Introduction
The gut microbiome exerts a significant influence on the host's cellular energy metabolism during homeostasis and disease, notably due to the production of metabolites (1), such as polyamines (2). Gut dysbiosis and bioenergetic alterations leading to metabolic shifts have been associated with altered cellular responses and are involved in intestinal disorders, such as inflammatory bowel disease (IBD) (3,4). Cadaverine, a gut polyamine derived from L-lysine decarboxylation, has been previously proposed to be transported into mitochondrial inner compartments in basal and induced conditions (5). On the other hand, it seems to be positively regulated in the gut of IBD patients (6). However, the biological significance in both contexts remains still unexplored.
Aims & Methods
This study uncovers the potential immunometabolic role of cadaverine in vitro and during intestinal inflammation. For that, single-cell energetic metabolism by profiling translation inhibition (SCENITH), luminescence and flow cytometry-based assays, Seahorse real-time cell metabolic analysis, metabolomics, RNAseq, and proteomics were applied to explore the role of cadaverine on energy metabolism in purified cells. Antibiotic-induced gut microbiota perturbations and dextran sodium sulfate (DSS)-induced colitis were carried out to further investigate its effect in vivo.
Results
Here we demonstrate that cadaverine enhances adenosine triphosphate (ATP) levels in THP-1 monocytic cell line as well as in human monocytes and macrophages obtained from healthy donors. Those results were associated with increased glucose uptake and utilization as a metabolic fuel and with higher mitochondrial dependence as a metabolic pathway, particularly elevating basal and maximal oxidative phosphorylation (OXPHOS) rates. The effects of cadaverine on mitochondrial functions persisted even in the presence of lipopolysaccharide (LPS) that triggers aerobic glycolysis in monocytes/macrophages. Interestingly, cadaverine presented immunomodulatory activity by increasing interleukin (IL)-10 levels and decreasing tumor necrosis factor (TNF)-α production in classical monocytes while triggering the polarization of macrophages to the M2 anti-inflammatory phenotype. Such immunomodulatory potential appears intricately dependent on mitochondrial respiration since this effect was blocked when OXPHOS was pharmacologically inhibited. Omics analysis reveals that itaconate metabolism and Krebs cycle modulation may be associated with cadaverine immunometabolic activity. Oral administration of cadaverine in antibiotics-induced gut microbiota-depleted mice rescued from both small intestine and colon macrophage energy deficiency. Furthermore, cadaverine also sustained OXPHOS and mitochondrial health features in those cells. As L-lysine decarboxylase genes are mostly expressed by gut Enterobacteriaceae, which in turn are augmented and suggested to be related to IBD, we specifically depleted this bacterial family with colistin in mice and induced colitis with DSS. In this setting cadaverine administration ameliorates disease severity by polarizing colon macrophages towards the M2 phenotype and preserving the overall mitochondrial features, such as mass, mitochondrial membrane potential, and reactive oxygen species, to sustain ATP production by OXPHOS.
Conclusion
Such discoveries at the metabolic level hold promise for identifying novel therapeutic strategies that target cellular energy metabolism and the gut microbiota to modulate monocyte and macrophage responses in IBD.
References
1. Michaudel C, Sokol H. The Gut Microbiota at the Service of Immunometabolism. Cell Metab. 2020 Oct 6;32(4):514-523.
2. Puleston DJ et al. Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. Cell Metab. 2019 Aug 6;30(2):352-363.e8.
3. Zeng Z et al. Glycolytic Activation of CD14+ Intestinal Macrophages Contributes to the Inflammatory Responses via Exosomal Membrane Tumor Necrosis Factor in Crohn's Disease. Inflamm Bowel Dis. 2024 Jan 5;30(1):90-102.
4. Lloyd-Price et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019 May;569(7758):655-662.
5. Toninello A, Dalla Via L, Testa S, Siliprandi D. Electrophoretic polyamine transport in rat liver mitochondria. Amino Acids. 1992 Feb;2(1-2):69-76.
6. Li M, Yang L, Mu C, Sun Y, Gu Y, Chen D, Liu T, Cao H. Gut microbial metabolome in inflammatory bowel disease: From association to therapeutic perspectives. Comput Struct Biotechnol J. 2022 Apr 4;20:2402-2414.
Disclosure
Harry Sokol reports lecture fees, board membership, or consultancy from Carenity, AbbVie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, BiomX, Biose, Novartis, Takeda, Biocodex and is cofounder of Exeliom Biosciences.