Faecalibacterium prausnitzii A2-165 metabolizes host- and media-derived chemicals and induces transcriptional changes in colonic epithelium in GuMI human gut microphysiological system

Yu-Ja Huang; Caroline A Lewis; Charles Wright; Kirsten Schneider; John Kemmitt; David L Trumper; David T Breault; Omer Yilmaz; Linda G Griffith; Jianbo Zhang

doi:10.20517/mrr.2024.14

Faecalibacterium prausnitzii A2-165 metabolizes host- and media-derived chemicals and induces transcriptional changes in colonic epithelium in GuMI human gut microphysiological system

Microbiome Res Rep. 2024 May 22;3(3):30. doi: 10.20517/mrr.2024.14. eCollection 2024.

Authors

Yu-Ja Huang¹, Caroline A Lewis^{2

3}, Charles Wright¹, Kirsten Schneider¹, John Kemmitt¹, David L Trumper⁴, David T Breault⁵, Omer Yilmaz¹, Linda G Griffith^{1

4

6}, Jianbo Zhang^{1

7

8}

Affiliations

¹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
³ current address: UMass Chan Medical School, Program in Molecular Medicine, Worcester, MA 01605, USA.
⁴ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam 1098 XH, the Netherlands.
⁸ Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam UMC, Location Academic Medical Center, Amsterdam 1105 BK, the Netherlands.

Abstract

Aim: Recently, a GuMI gut microphysiological system has been established to coculture oxygen-intolerant Faecalibacterium prausnitzii (F. prausnitzii) A2-165 with organoids-derived primary human colonic epithelium. This study aims to test if this GuMI system applies to different donors with different healthy states and uses metabolomics to reveal the role of gut microbes in modulating host- and diet-derived molecules in the gut lumen. Methods: Organoids-derived colonic monolayers were generated from an uninflamed region of diverticulitis, ulcerative colitis, and Crohn's disease patients and then integrated into the GuMI system to coculture with F. prausnitzii A2-165 for 2 to 4 days. Apical media was collected for metabolomic analysis. Targeted metabolomics was performed to profile 169 polar chemicals under three conditions: conventional static culture without bacteria, GuMI without bacteria, and GuMI with F. prausnitzii. The barrier function of monolayers was measured using transepithelial resistance. Results: GuMI successfully cocultured patient-derived monolayers and F. prausnitzii for up to 4 days, with active bacterial growth. Introducing flow and oxygen gradient significantly increases the barrier function, while exposure to F. prausnitzii slightly increases the barrier function. Targeted metabolomics screened 169 compounds and detected 76 metabolites, of which 70 significantly differed between at least two conditions. F. prausnitzii significantly modulates the levels of nucleosides, nucleobases, and amino acids on the apical side. Further analysis suggests that F. prausnitzii changes the mRNA level of 260 transcription factor genes in colonic epithelial cells. Conclusion: The GuMI physiomimetic system can maintain the coculture of F. prausnitzii and colonic epithelium from different donors. Together with metabolomics, we identified the modulation of F. prausnitzii in extracellular chemicals and colonic epithelial cell transcription in coculture with human colonic epithelium, which may reflect its function in gut lumen in vivo.

Keywords: Faecalibacterium prausnitzii A2-165; colonic epithelium; host-microbe interaction; metabolomics; microphysiological system.