The Effect of Body Mass Index on the KYN/TRP Pathway in the Pathogenesis of Periodontitis

Abstract

ABSTRACT Purpose: The tryptophan–kynurenine (TRP-KYN) pathway is associated with inflammation and kynurenine pathway (KP) dysregulation is present in overweight and obesity. Meanwhile, obesity and periodontitis are two of the most frequent noncommunicable illnesses, and epidemiological studies show that obesity has a role in the initiation and progression of periodontitis. However, the association between elevated body mass index and KP on periodontal disease etiology is unknown. As a result, our study is aimed to investigate the possible relationship within TRP/KYN ratio and BMI relationship in periodontitis. Materials & Method: The study comprised 20 periodontitis patients (P, Generalized Stage III Grade B, n=20) and 20 healthy persons (C, n=20). Clinical parameters (Bleeding index on probing (BOP), clinical attachment loss (CAL) and pocket depth (PD)), and BMI were recorded at the beginning of the study. Salivary and serum KYN/TRP ratios were analyzed by using mass spectrometry–liquid chromatography (LC-MS/MS). Results: Clinical periodontal parameters were statistically significantly higher in P group than in C group (p<0.05). While there was no change in serum KYN/TRP ratio across groups, salivary KYN/TRP ratio decreased in Group P compared with Group C (p<0.05). The salivary KYN/TRP ratio was positively correlated with the serum KYN/TRP ratio, while it showed a strong negative correlation with BOP, moderate correlation with PD and CAL, and lower negative correlation with BMI. Conclusion: KP dysregulation due to obesity may increase the risk of developing periodontal disease. Key Words: Periodontitis, Obesity, BMI, KYN/TRP, Tryptophan, Kynurenine

Keywords

• Periodontitis
• Obesity
• BMI
• KYN/TRP
• Tryptophan
• Kynurenine

References

1. 1. Schröcksnadel, K., Wirleitner, B., Winkler, C. & Fuchs, D. Monitoring tryptophan metabolism in chronic immune activation. Clinica chimica acta 364, 82-90 (2006).
2. 2. Widner, B., Laich, A., Sperner-Unterweger, B., Ledochowski, M. & Fuchs, D. Neopterin production, tryptophan degradation, and mental depression—what is the link? Brain, behavior, and immunity 16, 590-595 (2002).
3. 3. Leklem, J.E. Quantitative aspects of tryptophan metabolism in humans and other species: a review. The American journal of clinical nutrition 24, 659-672 (1971).
4. 4. Chen, Y. & Guillemin, G.J. Kynurenine pathway metabolites in humans: disease and healthy states. International journal of tryptophan research 2, IJTR. S2097 (2009).
5. 5. Van der Goot, A.T. & Nollen, E.A. Tryptophan metabolism: entering the field of aging and age-related pathologies. Trends in molecular medicine 19, 336-344 (2013).
6. 6. Wang, Y. et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature medicine 16, 279-285 (2010).
7. 7. Wang, Q. et al. Activation of NAD (P) H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo. Circulation research 114, 480-492 (2014).
8. 8. Mangge, H. et al. Disturbed tryptophan metabolism in cardiovascular disease. Current medicinal chemistry 21, 1931-1937 (2014).

9. 9. Nisapakultorn, K. et al. Indoleamine 2, 3‐dioxygenase expression and regulation in chronic periodontitis. Journal of periodontology 80, 114-121 (2009).
10. 10. Moon, J. et al. Lipopolysaccharide‐induced indoleamine 2, 3‐dioxygenase expression in the periodontal ligament. Journal of periodontal research 48, 733-739 (2013).
11. 11. Jones, S.P., Guillemin, G.J. & Brew, B.J. The kynurenine pathway in stem cell biology. International Journal of Tryptophan Research 6, IJTR. S12626 (2013).
12. 12. Monasterio, G. et al. IL‐22–expressing CD 4+ AhR+ T lymphocytes are associated with RANKL‐mediated alveolar bone resorption during experimental periodontitis. Journal of Periodontal Research 54, 513-524 (2019).
13. 13. Mondanelli, G. et al. Positive allosteric modulation of indoleamine 2, 3-dioxygenase 1 restrains neuroinflammation. Proceedings of the National Academy of Sciences 117, 3848-3857 (2020).
14. 14. Lovelace, M.D. et al. Current evidence for a role of the kynurenine pathway of tryptophan metabolism in multiple sclerosis. Frontiers in Immunology 7, 246 (2016).
15. 15. Cihan, M. et al. Kynurenine pathway in Coronavirus disease (COVID‐19): potential role in prognosis. Journal of Clinical Laboratory Analysis 36, e24257 (2022).
16. 16. Guillemin, G.J. Quinolinic acid, the inescapable neurotoxin. The FEBS journal 279, 1356-1365 (2012).
17. 17. Arboleda, S., Vargas, M., Losada, S. & Pinto, A. Review of obesity and periodontitis: an epidemiological view. British dental journal 227, 235-239 (2019).
18. 18. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860-867 (2006).
19. 19. Blüher, M. Adipose tissue dysfunction in obesity. Experimental and clinical endocrinology & diabetes, 241-250 (2009).
20. 20. Maury, E. & Brichard, S. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Molecular and cellular endocrinology 314, 1-16 (2010).
21. 21. De Heredia, F.P., Gómez-Martínez, S. & Marcos, A. Obesity, inflammation and the immune system. Proceedings of the Nutrition Society 71, 332-338 (2012).
22. 22. Lischka, J. et al. A branched‐chain amino acid‐based metabolic score can predict liver fat in children and adolescents with severe obesity. Pediatric obesity 16, e12739 (2021).
23. 23. Stone, T.W., McPherson, M. & Darlington, L.G. Obesity and cancer: existing and new hypotheses for a causal connection. EBioMedicine 30, 14-28 (2018).
24. 24. Bernard, A. et al. The tryptophan/kynurenine pathway: A novel cross-talk between nutritional obesity, bariatric surgery and taste of fat. Nutrients 13, 1366 (2021).
25. 25. Liu, J.-J., Movassat, J. & Portha, B. Emerging role for kynurenines in metabolic pathologies. Current Opinion in Clinical Nutrition & Metabolic Care 22, 82-90 (2019).
26. 26. Badawy, A.A. & Guillemin, G. The plasma [kynurenine]/[tryptophan] ratio and indoleamine 2, 3-dioxygenase: time for appraisal. International Journal of Tryptophan Research 12, 1178646919868978 (2019).
27. 27. Wang, Q., Liu, D., Song, P. & Zou, M.-H. Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Front Biosci (Landmark Ed) 20, 1116-1143 (2015).
28. 28. Miura, H. et al. A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress 11, 198-209 (2008).
29. 29. Sforzini, L., Nettis, M.A., Mondelli, V. & Pariante, C.M. Inflammation in cancer and depression: a starring role for the kynurenine pathway. Psychopharmacology 236, 2997-3011 (2019).
30. 30. Chaves Filho, A.J.M. et al. IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity. Progress in Neuro-Psychopharmacology and Biological Psychiatry 80, 234-249 (2018).
31. 31. Dounay, A.B., Tuttle, J.B. & Verhoest, P.R. Challenges and opportunities in the discovery of new therapeutics targeting the kynurenine pathway. Journal of medicinal chemistry 58, 8762-8782 (2015).
32. 32. Kurgan, Ş. et al. Influence of periodontal inflammation on tryptophan-kynurenine metabolism: a cross-sectional study. Clinical Oral Investigations 26, 5721-5732 (2022).
33. 33. Tonetti, M.S., Greenwell, H. & Kornman, K.S. Staging and grading of periodontitis: Framework and proposal of a new classification and case definition. Journal of periodontology 89, S159-S172 (2018).
34. 34. Önder, C. et al. Impact of non-surgical periodontal therapy on saliva and serum levels of markers of oxidative stress. Clinical Oral Investigations 21, 1961-1969 (2017).
35. 35. Di Gangi, I.M. et al. Simultaneous quantitative determination of NG, NG-dimethyl-l-arginine or asymmetric dimethylarginine and related pathway's metabolites in biological fluids by ultrahigh-performance liquid chromatography/electrospray ionization-tandem mass spectrometry. Analytica chimica acta 677, 140-148 (2010).
36. 36. Taylor, M.W. & Feng, G. Relationship between interferon‐γ, indoleamine 2, 3‐dioxygenase, and tryptophan catabolism. The FASEB Journal 5, 2516-2522 (1991).
37. 37. Badawy, A.A.-B. & Dougherty, D.M. Assessment of the human kynurenine pathway: comparisons and clinical implications of ethnic and gender differences in plasma tryptophan, kynurenine metabolites, and enzyme expressions at baseline and after acute tryptophan loading and depletion. International Journal of Tryptophan Research 9, IJTR. S38189 (2016).
38. 38. Sorgdrager, F.J., Naudé, P.J., Kema, I.P., Nollen, E.A. & Deyn, P.P.D. Tryptophan metabolism in inflammaging: from biomarker to therapeutic target. Frontiers in Immunology 10, 2565 (2019).
39. 39. Choera, T., Zelante, T., Romani, L. & Keller, N.P. A multifaceted role of tryptophan metabolism and indoleamine 2, 3-dioxygenase activity in Aspergillus fumigatus–host interactions. Frontiers in immunology 8, 1996 (2018).
40. 40. Correale, J. Immunosuppressive amino-acid catabolizing enzymes in multiple sclerosis. Frontiers in Immunology 11, 600428 (2021).
41. 41. Zeng, Q. et al. Shikonin prolongs allograft survival via induction of CD4+ FoxP3+ regulatory T cells. Frontiers in immunology 10, 652 (2019).
42. 42. Hao, T. et al. Porphyromonas gingivalis infection promotes inflammation via inhibition of the AhR signalling pathway in periodontitis. Cell Proliferation 56, e13364 (2023).
43. 43. Palm, E., Khalaf, H. & Bengtsson, T. Suppression of inflammatory responses of human gingival fibroblasts by gingipains from Porphyromonas gingivalis. Molecular oral microbiology 30, 74-85 (2015).
44. 44. Fuchs, D. et al. Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. Immunology letters 28, 207-211 (1991).
45. 45. Schroecksnadel, K., Winkler, C., Fuith, L.C. & Fuchs, D. Tryptophan degradation in patients with gynecological cancer correlates with immune activation. Cancer letters 223, 323-329 (2005).
46. 46. Barrington, G. et al. Obesity, dietary sugar and dental caries in Australian adults. International dental journal 69, 383-391 (2019).
47. 47. Khan, S. et al. Obesity and periodontitis in Australian adults: a population-based cross-sectional study. International dental journal 70, 53-61 (2020).
48. 48. Ylöstalo, P., Suominen‐Taipale, L., Reunanen, A. & Knuuttila, M. Association between body weight and periodontal infection. Journal of clinical periodontology 35, 297-304 (2008).
49. 49. Nascimento, G.G., Leite, F.R., Correa, M.B., Peres, M.A. & Demarco, F.F. Does periodontal treatment have an effect on clinical and immunological parameters of periodontal disease in obese subjects? A systematic review and meta-analysis. Clinical oral investigations 20, 639-647 (2016).
50. 50. Atabay, V., Lutfioğlu, M., Avci, B., Sakallioglu, E. & Aydoğdu, A. Obesity and oxidative stress in patients with different periodontal status: a case–control study. Journal of periodontal research 52, 51-60 (2017).
51. 51. Palle, A.R. et al. Association between obesity and chronic periodontitis: a cross-sectional study. The journal of contemporary dental practice 14, 168 (2013).
52. 52. Kang, J., Smith, S., Pavitt, S. & Wu, J. Association between central obesity and tooth loss in the non‐obese people: results from the continuous National Health and Nutrition Examination Survey (NHANES) 1999–2012. Journal of Clinical Periodontology 46, 430-437 (2019).
53. 53. Mangge, H. et al. Obesity‐related dysregulation of the Tryptophan–Kynurenine metabolism: Role of age and parameters of the metabolic syndrome. Obesity 22, 195-201 (2014).