Poly(D,l-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids

Laura E. McCoubrey, Fabiana Ferraro, Nidhi Seegobin, Jérémy Verin, Haya A. Alfassam, Atheer Awad, Massimo Marzorati, Lynn Verstrepen, Jonas Ghyselinck, Julie De Munck, Jelle De Medts, Evi Steppe, Valerie De Vleeschhauwer, Gilles De Rocker, Alexandra Droesbeke, Melanie De Rijck, Sara Vanthoor, Frédéric Moens, Juergen Siepmann, Florence SiepmannSimon Gaisford, Mine Orlu, Abdul W. Basit

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Abstract

The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs.
Original languageEnglish
Pages (from-to)163-178
Number of pages16
JournalJournal of Controlled Release
Volume369
Early online date26 Mar 2024
DOIs
Publication statusE-pub ahead of print - 26 Mar 2024

Keywords

  • PLGA
  • Microbiome medicine
  • Colonic drug delivery
  • Nanoparticles and microparticles
  • Metabolomics
  • Microbiome sequencing
  • Spray drying

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