Effect of fungal microbiota on RANKL and sclerostin in patients with Crohn's disease
Abstract
The etiology of Crohn's disease (CD) is still unknown. However, many factors, including a dysregulated immune system, altered microbiota, inheritance, and environmental factors, have been implicated. This work was conducted to estimate the effect of fungal microbiota on two bone mineral density markers, RANKL and sclerostin, in addition to the correlation between these markers and vitamin B12, D3, and zinc in CD patients, along with their potential effect on fungal microbiota and vice versa. Peripheral blood and carry-Blair Stool samples were collected from 88 participants (60 newly diagnosed with CD without treatment and 28 healthy controls) to detect serum levels of RANKL and sclerostin, and culture media were used to grow, isolate, and identify fungi attendant to CD and its effect on RANKL and sclerostin levels. Sociodemographic data (vitamin B12, D3, and zinc levels) were collected from patients' medical records. The results showed significant differences in RANKL and sclerostin levels in various types of fungal microbiota in CD patients along with a significant increase in RANKL and sclerostin levels in these patients. Moreover, RANKL levels were negatively significantly correlated with Zinc, while sclerostin levels correlated negatively with vit D3. The findings of this study suggest that fungal microbiota may play a role in the inflammatory process and interactions with bone density by affecting levels of RANKL and sclerostin, vitamin D3, and zinc, suggesting that the use of the fungal microbiota in the monitoring and treatment of CD patients.
References
- [1]Hasan AS, Alabassi HM, et al. The multifaceted role of dectin-1 and card9 in inflammatory bowel disease iraqi patients. History of Medicine. 2023;9:1763–88.
- [2]Ibraheem ZF, Muhsin HY. Roles of IL-36 in the pathogenesis of inflammatory bowel disease in a sample of iraqi patients. Pakistan Journal of Medical & Health Sciences. 2022;16:548-51.
- [3]Al-Abassi HM, Nazal MF, et al. Serum profile of cytokines in iraqi inflammatory bowel disease patients. Mustansiriya Medical Journal. 2015;14:11-6.
- [4]Targownik LE, Bernstein CN, et al. Inflammatory bowel disease and the risk of osteoporosis and fracture. Maturitas. 2013;76:315-9.
- [5]Jones K, Baker K, et al. Randomised clinical trial: Combined impact and resistance training in adults with stable crohn's disease. Alimentary pharmacology & therapeutics. 2020;52:964-75.
- [6]Chedid VG, Kane SV. Bone health in patients with inflammatory bowel diseases. Journal of Clinical Densitometry. 2020;23:182-9.
- [7]Chang JT. Pathophysiology of inflammatory bowel diseases. New England Journal of Medicine. 2020;383:2652-64.
- [8]Zhang I, Pletcher SD, et al. Fungal microbiota in chronic airway inflammatory disease and emerging relationships with the host immune response. Frontiers in Microbiology. 2017;8:2477.
- [9]Li Q, Wang C, et al. Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in crohn’s disease. Journal of clinical gastroenterology. 2014;48:513-23.
- [10]Hoarau G, Mukherjee P, et al. Bacteriome and mycobiome interactions underscore microbial dysbiosis in familial crohn’s disease. MBio. 2016;7:10.
- [11]Gouba N, Hien YE, et al. Digestive tract mycobiota and microbiota and the effects on the immune system. Human Microbiome Journal. 2019;12:100056.
- [12]Tu Y, Yang R, et al. The microbiota-gut-bone axis and bone health. Journal of leukocyte biology. 2021; 110(3), 525-537.
- [13]Lerner UH, Kindstedt E, et al. The critical interplay between bone resorbing and bone forming cells. Journal of clinical periodontology. 2019;46:33-51.
- [14]Naik S, Sahu S, et al. Serum levels of osteoprotegerin, rank-l & vitamin d in different stages of osteoarthritis of the knee. Indian Journal of Medical Research. 2021;154:491-6.
- [15]Ismael AK, Alabassi HM. The dynamic role of pd-1, vitamin d, rankl, and sclerostin in iraqi patients with systemic lupus erythematosus. Ibn AL-Haitham Journal For Pure and Applied Sciences. 2024;37:9-18.
- [16]Munir A, Reseland JE, et al. Osteocyte‐like cells differentiated from primary osteoblasts in an artificial human bone tissue model. Journal of Bone and Mineral Research Plus. 2023;7:e10792.
- [17]Oniszczuk A, Kaczmarek A, et al. Sclerostin as a biomarker of physical exercise in osteoporosis: A narrative review. Frontiers in endocrinology. 2022;13:954895.
- [18]Compton JT, Lee FY. A review of osteocyte function and the emerging importance of sclerostin. JBJS. 2014;96:1659-68.
- [19]Belal A, Mahmoud R, et al. Therapeutic potential of zeolites/vitamin b12 nanocomposite on complete freund’s adjuvant-induced arthritis as a bone disorder: In vivo study and bio-molecular investigations. Pharmaceuticals. 2023;16:285.
- [20]Rizzoli R, Biver E. Are probiotics the new calcium and vitamin d for bone health? Current osteoporosis reports. 2020;18:273-84.
- [21]Huang T, Yan G, et al. Zinc homeostasis in bone: Zinc transporters and bone diseases. International journal of molecular sciences. 2020;21:1236.
- [22]Granato PA, Granato PA. Laboratory manual and workbook in microbiology: Applications to patient care: McGraw-Hill; 2011.
- [23]Mohajan D, Mohajan HK. Body mass index (bmi) is a popular anthropometric tool to measure obesity among adults. Journal of Innovations in Medical Research. 2023;2:25-33.
- [24]Liguori G, Lamas B, et al. Fungal dysbiosis in mucosa-associated microbiota of crohn’s disease patients. Journal of Crohn's and Colitis. 2016;10:296-305.
- [25]Stamatiades GA, Ioannou P, et al. Fungal infections in patients with inflammatory bowel disease: A systematic review. Mycoses. 2018;61:366-76.
- [26]Wang H, Liu J, et al. Gut microbiota signatures and fecal metabolites in postmenopausal women with osteoporosis. Gut Pathogens. 2023;15:33.
- [27]Zhang J, Lu Y, et al. The impact of the intestinal microbiome on bone health. Intractable & rare diseases research. 2018;7:148-55.
- [28]Sylvester FA. Inflammatory bowel disease: Effects on bone and mechanisms. Understanding the Gut-Bone Signaling Axis: Mechanisms and Therapeutic Implications. 2017:133-50.
- [29]Chen Y, Wang X, et al. Gut microbiota and bone diseases: A growing partnership. Frontiers in Microbiology. 2022;13:877776.
- [30]Schett G. Effects of inflammatory and anti‐inflammatory cytokines on the bone. European journal of clinical investigation. 2011;41:1361-6.
- [31]Palatianou ME, Karamanolis G, et al. Signaling pathways associated with bone loss in inflammatory bowel disease. Annals of Gastroenterology. 2023;36:132.
- [32]Onal M, Xiong J, et al. Receptor activator of nuclear factor κb ligand (rankl) protein expression by b lymphocytes contributes to ovariectomy-induced bone loss. Journal of Biological Chemistry. 2012;287:29851-60.
- [33]Jridi I, Canté-Barrett K, et al. Inflammation and wnt signaling: Target for immunomodulatory therapy? Frontiers in cell and developmental biology. 2021;8:615131.
- [34]Chin K-Y, Ekeuku SO, et al. Sclerostin in the development of osteoarthritis: A mini review. The Malaysian Journal of Pathology. 2022;44:1-18.
- [35]Luchetti MM, Ciccia F, et al. Sclerostin and antisclerostin antibody serum levels predict the presence of axial spondyloarthritis in patients with inflammatory bowel disease. The Journal of rheumatology. 2018;45:630-7.
- [36]Briot K, Geusens P, et al. Inflammatory diseases and bone fragility. Osteoporosis International. 2017;28:3301-14.
- [37]Sgambato D, Gimigliano F, et al. Bone alterations in inflammatory bowel diseases. World journal of clinical cases. 2019;7:1908.
- [38]Fernandez-Roldan C, Genre F, et al. Sclerostin serum levels in patients with systemic autoimmune diseases. BoneKEy reports. 2016;5.
- [39]Li Q, Wang C, et al. Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in Crohn’s disease. Journal of clinical gastroenterology. 2014; 48(6), 513-523
- [40]Hardy R, Cooper MS. Bone loss in inflammatory disorders. Journal of Endocrinology, 2009;201(3), 309-320.
- [41]Duffuler P, Bhullar KS et al. Targeting gut microbiota in osteoporosis: Impact of the microbial-based functional food ingredients. Food Science and Human Wellness.2024;13(1), 1-15..
- [42]Nielsen OH, Rejnmark L, et al. Role of vitamin d in the natural history of inflammatory bowel disease. Journal of Crohn's and Colitis. 2018;12:742-52.
- [43]Luthold RV, Fernandes GR, et al. Gut microbiota interactions with the immunomodulatory role of vitamin d in normal individuals. Metabolism. 2017;69:76-86.
- [44]Kim J-H, Kim AR, et al. Tumor necrosis factor-α antagonist diminishes osteocytic rankl and sclerostin expression in diabetes rats with periodontitis. PLoS One. 2017;12:e0189702.
- [45]Bafutto M, Oliveira EC, et al. Use of vitamin d with anti-tumor necrosis factor therapy for crohn’s disease. Gastroenterology Research. 2020;13:101.
- [46]Weyh C, Krüger K, et al. The role of minerals in the optimal functioning of the immune system. Nutrients. 2022;14:644.
- [47]Siva S, Rubin DT, et al. Zinc deficiency is associated with poor clinical outcomes in patients with inflammatory bowel disease. Inflammatory Bowel Diseases. 2017;23:152-7.
- [48]Amin N, Clark CC, et al. Zinc supplements and bone health: The role of the rankl-rank axis as a therapeutic target. Journal of Trace Elements in Medicine and Biology. 2020;57:126417.