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Patients with ulcerative colitis (UC) who are in remission from their disease lack luminal signals capable of inducing macrophage hyporesponsiveness, which may contribute to a patient’s persistent vulnerability to relapse, according to a new study.
“Together with the distinct fecal metabolomic profile of UC patients in remission, our data suggest that UC patients may lack the signals required for proper macrophage education, rendering them vulnerable to relapse,” wrote study authors Lujain Maasfeh, PhD, of the University of Gothenburg (Sweden) and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
Macrophages found in the lamina propria play a role in sustaining intestinal homeostasis. Through education by local signals, intestinal macrophages adopt a hyporesponsive phenotype and tolerogenic nature and are replenished constantly from monocytes. In patients with UC who are in remission, however, the lack of proper macrophage maturation may result in gut inflammation.
Current evidence has yet to define fully the immunomodulating determinants in the education of intestinal macrophages; however, Dr. Maasfeh and associates wrote that “intestinal microbiota and microbiota-derived metabolites increasingly are recognized for their role in imprinting tissue-specific features of intestinal macrophages.”
The researchers added that previous evidence has established that patients with UC demonstrate dysbiosis, which may impact maturation of intestinal macrophages. As such, the hyporesponsive state of intestinal lamina propria macrophages induced by the microbiota may be lost in patients with UC who are in remission, ultimately resulting in disease relapse.
To gauge the effects of fecal luminal factors on macrophage phenotype and function, the researchers extracted fecal supernatants (FS) from the fecal samples of 10 healthy volunteers and 17 patients with UC who were in remission. Following maturation of monocytes to macrophages in the presence of granulocyte-macrophage colony-stimulating factor without and with FS, the researchers assessed macrophage phenotype and function. The investigators also used gas chromatography and mass spectrometry to analyze fecal metabolomic profiles.
In healthy donors, fecal luminal factors effectively downregulated Toll-like receptor signaling, cytokine signaling, as well as antigen presentation in macrophages. In contrast, the fecal luminal factors in patients with UC demonstrated less potency in their ability to induce lipopolysaccharide hyporesponsiveness. An immune pathway scoring analysis also showed a consistently higher reaction potential among UC remission FS-treated macrophages vs. healthy FS-treated macrophages.
While FS treatment did not seem to affect the phagocytic and bactericidal abilities of macrophages, the researchers observed that the healthy FS-treated macrophages better suppressed a cluster of differentiation 4+ T-cell activation as well as interferon gamma secretion vs. FS-treated macrophages from patients with UC in remission. The FS-treated macrophages in the UC remission population also featured less potency in their ability to suppress CD4+ T-cell activation and cytokine secretion.
The authors acknowledged a few limitations, including the small sample size and the effects from using in vitro system.
“Identification of the factors involved in intestinal macrophage education is important to maintain/reestablish gut homeostasis in patients with UC,” they concluded.
The study received financial support from Swedish Research Council-Medicine, in addition to funding from a Region Västra Götaland ALF-agreement, the Knut och Alice Wallenberg Foundation Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Ruth and Richard Julin’s foundation, Adlerbertska Foundation, Wilhelm and Martina Lundgren Foundation, and Apotekare Hedberg’s Foundation. The authors disclose no conflicts.
Current therapies for ulcerative colitis, including anti-inflammatory drugs and biologics such as anti–tumor necrosis factor therapies and anti-interleukin-12/23 antibodies, are aimed at inducing and maintaining remission. However, approximately 20%-40% of patients are primary nonresponders and about 23%-46% patients lose response within 12 months of treatment, which suggests an unmet need to look for new therapeutic targets.
Intestinal macrophages are essential in the maintenance of intestinal immune homeostasis by acquiring a hyporesponsive state in response to microbial stimuli. This study by Maasfeh and colleagues highlights the role of luminal factors in shaping the macrophage response. The authors show that human monocyte-derived macrophage treated with fecal luminal factors derived from patients with ulcerative colitis in remission are less hyporesponsive to lipopolysaccharide stimulation. They are also less efficient in modulating cytokine and Toll-like receptor signaling pathway genes and have a dampened ability to suppress CD4+ T-cell activation and interferon gamma secretion compared to controls.
Luminal factors derived from gut microbiota (short-chain fatty acids, indole derivatives, polyamines, and bile acids) can shape macrophage differentiation and antibacterial response. This study points toward key luminal factors, which might be playing pivotal roles in maintaining homeostasis. However, the current study needs further validation in a larger cohort of patients and in the lamina propria macrophages. In addition, it will be important to know the physiologically relevant concentration to achieve functional effect. The identification of specific metabolites responsible for inducing hyporesponsiveness in macrophages could be an approach for mining potential therapeutic targets.
Dr. Sumeet Pandey is in the Translational Gastroenterology Unit at John Radcliffe Hospital at the University of Oxford (England). He has no conflicts of interest.
Current therapies for ulcerative colitis, including anti-inflammatory drugs and biologics such as anti–tumor necrosis factor therapies and anti-interleukin-12/23 antibodies, are aimed at inducing and maintaining remission. However, approximately 20%-40% of patients are primary nonresponders and about 23%-46% patients lose response within 12 months of treatment, which suggests an unmet need to look for new therapeutic targets.
Intestinal macrophages are essential in the maintenance of intestinal immune homeostasis by acquiring a hyporesponsive state in response to microbial stimuli. This study by Maasfeh and colleagues highlights the role of luminal factors in shaping the macrophage response. The authors show that human monocyte-derived macrophage treated with fecal luminal factors derived from patients with ulcerative colitis in remission are less hyporesponsive to lipopolysaccharide stimulation. They are also less efficient in modulating cytokine and Toll-like receptor signaling pathway genes and have a dampened ability to suppress CD4+ T-cell activation and interferon gamma secretion compared to controls.
Luminal factors derived from gut microbiota (short-chain fatty acids, indole derivatives, polyamines, and bile acids) can shape macrophage differentiation and antibacterial response. This study points toward key luminal factors, which might be playing pivotal roles in maintaining homeostasis. However, the current study needs further validation in a larger cohort of patients and in the lamina propria macrophages. In addition, it will be important to know the physiologically relevant concentration to achieve functional effect. The identification of specific metabolites responsible for inducing hyporesponsiveness in macrophages could be an approach for mining potential therapeutic targets.
Dr. Sumeet Pandey is in the Translational Gastroenterology Unit at John Radcliffe Hospital at the University of Oxford (England). He has no conflicts of interest.
Current therapies for ulcerative colitis, including anti-inflammatory drugs and biologics such as anti–tumor necrosis factor therapies and anti-interleukin-12/23 antibodies, are aimed at inducing and maintaining remission. However, approximately 20%-40% of patients are primary nonresponders and about 23%-46% patients lose response within 12 months of treatment, which suggests an unmet need to look for new therapeutic targets.
Intestinal macrophages are essential in the maintenance of intestinal immune homeostasis by acquiring a hyporesponsive state in response to microbial stimuli. This study by Maasfeh and colleagues highlights the role of luminal factors in shaping the macrophage response. The authors show that human monocyte-derived macrophage treated with fecal luminal factors derived from patients with ulcerative colitis in remission are less hyporesponsive to lipopolysaccharide stimulation. They are also less efficient in modulating cytokine and Toll-like receptor signaling pathway genes and have a dampened ability to suppress CD4+ T-cell activation and interferon gamma secretion compared to controls.
Luminal factors derived from gut microbiota (short-chain fatty acids, indole derivatives, polyamines, and bile acids) can shape macrophage differentiation and antibacterial response. This study points toward key luminal factors, which might be playing pivotal roles in maintaining homeostasis. However, the current study needs further validation in a larger cohort of patients and in the lamina propria macrophages. In addition, it will be important to know the physiologically relevant concentration to achieve functional effect. The identification of specific metabolites responsible for inducing hyporesponsiveness in macrophages could be an approach for mining potential therapeutic targets.
Dr. Sumeet Pandey is in the Translational Gastroenterology Unit at John Radcliffe Hospital at the University of Oxford (England). He has no conflicts of interest.
Patients with ulcerative colitis (UC) who are in remission from their disease lack luminal signals capable of inducing macrophage hyporesponsiveness, which may contribute to a patient’s persistent vulnerability to relapse, according to a new study.
“Together with the distinct fecal metabolomic profile of UC patients in remission, our data suggest that UC patients may lack the signals required for proper macrophage education, rendering them vulnerable to relapse,” wrote study authors Lujain Maasfeh, PhD, of the University of Gothenburg (Sweden) and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
Macrophages found in the lamina propria play a role in sustaining intestinal homeostasis. Through education by local signals, intestinal macrophages adopt a hyporesponsive phenotype and tolerogenic nature and are replenished constantly from monocytes. In patients with UC who are in remission, however, the lack of proper macrophage maturation may result in gut inflammation.
Current evidence has yet to define fully the immunomodulating determinants in the education of intestinal macrophages; however, Dr. Maasfeh and associates wrote that “intestinal microbiota and microbiota-derived metabolites increasingly are recognized for their role in imprinting tissue-specific features of intestinal macrophages.”
The researchers added that previous evidence has established that patients with UC demonstrate dysbiosis, which may impact maturation of intestinal macrophages. As such, the hyporesponsive state of intestinal lamina propria macrophages induced by the microbiota may be lost in patients with UC who are in remission, ultimately resulting in disease relapse.
To gauge the effects of fecal luminal factors on macrophage phenotype and function, the researchers extracted fecal supernatants (FS) from the fecal samples of 10 healthy volunteers and 17 patients with UC who were in remission. Following maturation of monocytes to macrophages in the presence of granulocyte-macrophage colony-stimulating factor without and with FS, the researchers assessed macrophage phenotype and function. The investigators also used gas chromatography and mass spectrometry to analyze fecal metabolomic profiles.
In healthy donors, fecal luminal factors effectively downregulated Toll-like receptor signaling, cytokine signaling, as well as antigen presentation in macrophages. In contrast, the fecal luminal factors in patients with UC demonstrated less potency in their ability to induce lipopolysaccharide hyporesponsiveness. An immune pathway scoring analysis also showed a consistently higher reaction potential among UC remission FS-treated macrophages vs. healthy FS-treated macrophages.
While FS treatment did not seem to affect the phagocytic and bactericidal abilities of macrophages, the researchers observed that the healthy FS-treated macrophages better suppressed a cluster of differentiation 4+ T-cell activation as well as interferon gamma secretion vs. FS-treated macrophages from patients with UC in remission. The FS-treated macrophages in the UC remission population also featured less potency in their ability to suppress CD4+ T-cell activation and cytokine secretion.
The authors acknowledged a few limitations, including the small sample size and the effects from using in vitro system.
“Identification of the factors involved in intestinal macrophage education is important to maintain/reestablish gut homeostasis in patients with UC,” they concluded.
The study received financial support from Swedish Research Council-Medicine, in addition to funding from a Region Västra Götaland ALF-agreement, the Knut och Alice Wallenberg Foundation Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Ruth and Richard Julin’s foundation, Adlerbertska Foundation, Wilhelm and Martina Lundgren Foundation, and Apotekare Hedberg’s Foundation. The authors disclose no conflicts.
Patients with ulcerative colitis (UC) who are in remission from their disease lack luminal signals capable of inducing macrophage hyporesponsiveness, which may contribute to a patient’s persistent vulnerability to relapse, according to a new study.
“Together with the distinct fecal metabolomic profile of UC patients in remission, our data suggest that UC patients may lack the signals required for proper macrophage education, rendering them vulnerable to relapse,” wrote study authors Lujain Maasfeh, PhD, of the University of Gothenburg (Sweden) and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
Macrophages found in the lamina propria play a role in sustaining intestinal homeostasis. Through education by local signals, intestinal macrophages adopt a hyporesponsive phenotype and tolerogenic nature and are replenished constantly from monocytes. In patients with UC who are in remission, however, the lack of proper macrophage maturation may result in gut inflammation.
Current evidence has yet to define fully the immunomodulating determinants in the education of intestinal macrophages; however, Dr. Maasfeh and associates wrote that “intestinal microbiota and microbiota-derived metabolites increasingly are recognized for their role in imprinting tissue-specific features of intestinal macrophages.”
The researchers added that previous evidence has established that patients with UC demonstrate dysbiosis, which may impact maturation of intestinal macrophages. As such, the hyporesponsive state of intestinal lamina propria macrophages induced by the microbiota may be lost in patients with UC who are in remission, ultimately resulting in disease relapse.
To gauge the effects of fecal luminal factors on macrophage phenotype and function, the researchers extracted fecal supernatants (FS) from the fecal samples of 10 healthy volunteers and 17 patients with UC who were in remission. Following maturation of monocytes to macrophages in the presence of granulocyte-macrophage colony-stimulating factor without and with FS, the researchers assessed macrophage phenotype and function. The investigators also used gas chromatography and mass spectrometry to analyze fecal metabolomic profiles.
In healthy donors, fecal luminal factors effectively downregulated Toll-like receptor signaling, cytokine signaling, as well as antigen presentation in macrophages. In contrast, the fecal luminal factors in patients with UC demonstrated less potency in their ability to induce lipopolysaccharide hyporesponsiveness. An immune pathway scoring analysis also showed a consistently higher reaction potential among UC remission FS-treated macrophages vs. healthy FS-treated macrophages.
While FS treatment did not seem to affect the phagocytic and bactericidal abilities of macrophages, the researchers observed that the healthy FS-treated macrophages better suppressed a cluster of differentiation 4+ T-cell activation as well as interferon gamma secretion vs. FS-treated macrophages from patients with UC in remission. The FS-treated macrophages in the UC remission population also featured less potency in their ability to suppress CD4+ T-cell activation and cytokine secretion.
The authors acknowledged a few limitations, including the small sample size and the effects from using in vitro system.
“Identification of the factors involved in intestinal macrophage education is important to maintain/reestablish gut homeostasis in patients with UC,” they concluded.
The study received financial support from Swedish Research Council-Medicine, in addition to funding from a Region Västra Götaland ALF-agreement, the Knut och Alice Wallenberg Foundation Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Ruth and Richard Julin’s foundation, Adlerbertska Foundation, Wilhelm and Martina Lundgren Foundation, and Apotekare Hedberg’s Foundation. The authors disclose no conflicts.