1. Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During RemissionSummary
- Author
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Otto Savolainen, Johanna Sundin, Stefan Isaksson, Hans Strid, Lena Öhman, Lujain Maasfeh, Maria K. Magnusson, Anetta Härtlova, and Georgios Mavroudis
- Subjects
Lipopolysaccharides ,0301 basic medicine ,Lipopolysaccharide ,medicine.medical_treatment ,FLA, flagella ,TNF ,RC799-869 ,FS, fecal supernatant ,Monocytes ,Feces ,chemistry.chemical_compound ,0302 clinical medicine ,CXCL, C-X-C motif chemokine ligand ,LP, lamina propria ,Macrophage ,Intestinal Mucosa ,Original Research ,TNF, tumor necrosis factor ,IBD, inflammatory bowel disease ,PGN, peptidoglycan ,Toll-Like Receptors ,Gastroenterology ,Disease Management ,ELISA, enzyme-linked immunosorbent assay ,Diseases of the digestive system. Gastroenterology ,Ulcerative colitis ,Phenotype ,M1MQ, M1 (proinflammatory) macrophage ,Cytokine ,SCFA, short-chain fatty acid ,Metabolome ,Cytokines ,LPS, lipopolysaccharide ,030211 gastroenterology & hepatology ,Tumor necrosis factor alpha ,Disease Susceptibility ,Inflammation Mediators ,GM-CSF, granulocyte-macrophage colony-stimulating factor ,Signal Transduction ,TLR, Toll-like receptor ,CD, cluster of differentiation ,Antigen presentation ,GC-MS/MS, gas chromatography coupled to a tandem mass spectrometer ,IFNγ, interferon γ ,ODN, oligodeoxynucleotides ,Immunophenotyping ,03 medical and health sciences ,Phagocytosis ,medicine ,Humans ,Metabolomics ,Ulcerative Colitis ,Th, T-helper ,PCA, principal component analysis ,Hepatology ,Cluster of differentiation ,business.industry ,Macrophages ,Macrophage Activation ,medicine.disease ,IL, interleukin ,UC, ulcerative colitis ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,Case-Control Studies ,Immunology ,Colitis, Ulcerative ,business ,Biomarkers ,TLR Signaling - Abstract
Background & Aims Intestinal macrophages adopt a hyporesponsive phenotype through education by local signals. Lack of proper macrophage maturation in patients with ulcerative colitis (UC) in remission may initiate gut inflammation. The aim, therefore, was to determine the effects of fecal luminal factors derived from healthy donors and UC patients in remission on macrophage phenotype and function. Methods Fecal supernatants (FS) were extracted from fecal samples of healthy subjects and UC patients in remission. Monocytes were matured into macrophages in the presence of granulocyte-macrophage colony-stimulating factor without/with FS, stimulated with lipopolysaccharide, and macrophage phenotype and function were assessed. Fecal metabolomic profiles were analyzed by gas-chromatography/mass-spectrometry. Results Fecal luminal factors derived from healthy donors were effective in down-regulating Toll-like receptor signaling, cytokine signaling, and antigen presentation in macrophages. Fecal luminal factors derived from UC patients in remission were less potent in inducing lipopolysaccharide hyporesponsiveness and modulating expression of genes involved in macrophage cytokine and Toll-like receptor signaling pathways. Although phagocytic and bactericidal abilities of macrophages were not affected by FS treatment, healthy FS-treated macrophages showed a greater ability to suppress cluster of differentiation 4+ T-cell activation and interferon γ secretion compared with UC remission FS-treated counterparts. Furthermore, metabolomic analysis showed differential fecal metabolite composition for healthy donors and UC patients in remission. Conclusions Our data indicate that UC patients in remission lack luminal signals able to condition macrophages toward a hyporesponsive and tolerogenic phenotype, which may contribute to their persistent vulnerability to relapse., Graphical abstract
- Published
- 2021