Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During Remission

Abstract

Fecal luminal factors from ulcerative colitis patients in remission, unlike from healthy individuals, fail to induce macrophage hyporesponsiveness, a feature typical of intestinal macrophages. This suggests a role for fecal luminal factors in guiding macrophage maturation under physiological conditions and disease. 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 þ T-cell activation and interferon g 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.

Fecal luminal factors from patients with irritable bowel syndrome induce distinct gene expression of colonoids

“…Interestingly, fecal supernatants had a suppressive effect on cytokine secretion of colonoid monolayers as compared to PBS (negative control) and LPS (positive control). This is in line with a previous study of our group, where macrophages showed reduced cytokine production after conditioning with fecal supernatants as compared to untreated cells 47 . Altogether, our results sustain the concept of the intestinal microenvironment educating the host to stay unresponsive to the load of bacterial stimuli constantly present in the gut to maintain homeostasis 47 …”

“…This is in line with a previous study of our group, where macrophages showed reduced cytokine production after conditioning with fecal supernatants as compared to untreated cells. 47 Altogether, our results sustain the concept of the intestinal microenvironment educating the host to stay unresponsive to the load of bacterial stimuli constantly present in the gut to maintain homeostasis. 47 The fecal microbiota profiles differed between IBS patients and healthy subjects.…”

“…47 Altogether, our results sustain the concept of the intestinal microenvironment educating the host to stay unresponsive to the load of bacterial stimuli constantly present in the gut to maintain homeostasis. 47 The fecal microbiota profiles differed between IBS patients and healthy subjects. The taxa Proteobacteria, Pseudomonas spp., Dorea spp.…”

Gut microbiota from nCAL patients promotes colon anastomotic healing by inducing collagen synthesis in epithelial cells

“…Fecal supernatant aliquots were stored at À80°C for future use. 20 Rat treatments and fecal transplantation experiments. To elucidate the contribution of gut microbiota to CAL establishment, we performed FMT experiment in rat models.…”

Wu-Mei-Wan Ameliorates Murine Ulcerative Colitis by Regulating Macrophage Polarization

“…An increasing volume of evidence shows that macrophages play an important role in the pathogenesis and persistence of UC. It has been reported that macrophage polarization and changes in related signaling pathways have protective effects against intestinal inflammation ( De Schepper et al, 2018 ; Maasfeh et al, 2021 ). Macrophages can be transformed into classically activated (M1) macrophages or alternatively activated (M2) macrophages according to different environmental stimulus responses.…”