Gut-derived serotonin contributes to bone deficits in colitis

Lavoie, Brigitte; Roberts, Jane; Haag, Melody M; Spohn, Stephanie N.; Margolis, Kara Gross; Sharkey, Keith A.; Lian, Jane B.; Mawe, Gary M.

doi:10.1016/j.phrs.2018.07.018

Cited by 20 publications

(17 citation statements)

References 41 publications

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“…Conversely, inhibition of gutderived serotonin might become a treatment option for osteoporosis. These findings are now experimentally observed in animal studies, and corroboration of these findings in humans is awaited [45,46].…”

Section: Introductionmentioning

confidence: 56%

Perspective on skeletal health in inflammatory bowel disease

Bodegraven

Bravenboer

2019

Osteoporos Int

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Osteopenia and osteoporosis are common features in inflammatory bowel disease (IBD), comprising both Crohn's disease and ulcerative colitis. Moreover, Crohn's disease is associated with increased fracture risk. The etiology of bone loss in IBD is multifactorial. It includes insufficient intake or absorption of calcium, vitamin D, and potassium; smoking; a low peak bone mass; a low body mass index; and decreased physical activity. In several studies, it has been shown that elevated concentrations of systemic and local pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon-γ (IFNγ), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-13, and IL-17, present in IBD patients are potentially detrimental for bone metabolism and may be responsible for bone loss and increased fracture risk. This perspective aims to review the current literature on the role of inflammatory factors in the pathophysiology of skeletal problems in IBD and to suggest potential treatment to improve bone health, based on a combination of evidence and clinical and pathophysiological reasoning.

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Section: Introductionmentioning

confidence: 56%

Perspective on skeletal health in inflammatory bowel disease

Bodegraven

Bravenboer

2019

Osteoporos Int

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“…25 To date, only 1 study has reported a potential link between high GDS levels and bone deficits in DSS model of colitis. 26 However in this study, authors reported GDS-mediated effects on bone pathology only for 21 days of colitis. Unlike studies in models of chemically induced colitis, Winnie mouse model permits bone studies for the long-term, throughout the chronic disease course for up to approximately 6 to 7 months, thus, mimicking the onset and progression of UC.…”

Section: Introductionmentioning

confidence: 60%

“…This alteration in bone microarchitecture is in agreement with earlier reports in a model of DSS-induced colitis. 11,26 Biomechanical studies have demonstrated that the structural properties of whole-bone specimens are highly determined by the contribution of cortical bone. 47 To understand the quality and strength of cortical bone compartments, we subjected bones from Winnies and controls to a 3-point bending test to determine ultimate force (the maximum force that breaks the bone).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Skeletal Phenotype and Associated Mechanisms With Chronic Intestinal Inflammation in theWinnieMouse Model of Spontaneous Chronic Colitis

Saedi

Hassan

et al. 2021

Inflammatory Bowel Diseases

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Background Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, studies have been scarce, mainly because of the lack of an appropriate animal model of colitis-associated bone loss. In this study, we aimed to decipher skeletal manifestations in the Winnie mouse model of spontaneous chronic colitis, which carries a MUC2 gene mutation and closely replicates ulcerative colitis. In our study, Winnie mice, prior to the colitis onset at 6 weeks old and progression at 14 and 24 weeks old, were compared with age-matched C57BL/6 controls. We studied several possible mechanisms involved in colitis-associated bone loss. Methods We assessed for bone quality (eg, microcomputed tomography [micro-CT], static and dynamic histomorphometry, 3-point bending, and ex vivo bone marrow analysis) and associated mechanisms (eg, electrochemical recordings for gut-derived serotonin levels, real-time polymerase chain reaction [qRT-PCR], double immunofluorescence microscopy, intestinal inflammation levels by lipocalin-2 assay, serum levels of calcium, phosphorus, and vitamin D) from Winnie (6–24 weeks) and age-matched C57BL6 mice. Results Deterioration in trabecular and cortical bone microarchitecture, reductions in bone formation, mineral apposition rate, bone volume/total volume, osteoid volume/bone surface, and bone strength were observed in Winnie mice compared with controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice compared with controls. Upregulation of 5-HTR1B gene and increased association of FOXO1 with ATF4 complex were identified as associated mechanisms concomitant to overt inflammation and high levels of gut-derived serotonin in 14-week and 24-week Winnie mice. Conclusions Skeletal phenotype of the Winnie mouse model of spontaneous chronic colitis closely represents manifestations of IBD-associated osteoporosis/osteopenia. The onset and progression of intestinal inflammation are associated with increased gut-derived serotonin level, increased bone resorption, and decreased bone formation.

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“…24 To date, only one study has reported a potential link between high GDS levels and bone deficits in DSS model. 25 However, in this study GDS-mediated effects on bone pathology have been revealed for 21 days of colitis only. Interestingly, a high level of GDS is prominent in Winnie mice.…”

Section: Mouse Models Have Been Widely Used To Understand Pathophysiomentioning

confidence: 74%

“…Consistently, Lavoie et al (2019) demonstrated deleterious effect on bone caused by high GDS levels in the DSS model of colitis. 25 It has been speculated that GDS triggers immune cells for the production of proinflammatory mediators in the context of intestinal inflammation and inflammatory joint diseases. 24,38 Likewise, GDS may have a pro-inflammatory role in causing bone loss in colitis.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Phenotype and Mechanisms of Bone Loss inWinnieMice as a Model for Inflammatory Bowel Disease

Saedi

Hassan

et al. 2020

Preprint

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ObjectiveWe aimed to investigate the skeletal phenotype of Winnie mouse model of spontaneous chronic colitis, which carries a mutation in the Muc2 gene and closely replicates IBD symptoms and pathophysiology. These mice have a high level of gut-derived serotonin (GDS), a potent osteoblastogenesis inhibitor. We explored the underlying mechanisms of bone loss associated with chronic intestinal inflammation.DesignWinnie male and female mice prior to colitis onset (6 weeks old) and progression (14 and 24 weeks) were compared to age- and sex-matched C57BL/6 controls. We assessed bone quality (static and dynamic histomorphometry, micro-CT, 3-point bending), intestinal inflammation (lipocalin-2), GDS levels, serum levels of calcium, phosphorus and vitamin D, ex vivo bone marrow analysis and molecular mechanisms inhibiting osteoblastogenesis.ResultsSignificant deterioration in trabecular and cortical microarchitecture, reductions in bone formation, mineral apposition rate, bone volume, osteoid volume and bone strength were observed in Winnie mice compared to C57BL/6 controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice. We report for the first time that elevated GDS cross-talks with molecular pathways to inhibit bone formation in Winnie mice. Increased expression of 5-HTR1B and FOXO1 mRNAs, dissociation of FOXO1/CREB1 complex and association of FOXO1 with ATF4, promoting the transcriptional activity of FOXO1, results in suppression of osteoblast proliferation in Winnie mice compared to controls.ConclusionThese findings open avenues for the development of targeted therapies for IBD-related bone loss.Significance of this studyWhat is already known on this subject?- Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD).- Currently available treatments are not effective for IBD-associated bone loss.- The mechanisms of bone loss are poorly understood. A major limitation has been the lack of an appropriate animal model for IBD-associated bone loss.What are the new findings?- We report for the first-time the skeletal phenotype in Winnie mouse model of IBD- This study presents a novel mechanism of IBD-associated bone loss, involving elevated gut-derived serotonin crosstalk with molecular pathways inhibiting bone formation.How might it impact on clinical practice in the foreseeable future- These findings open avenues for the development of targeted therapies for IBD-related bone loss.

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Gut-derived serotonin contributes to bone deficits in colitis

Cited by 20 publications

References 41 publications

Perspective on skeletal health in inflammatory bowel disease

Perspective on skeletal health in inflammatory bowel disease

Characterization of Skeletal Phenotype and Associated Mechanisms With Chronic Intestinal Inflammation in theWinnieMouse Model of Spontaneous Chronic Colitis

Skeletal Phenotype and Mechanisms of Bone Loss inWinnieMice as a Model for Inflammatory Bowel Disease

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