Gut Microbiota, Tryptophan Metabolism, Quality of Life, Psychoemotional and Cognitive Impairments in Functional Constipation

Aim: to investigate the relationship between tryptophan metabolism features, gut microbiota composition, systemic inflammation markers, cortisol levels, quality of life, and psychoemotional and cognitive status in female patients with functional constipation (FC).
Materials and methods. The study included 64 female patients with FC and 26 age- and BMI-matched women without FC (p > 0.05). All participants underwent assessment of gut microbiota composition in stool samples (via 16S rRNA sequencing), health-related quality of life (SF-36), psychoemotional status (4DSQ, Spielberger — Hanin test, Hamilton scale), and cognitive function (BACS cognitive tests). Tryptophan metabolism was evaluated by measuring levels of interleukin-1β, cortisol, brain-derived neurotrophic factor (BDNF), tryptophan, kynurenine, kynurenic acid, and serum and platelet serotonin.
Results. Compared to women without FC, female patients with FC had higher levels of cortisol (325 [266; 403] vs. 275 [255; 304] nmol/L; p = 0.025), interleukin-1β (10.0 [9.2; 11.2] vs. 7.2 [6.5; 7.8] pg/mL; p < 0.001), and blood kynurenine (0.65 [0.54; 0.82] vs. 0.44 [0.35; 0.48] μg/mL; p < 0.001), as well as lower plasma serotonin levels (108 [85; 134] vs. 163 [117; 190] ng/mL; p < 0.001). No differences were found between groups in plasma tryptophan, BDNF, kynurenic acid, or platelet serotonin. Patients with FC exhibited more pronounced depression (Hamilton scale: 8 [6; 9] vs. 3 [2; 3] points; p < 0.001) and somatization (9 [7; 12] vs. 5 [3; 9] points; p < 0.001); lower cognitive function scores (50 [45; 54] vs. 54 [53; 56] points; p < 0.001), particularly in auditory-verbal memory (p < 0.001) and information processing speed (p < 0.001); and reduced quality of life (SF-36) in physical functioning (90 [83; 95] vs. 95 [95; 95] points; p < 0.001) and bodily pain (60 [50; 70] vs. 75 [56; 85] points; p < 0.001). Cortisol levels positively correlated with bodily pain (r = 0.379; p = 0.003), while interleukin-1β levels inversely correlated with bodily pain (r = –0.391; p = 0.002), physical functioning (r = –0.448; p < 0.001), and verbal memory (r = –0.252; p = 0.046), and positively correlated with depression (r = 0.311; p = 0.013) and somatization (r = 0.266; p = 0.035). Cortisol levels correlated positively with Oscillospira (r = 0.45; p = 0.01), while kynurenine levels correlated with Alistipes (r = 0.36; p = 0.04) abundance. Plasma serotonin positively correlated with Haemophilus (r = 0.37; p = 0.03) and inversely with Bacteroides plebeius (r = –0.40; p = 0.02) abundance. Physical functioning (SF-36) positively correlated with Lachnospiraceae NK4B4 group (r = 0.35; p = 0.04), while depression severity (4DSQ) inversely correlated with Alistipes abundance (r = –0.37; p = 0.03). Information processing speed is inversely correlated with abundance of Bacilli (r = –0.48; p = 0.004), Lactobacillales (r = –0.48; p = 0.004), Pasteurellales (r = –0.36; p = 0.03), Pasteurellaceae (r = –0.36; p = 0.03), Streptococcaceae (r = –0.47; p = 0.006), Haemophilus (r = –0.41; p = 0.02), and Streptococcus (r = –0.38; p = 0.02).
Conclusion. The findings indicate that women with functional constipation exhibit altered tryptophan metabolism and gut microbiota dysbiosis, associated with depression, somatization, cognitive impairment, and reduced health-related quality of life.

1. Mearin F., Lacy B.E., Chang L., Chey W.D., Lembo A.J., Simren M., et al. Bowel disorders. Gastroenterology. 2016; S0016-5085(16)00222-5. DOI: 10.1053/j.gastro.2016.02.031

2. Tomita T., Kazumori K., Baba K., Zhao X., Chen Y., Miwa H. Impact of chronic constipation on health-related quality of life and work productivity in Japan. J Gastroenterol Hepatol. 2021;36(6):1529–37. DOI: 10.1111/jgh.15295

3. Liang J., Zhao Y., Xi Y., Xiang C., Yong C., Huo J., et al. Association between depression, anxiety symptoms and gut microbiota in Chinese elderly with functional constipation. Nutrients. 2022;14(23):5013. DOI: 10.3390/nu14235013

4. Salvadori M., Rosso G. Update on the gut microbiome in health and diseases. World J Methodol. 2024;14(1):89196. DOI: 10.5662/wjm.v14.i1.89196

5. Hou K., Wu Z.X., Chen X.Y., Wang J.Q., Zhang D., Xiao C., et al. Microbiota in health and diseases. Signal Transduct Target Ther. 2022;7(1):135. DOI: 10.1038/s41392-022-00974-4

6. Cao H., Liu X., An Y., Zhou G., Liu Y., Xu M., et al. Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine. Sci Rep. 2017;7(1):10322. DOI: 10.1038/s41598-017-10835-8

7. Yang C., Hu T., Xue X., Su X., Zhang X., Fan Y., et al. Multi-omics analysis of fecal microbiota transplantation’s impact on functional constipation and comorbid depression and anxiety. BMC Microbiol. 2023;23(1):389. DOI: 10.1186/s12866-023-03123-1

8. Kolobaric A., Andreescu C., Jašarević E., Hong C.H., Roh H.W., Cheong J.Y., et al. Gut microbiome predicts cognitive function and depressive symptoms in late life. Mol Psychiatry. 2024;29(10):3064–75. DOI: 10.1038/s41380-024-02551-3

9. Ivashkin V.T., Shelygin Yu.A., Maev I.V., Sheptulin A.A., Aleshin D.V., Achkasov S.I., et al. Clinical Recommendations of the Russian Gastroenterological Association and Association of Coloproctologists of Russia on Diagnosis and Treatment of Constipation in Adults. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(6):69–85. (In Russ.)]. DOI: 10.22416/1382-4376-2020-30-6-69-85

10. Waclawiková B., Codutti A., Alim K., El Aidy S. Gut microbiota-motility interregulation: Insights from in vivo, ex vivo and in silico studies. Gut Microbes. 2022;14(1):1997296. DOI: 10.1080/19490976.2021.1997296

11. Ivashkin V.T., Fomin V.V., Tkacheva O.N., Medvedev O.S., Poluektova E.A., Abdulganieva D.I., et al. Small intestinal bacterial overgrowth in various specialties of medical practice (literature review and Expert Council resolution). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2024;34(2):14– 34. (In Russ.)]. DOI: 10.22416/1382-4376-2024-954

12. Browning K.N., Travagli R.A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr Physiol. 2014;4(4):1339–68. DOI: 10.1002/cphy.c130055

13. Chojnacki C., Błońska A., Konrad P., Chojnacki M., Podogrocki M., Poplawski T. Changes in tryptophan metabolism on serotonin and kynurenine pathways in patients with irritable bowel syndrome. Nutrients. 2023;15(5):1262. DOI: 10.3390/nu15051262

14. Zhu Q., Wan L., Huang H., Liao Z. IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment? Front Neurosci. 2024;18:1370406. DOI: 10.3389/fnins.2024.1370406

15. Santi N.S., Biswal S.B., Naik B.N., Sahoo J.P., Rath B. Comparison of Hamilton Depression Rating Scale and Montgomery-Åsberg Depression Rating Scale: Baked straight from a randomized study. Cureus. 2023;15(9):e45098. DOI: 10.7759/cureus.45098

16. Zhang Y.L., Li Z.J., Gou H.Z., Song X.J., Zhang L. The gut microbiota-bile acid axis: A potential therapeutic target for liver fibrosis. Front Cell Infect Microbiol. 2022;12:945368. DOI: 10.3389/fcimb.2022.945368

17. Vincent A.D., Wang X.Y., Parsons S.P., Khan W.I., Huizinga J.D. Abnormal absorptive colonic motor activity in germ-free mice is rectified by butyrate, an effect possibly mediated by mucosal serotonin. Am J Physiol Gastrointest Liver Physiol. 2018;315(5):G896–907. DOI: 10.1152/ajpgi.00237.2017

18. Losol P., Wolska M., Wypych T.P., Yao L., O'Mahony L., Sokolowska M. A cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases. Clin Transl Allergy. 2024;14(2):e12339. DOI: 10.1002/clt2.12339

19. Maslennikov R., Ivashkin V., Efremova I., Alieva A., Kashuh E., Tsvetaeva E., et al. Gut dysbiosis is associated with poorer long-term prognosis in cirrhosis. World J Hepatol. 2021;13(5):557–70. DOI: 10.4254/wjh.v13.i5.557

20. Cheng J., Hu H., Ju Y., Liu J., Wang M., Liu B., et al. Gut microbiota-derived short-chain fatty acids and depression: Deep insight into biological mechanisms and potential applications. Gen Psychiatr. 2024;37(1):e101374. DOI: 10.1136/gpsych-2023-101374

21. Alemi F., Poole D.P., Chiu J., Schoonjans K., Cattaruzza F., Grider J.R., et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology. 2013;144(1):145–54. DOI: 10.1053/j.gastro.2012.09.055

22. Oluwagbemigun K., Schnermann M.E., Schmid M., Cryan J.F., Nöthlings U. A prospective investigation into the association between the gut microbiome composition and cognitive performance among healthy young adults. Gut Pathog. 2022;14(1):15. DOI: 10.1186/s13099-022-00487-z

23. Martín R., Rios-Covian D., Huillet E., Auger S., Khazaal S., Bermúdez-Humarán L.G., et al. Faecalibacterium: A bacterial genus with promising human health applications. FEMS Microbiol Rev. 2023;47(4):fuad039. DOI: 10.1093/femsre/fuad039

24. Dinh D.M., Volpe G.E., Duffalo C., Bhalchandra S., Tai A.K., Kane A.V., et al. Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. J Infect Dis. 2015;211(1):19–27. DOI: 10.1093/infdis/jiu409

25. Chen Y.R., Zheng H.M., Zhang G.X., Chen F.L., Chen L.D., Yang Z.C. High Oscillospira abundance indicates constipation and low BMI in the Guangdong Gut Microbiome Project. Sci Rep. 2020;10(1):9364. DOI: 10.1038/s41598-020-66369-z