دورية أكاديمية
Oral administration of CXCL12-expressing Limosilactobacillus reuteri improves colitis by local immunomodulatory actions in preclinical models.
| العنوان: | Oral administration of CXCL12-expressing Limosilactobacillus reuteri improves colitis by local immunomodulatory actions in preclinical models. |
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| المؤلفون: | Öhnstedt E; Ilya Pharma AB, Uppsala, Sweden.; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Doñas C; Ilya Pharma AB, Uppsala, Sweden., Parv K; Ilya Pharma AB, Uppsala, Sweden., Pang Y; Ilya Pharma AB, Uppsala, Sweden., Lofton Tomenius H; Ilya Pharma AB, Uppsala, Sweden.; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Carrasco López M; Ilya Pharma AB, Uppsala, Sweden., Gannavarapu VR; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Choi J; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Ovezik M; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Frank P; Ilya Pharma AB, Uppsala, Sweden., Jorvid M; Ilya Pharma AB, Uppsala, Sweden., Roos S; Department of Molecular Sciences, Swedish University of Agriculture, Uppsala, Sweden., Vågesjö E; Ilya Pharma AB, Uppsala, Sweden.; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Phillipson M; Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.; The Science for Life Laboratory, Uppsala University, Uppsala, Sweden. |
| المصدر: | American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2024 Aug 01; Vol. 327 (2), pp. G140-G153. Date of Electronic Publication: 2024 May 23. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901227 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1547 (Electronic) Linking ISSN: 01931857 NLM ISO Abbreviation: Am J Physiol Gastrointest Liver Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Physiological Society |
| مواضيع طبية MeSH: | Colitis*/immunology , Colitis*/chemically induced , Colitis*/drug therapy , Colitis*/therapy , Colitis*/metabolism , Limosilactobacillus reuteri* , Chemokine CXCL12*/metabolism , Chemokine CXCL12*/genetics , Dextran Sulfate* , Disease Models, Animal*, Animals ; Mice ; Administration, Oral ; Rabbits ; Probiotics/administration & dosage ; Mice, Inbred C57BL ; Female ; Colon/metabolism ; Colon/microbiology ; Colon/immunology ; Male |
| مستخلص: | Treatments of colitis, inflammation of the intestine, rely on induction of immune suppression associated with systemic adverse events, including recurrent infections. This treatment strategy is specifically problematic in the increasing population of patients with cancer with immune checkpoint inhibitor (ICI)-induced colitis, as immune suppression also interferes with the ICI-treatment response. Thus, there is a need for local-acting treatments that reduce inflammation and enhance intestinal healing. Here, we investigated the effect and safety of bacterial delivery of short-lived immunomodulating chemokines to the inflamed intestine in mice with colitis. Colitis was induced by dextran sulfate sodium (DSS) alone or in combination with ICI (anti-PD1 and anti-CTLA-4), and Limosilactobacillus reuteri R2LC ( L. reuteri R2LC) genetically modified to express the chemokine CXCL12-1α (R2LC_CXCL12, emilimogene sigulactibac) was given perorally. In addition, the pharmacology and safety of the formulated drug candidate, ILP100-Oral, were evaluated in rabbits. Peroral CXCL12-producing L. reuteri R2LC significantly improved colitis symptoms already after 2 days in mice with overt DSS and ICI-induced colitis, which in benchmarking experiments was demonstrated to be superior to treatments with anti-TNF-α, anti-α4β7, and corticosteroids. The mechanism of action involved chemokine delivery to Peyer's patches (PPs), confirmed by local CXCR4 signaling, and increased numbers of colonic, regulatory immune cells expressing IL-10 and TGF-β1. No systemic exposure or engraftment could be detected in mice, and product feasibility, pharmacology, and safety were confirmed in rabbits. In conclusion, peroral CXCL12-producing L. reuteri R2LC efficiently ameliorates colitis, enhances mucosal healing, and has a favorable safety profile. NEW & NOTEWORTHY Colitis symptoms are efficiently reduced by peroral administration of probiotic bacteria genetically modified to deliver CXCL12 locally to the inflamed intestine in several mouse models. |
| معلومات مُعتمدة: | NA Ilya Pharma AB; BioX grant from STUND to Ilya Pharma; Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation) |
| فهرسة مساهمة: | Keywords: ILP100; Limosilactobacillus reuteri; colitis; drug delivery; immunotherapies |
| المشرفين على المادة: | 0 (Chemokine CXCL12) 9042-14-2 (Dextran Sulfate) 0 (Cxcl12 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240523 Date Completed: 20240724 Latest Revision: 20240724 |
| رمز التحديث: | 20240726 |
| DOI: | 10.1152/ajpgi.00022.2024 |
| PMID: | 38780469 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1547 |
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| DOI: | 10.1152/ajpgi.00022.2024 |