Introduction

A marked decrease of Faecalibacterium prausnitzii is a well-established hallmark of Crohn’s disease (CD)-associated dysbiosis and predicts disease relapse (1-2). Several strains of F. prausnitzii exhibit anti-inflammatory effects in vitro and in rodents colitis models, positioning this species as a promising therapeutic candidate (3-4). However, it has never been administered to humans. Here, we present the development and first-in-human evaluation of F. prausnitzii strain EXL01 for CD treatment.

Aims & Methods

F. prausnitzii EXL01, isolated from a healthy donor, was selected based on strict safety and preliminary in vitro efficacy criteria. Its anti-inflammatory effect was tested in trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats and dextran sodium sulfate (DSS)-induced colitis in mice. After favorable toxicological studies, a first-in-human, open-label, single-arm study (Part A) was conducted in patients with mild to moderate ileal CD (CDAI 180–350), following clinical remission (CDAI <150) or response (CDAI decrease ≥70) after corticosteroids (CS). EXL01 (10¹⁰ total cell count/day) was administered orally for 24 weeks, with a 6-week CS taper. Colonoscopies were performed at baseline and week 24. The primary endpoint was safety; secondary endpoints included clinical efficacy, blood/fecal biomarkers, transcriptomic analysis, and gut microbiota profiling. Part B, initially planned as a placebo-controlled phase, was not pursued due to low recruitment.

Results

According to classical evaluation endpoints, EXL01 demonstrated dose-dependent anti-inflammatory effects in both TNBS and DSS models. Between March 2023 and October 2024, 8 patients were enrolled across Belgium and Poland. Baseline characteristics were consistent with the target CD population. After corticosteroid induction, the parameters were as follow: CDAI = 78.1 (42-105); SES-CD= 6.9 (2-17); CRP = 5.7mg/l (3-13). EXL01 was well tolerated; no treatment-related serious adverse events or safety signals were observed. Six participants (75%) completed the 24-week treatment; two discontinued due to disease flare. Compared to patients who remained in remission, those who flared during the study showed higher baseline systemic inflammation markers (CRP, neutrophils, platelets) and innate immunity gene expression, with limited corticosteroid response. While gut microbiota composition remained largely stable, transcriptomic analyses revealed distinct changes in ileal gene expression following EXL01 treatment, notably modulation of immune-related genes and upregulation of energy metabolism pathways, similar to what we saw previously in vitro (bioRxiv 2024.10.06.616495).

Conclusion

EXL01, administered during and after CS tapering, was safe and well tolerated for up to 24 weeks in patients with CD. Though limited by small sample size, the study supports the biological activity of EXL01, notably through its impact on ileal gene expression. A phase 2 randomized controlled trial is ongoing to further assess efficacy.

References

1. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis. 2014 Jun;20(6):978-86. doi: 10.1097/MIB.0000000000000036. PMID: 24788220.
2. Pascal V, Pozuelo M, Borruel N, et al. A microbial signature for Crohn's disease. Gut. 2017;66(5):813-22.
3. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-6.
4. Martin R, Chain F, Miquel S, et al. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm Bowel Dis. 2014;20(3):417-30.

Disclosure

HS, PhL and BH are co-founder of Exeliom. PR, DS, BH are employees of Exeliom Biosciences

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.

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

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64, a receptor on cells that produce IL-23. In the QUASAR studies, GUS intravenous (IV) induction and subcutaneous (SC) maintenance demonstrated symptomatic, endoscopic, and histologic efficacy through 2 years.^1,2 Here, we describe maintenance of endoscopic and histologic efficacy in the long-term extension (LTE).

Aims & Methods

At maintenance week (W) 0, GUS IV induction responders were randomized 1:1:1 to GUS 100 mg SC every 8 weeks (q8w), GUS 200 mg SC q4w or placebo (GUS withdrawal). Participants (pts) completing the W44 visit could enter the LTE and continue the treatment regimen they were receiving at W44. Placebo pts discontinued after study unblinding. Efficacy data for randomized pts who continued to receive their GUS regimen assigned at W0 in the LTE were analyzed using 2 methods: 1) nonresponder imputation (NRI) accounting for pts with treatment failure or missing data, and 2) “as observed.”

Results

Overall, 303 randomized pts (155 for 100 mg q8w and 148 for 200 mg q4w) continued their GUS treatment assigned at W0 in the LTE. Of pts who achieved endoscopic improvement at W44, 87.2% of GUS 100 mg q8w pts and 80.2% GUS 200 mg q4w pts maintained endoscopic improvement through W92 (NRI analysis; Table). Of pts who achieved histologic improvement at W44, 77.9% and 75.2%, respectively, maintained histologic improvement at W92. Of pts who achieved histo-endoscopic mucosal improvement (HEMI) at W44, 73.5% and 75.5%, respectively, maintained HEMI through W92. Of pts who were in histologic remission at W44, 71.2% maintained histologic remission at W92 in both GUS groups. Results of the as-observed analysis were consistent with the NRI analysis; the dropout rate was low among GUS-treated pts in the LTE. Proportions of pts who maintained endoscopic and histologic outcomes from W0 to W92 are presented in the Table.

Conclusion

High rates of long-term sustained endoscopic and histologic endpoints were observed at W92 of the LTE with both GUS dose regimens.

References

1. Rubin DT, et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025;405(10472):33-49.
2. Lichtenstein GR, et al. Efficacy and safety of guselkumab for ulcerative colitis through week 92 of the QUASAR long-term extension study. Presented at: Digestive Disease Week (DDW); May 4–6, 2025; San Diego, CA.

Disclosure

Study support: Johnson & Johnson.
TH: AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., JIMRO, Eli Lilly, Gilead Sciences, Johnson & Johnson, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc, Takeda Pharmaceutical Co., Ltd.
JP: AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, Wasserman.
FM: AbbVie, Arena, Celltrion, Eli Lilly and Company, Ferring, Fresenius, Galapagos, GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Prometheus Biosciences, Roche, Sandoz, Tillots, Takeda, Teva.
GRL: AbbVie, American College of Gastroenterology, CellCeutrix, Celgene, Clinical Advances in Gastroenterology, Ferring, Gastroenterology and Hepatology [Gastro-Hep Communications], Gilead, Johnson & Johnson, Orthobiotech, Eli Lilly, Luitpold / American Regent, Merck, McMahon Publishing, Pfizer, Prometheus, Romark, Salix/ Valeant, Shire, SLACK, Springer, Takeda, UCB, Up-To-Date, Vindico, Virgo.
JRA: Abbvie, Bristol Myer Squibb, Ferring, Finch, Iterative Scopes, Johnson & Johnson, Merck, Pfizer, Roivant, Seres Therapeutics, Roivant Adiso.
BB: AbbVie, Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Business Intelligence, Celgene, Celltrion, Eupraxia Fresenius Kabi, Ferring, Genentech/Roche, Gilead, Iterative Scopes, GlaxoSmithKline, Jamp, Johnson & Johnson, Merck, Microbiome Insights, Mylan, Novartis, Organon, Pendopharm, Pfizer, Protagonist, Qu Biologic, Sandoz, Takeda, Viatris.
WA: AbbVie, Amgen, BMS, Dynacare, Eli-Lilly, Johnson & Johnson, Merck, Novartis, Pfizer, Prometheus, Sandoz, Sanofi, Takeda, Theradiag.
MAS: AbbVie, Bristol-Myers Squibb, Falk, Galapagos, Janssen, Lilly, MSD, Pfizer, Samsung Bioepis, Sandoz, Sanofi, STADA, Takeda, Tillotts.
BDY: AbbVie Korea, BMS Pharmaceutical Korea Ltd., Celltrion, Chong Kun Dang Pharm, CJ Red BIO, Cornerstones Health, Curacle, Daewoong Pharm, Dong-A ST, Eisai Korea, Eli Lilly and Company Korea, Ferring Korea, Imscout, IQVIA, Johnson & Johnson, Johnson & Johnson Korea, JEIL PHARMACEUTICAL CO., Kangstem Biotech, Korea Otsuka Pharm, Korea United Pharm, Medtronic Korea, NanoEntek, ORGANOIDSCIENCES LTD, Pfizer Korea, Samsung Bioepis, Takeda, Takeda Korea, Yuhan.
SY, MG, NS, DP, YM, HZ: Johnson & Johnson.
AD: Abivax, AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CED Service GmbH, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, High5MD, Johnson & Johnson, Lilly, Materia Prima, MedToday, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Thieme, Tillotts, UniMed Verlag, Vifor Pharma.
DTR: Abbvie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Johnson & Johnson, Lilly, Pfizer, Samsung Neurologica, Takeda.
BES: AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics.