A human microbiome-derived therapeutic for ulcerative colitis promotes mucosal healing and immune homeostasis

  1. Páraic Ó Cuív
  2. Johanna K. Ljungberg
  3. Joyce Zhou
  4. Michael Nissen
  5. Annika Krueger
  6. Joel Boyd
  7. Mareike Bongers
  8. Jimenez Loayza Jeimy
  9. Charlotte Vivian
  10. Ella Reich
  11. Andrea Rabellino
  12. Rhys Newell
  13. Liang Fang
  14. Samantha MacDonald
  15. Alena Pribyl
  16. Shandelle Caban
  17. Huw McCarthy
  18. Joanne Soh
  19. Luke Reid
  20. Blake Wills
  21. Duncan McHale
  22. David L.A. Wood
  23. Ian H. Frazer
  24. Nicola Angel
  25. Hiram Chipperfield
  26. Jakob Begun
  27. Simon Keely
  28. Gene W. Tyson
  29. Philip Hugenholtz
  30. Trent Munro
  31. Lutz Krause
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Abstract

The gut microbiome is central to the pathogenesis of ulcerative colitis (UC), and microbiome-derived therapeutics are a promising new treatment option. Using a metagenome-guided, large cohort-based approach, we identifiedHominenteromicrobium mulierisas prevalent in healthy individuals but depleted in UC. Here, we present a Live Biotherapeutic Product (LBP) candidate, MAP 315, derived from a newly isolated strain of this species (MH27-2). In mouse colitis models, MH27-2 improved disease pathology, and accelerated gut healing, marked by epithelial restitution and reduced immune cell infiltration.In vitrostudies showed that MH27-2 promotes mucosal healing through accelerated epithelial cell migration and proliferation, accelerated wound closure, and improved gut barrier integrity. Importantly, MH27-2 supports immune homeostasis through the promotion of regulatory T-cells, suppression of TL1A signaling, and induction of anti-inflammatory IL-10. Manufacturing processes were developed, and MH27-2 drug product (MAP 315) demonstrated to be safe and well-tolerated in a first-in-human Phase 1 clinical trial.

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