments and determine its relation to the clinical course of disease. Biopsies from terminal ileum and six segments of the colon were collected during diagnostic colonoscopies. DNA extraction was performed using AllPrep DNA/RNA Micro Kit (Qiagen) following the manufacturer’s instructions. To determine bacterial composition, sequencing of the 16S rRNA variable region V3-V4 was conducted using the 27F and 338R polymerase chain reaction primers and sequenced on a MiSeq (2×250 bp; Illumina, Hayward, CA). Bioinformatic analysis was performed using DADA2, and taxonomic classification was carried out with the RDP classifier.

Results

Biopsy samples from 20 active CC patients, 20 active LC patients, and 50 controls demonstrated distinct microbial profiles across different intestinal segments, as revealed by beta-diversity and differential compositional analyses. Compared with controls, CC patients had consistent alterations in three bacterial families throughout the entire colon, with Erysipelatoclostridiaceae and Coriobacteriaceae decreased and Pasteurellaceae increased. Additionally, 35 families had segment-specific changes, and 25 families displayed altered abundance in the terminal ileum.
LC patients exhibited a consistent increase in Erisypelotrichaceae across the entire colon, with 38 other families showing segmental changes, and 12 families displaying altered abundance in the terminal ileum. Comparing LC and CC revealed a significantly different bacterial profile. LC showed lower abundance across many families, particularly in the right colon and terminal ileum. After sample collection, 15 CC patients and 12 LC patients received budesonide, with 3 CC and 2 LC patients having incomplete response. Beta diversity analysis revealed significant differences in the ascending colon and left side of the colon of CC patients based on response to budesonide. Patients with incomplete response to budesonide had an increased abundance of the genus Paucibacter. Similar tendencies were not observed in LC.
1 CC patient exhibited a quiescent disease course, 6 reached a sustained remission after treatment, 7 had a relapsing and 6 had a chronic active disease. Significant differences in beta diversity were observed in transverse, descending colon and rectum. Beta diversity of the descending colon had a medium correlation with disease behaviour. In the LC group 6 patients had a quiescent disease, 8 had a sustained remission after treatment, 3 exhibited a relapsing and 4 had a chronic active disease. No significant correlation between microbiota and disease behaviour was observed in LC.

Conclusion

This study showed significant differences in bacterial composition between CC, LC and controls in the terminal ileum and colon. In both CC and LC, bacterial alterations were not consistent throughout the entire colon but varied between different colonic segments. Microbiome differences based on response to budesonide and disease behaviour were observed in CC, but not LC.

References

1. Verhaegh BPM, Münch A, Guagnozzi D, et al. Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study. J Crohns Colitis. 2021;15(7):1174-1183.
2. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. Published online 2020.
3. Burke KE, D’Amato M, Ng SC, Pardi DS, Ludvigsson JF, Khalili H. Microscopic colitis. Nat Rev Dis Primers. 2021;7(1).

Introduction

Microplastic particles (MPs), defined as plastic fragments smaller than 5 mm, are pervasive pollutants that accumulate in ecosystems and the human food chain (1). Literature points at various health risks, including the induction of carcinogenesis (2). Emerging evidence from animal models (3) suggests that MPs may influence the gut microbiome, but the impact on the human gut microbiome remains poorly understood.

Aims & Methods

This study aimed to evaluate how various MP types influence gut microbial composition and metabolism using an ex vivo bioreactor model, with a focus on exploring potential carcinogenic effects arising from MP–microbiome interactions.
Stool samples from healthy donors were used to inoculate bioreactor cultures, which were maintained under anaerobic conditions for five days with daily nutrient feeding. These cultures were exposed to five common MP types—polystyrene (PS), polypropylene (PP), low-density polyethylene (LDPE), poly(methyl methacrylate) (PMMA), and polyethylene terephthalate (PET)—at concentrations mimicking both estimated human exposure (4) and higher doses to assess dose-dependence. Cell viability and total bacterial counts, as well as culture pH, were measured throughout the experiment. To further explore potential microbiome and metabolic alterations, 16S rRNA gene sequencing and targeted metabolomics were performed.

Results

MP exposure did not lead to significant changes in total or viable bacterial cell counts. However, MP-treated cultures exhibited a consistent and significant decrease in pH compared to controls, suggesting changes in microbial metabolic activity. Microbiome sequencing revealed plastic-type-dependent alterations in microbial composition, with certain bacterial taxa increasing or decreasing in abundance depending on the MP type. These shifts occurred across multiple genera within diverse families, including Lachnospiraceae, Oscillospiraceae, Enterobacteriaceae, and Ruminococcaceae, with the majority of changes occurring withing the phylum Bacillota. These compositional changes were accompanied by shifts in the metabolomic profiles, some of which correlated with the observed pH changes. Several plastic types induced changes in valeric acid levels, while individual MP types were associated with alterations in distinct metabolites such as uracil, lactic acid, and acetic acid.

Conclusion

This study demonstrates that MPs can affect gut microbial activity and metabolism without significantly altering overall bacterial abundance in the short term. The variation in microbiome response across plastic types highlights the complexity of MP-microbiome interactions. Changes in faecal pH are known to be associated with various gastrointestinal diseases (5). Interestingly, some of the MP-induced changes in microbial composition resembled patterns linked to diseases such as depression and colorectal cancer. In contrast, other changes showed patterns that differed from those typically associated with conditions like Parkinson’s disease and irritable bowel syndrome, highlighting the complexity of these associations and the dependency on the context. The bioreactor model provided a controlled environment for identifying direct MP-microbiome interactions; however, in humans, additional factors like diet, immune response, and individual microbiome variations play a role in determining long-term effects. Exposure duration may also play a critical role in shaping the extent and nature of microbiome alterations (6), underscoring the need for further research into the effects of chronic MP exposure and associated health risks.

References

(1) Mamun, A. A., Prasetya, T. A. E., Dewi, I. R., & Ahmad, M. (2023). Microplastics in human food chains: Food becoming a threat to health safety. The Science of the total environment, 858(Pt 1), 159834. https://doi.org/10.1016/j.scitotenv.2022.159834
(2) Kumar, R., Manna, C., Padha, S., Verma, A., Sharma, P., Dhar, A., Ghosh, A., & Bhattacharya, P. (2022). Micro(nano)plastics pollution and human health: How plastics can induce carcinogenesis to humans?. Chemosphere, 298, 134267. https://doi.org/10.1016/j.chemosphere.2022.134267
(3) Hirt, N., & Body-Malapel, M. (2020). Immunotoxicity and intestinal effects of nano- and microplastics: a review of the literature. Particle and fibre toxicology, 17(1), 57. https://doi.org/10.1186/s12989-020-00387-7
(4) Senathirajah, K., Attwood, S., Bhagwat, G., Carbery, M., Wilson, S., & Palanisami, T. (2021). Estimation of the mass of microplastics ingested - A pivotal first step towards human health risk assessment. Journal of hazardous materials, 404(Pt B), 124004. https://doi.org/10.1016/j.jhazmat.2020.124004
(5) Yamamura, R., Inoue, K. Y., Nishino, K., & Yamasaki, S. (2023). Intestinal and fecal pH in human health. Frontiers in Microbiomes, 2, 1192316.
(6) Yin, L., Yang, M., Teng, A., Ni, C., Wang, P., & Tang, S. (2025). Unraveling Microplastic Effects on Gut Microbiota across Various Animals Using Machine Learning. ACS nano, 19(1), 369–380. https://doi.org/10.1021/acsnano.4c07885

Introduction

Complex perianal fistulas represent one of the most challenging manifestations of Crohn’s disease. Combined surgical and medical therapy with biologic drugs represents today the first-line treatment option, but its efficacy does not exceed 60% in terms of healing. Recently, new therapeutic approaches, such as autologous microfragmented adipose tissue (M-Fat) injection, have shown promising results. Indeed, a recent non-profit prospective pilot study on 15 patients has demonstrated that the local injection of M-Fat is a safe and promising “rescue therapy” for patients with multiresistant complex fistulizing Crohn’s disease (PCD), with a 66.7% rate of combined remission in such difficult patients. It has to be highlighted that the M-Fat injection is minimally invasive, with less risk of sphincteric damage and can be carried out in day-surgery setting.

Aims & Methods

The primary aim of this multicentre double-blind randomized controlled trial (ATTIC) is to evaluate the efficacy of the infiltration of M-Fat in the healing of perianal complex fistulas not-responding to treatment with biologics. Consecutive patients referring to the 6 investigation Centers for surgical treatment of persistent complex fistulizing PCD refractory to biosurgical approach were assessed for eligibility. After baseline pelvic magnetic resonance imaging, those included were submitted to surgical drainage with “cone-like” fistulectomy, and then randomized to receive a 15 to 20 cc local injection, at the internal orifice level and along fistula tracts, of M-Fat obtained by a lipoaspiration and processed with an enzyme-free technology (treatment group), or a suture placement and injection of 15 cc of saline solution at the internal orifice (control group). Clinical follow-up were conducted at 2, 4, 8, 12, and 24 weeks; at 24 weeks after surgery, pelvic magnetic resonance was obtained. Success was defined as “combined remission”, combination of clinical (absence of drainage upon gentle finger compression) and radiological healing (absence of residual collections > 3 mm). Clinical remission was defined as clinical healing of all external openings not confirmed at radiological assessment.

Results

An overall 92 patients were screened, and 66 (33 per group) completed the 24-week follow-up. A statistically significant difference in favour of the treatment group in terms of combined remission emerged at the primary endpoint at 24-week follow-up (control group, 18.18%; treatment group: 57.58%; p = 0.0020). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of recurrence rate, complication rate, and number of adverse events. Clinical remission was 63.64% in the treatment group compared to 51.52% in the control group with no statistically significant difference (p > 0.05).

Conclusion

This multicentre double-blind randomized controlled trial demonstrates that the intraoperative injection of M-Fat, associated with surgical complete drainage of perianal sepsis, is safe, effective, and reproducible in healing complex multirefractory perianal Crohn's disease, while improving the quality of life and significantly reducing the risk of definitive oostomy.