Endogenous and microbial modulators of inflammation
Abstract
Cardiometabolic disease is characterized by dysregulated, chronic inflammation, that may result from impaired resolution pathways or alterations in the gut microbiota. Thus, restoring specialized pro-resolving mediators (SPMs) or intestinal bacteria with immunomodulatory properties represent potential therapeutic strategies for patients.
First, we investigated the ability of the SPMs, lipoxins, to modulate neutrophils from individuals with atherosclerosis. Treatment of neutrophils from patients with atherosclerosis with lipoxins attenuated elevated reactive oxygen species production and expression of the high-affinity conformation of CD11b/18 integrin, and enhanced lymphatic migration. The potential therapeutic effect of lipoxins in atherosclerosis was demonstrated, along with the need to tailor treatment to the requirements of the individual.
Second, for the development of a next-generation probiotic supplementation, we co-isolated Faecalibacterium prausnitzii with Desulfovibrio piger and demonstrated a cross-feeding mechanism that enhanced growth and butyrate production. F. prausnitzii is a highly prevalent and abundant human gut bacteria with immunomodulatory properties and associations with health. For development into a next-generation probiotic, F. prausnitzii was adapted to tolerate exposure to oxygen. F. prausnitzii and D. piger formulation was well tolerated by mice and humans. We demonstrated a method by which strict anaerobic bacteria can be adapted to tolerate oxygen without impacting potential beneficial properties.
Finally, D. piger has been found to be both ubiquitous among individuals but has also been associated with disease. To identify if the discrepancies lie in inter-strain variation, we isolated a D. piger strain with genomic similarity to FI11049, previously isolated from a patient with colitis, to compare with the strain co-isolated with F. prausnitzii. Anti-inflammatory properties and phenotypic differences were found between the strains. Further studies are required to investigate inter-strain variation to understand disease associations.
Parts of work
I. Kraft, J.D., Blomgran, R., Bergström, I., Soták, M., Clark, M., Rani, A., Rohini Rajan, M., Dalli, J., Nyström, S., Quiding-Järbrink, M., Bromberg, J., Skoog, P., Börgeson, E. (2022) Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis. The FASEB Journal, 36 (3) e22173. https://doi.org/10.1096/fj.202101219RR II. Khan, M.T., Dwibedi, C., Sundh, D., Pradhan, M., Kraft, J.D., Caesar, R., Tremaroli, V., Lorentzon, M., Bäckhed, F. (2023) Synergy and oxygen adaptation for development of next-generation probiotics. Nature 620, 381-385. https://doi.org/10.1038/s41586-023-06378-w III. Kraft, J.D., Dwibedi, C., Makki, K., Florén, A., Hempenstall, E., Bäckhed, F., Khan, M.T., Tremaroli, V., Caesar, R. Phenotypic variation of novel Desulfovibrio piger stains isolated from human faeces. Manuscript
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Medicine. Department of Molecular and Clinical Medicine
Disputation
Torsdag den 21 december, kl. 9.00, Hjärtats Aula, Blå stråket 5, Sahlgrenska universitetssjukhuset, Göteborg
Date of defence
2023-12-21
jamie.kraft@wlab.gu.se
Date
2023-12-05Author
Kraft, Jamie Dale
Keywords
Inflammation
Resolution
Specialized pro-resolving mediators
Lipoxins
Neutrophils
Cardiometabolic disease
Next-generation probiotic
Oxygen-tolerance
Faecalibacterium prausnitzii
Desulfovibrio piger
Inter-strain variation
Publication type
Doctoral thesis
ISBN
978-91-8069-532-9 (PDF)
978-91-8069-531-2 (Print)
Language
eng