Impact of Prucalopride and Multi-Strain Probiotic on Symptoms, Gut Microbiota Composition, Psychoemotional Status, Cognitive Function, and Quality of Life in Female Patients with Functional Constipation

Aim: to investigate the interrelationships between the severity of clinical symptoms, features of tryptophan metabolism, gut microbiota composition, quality of life, psychoemotional and cognitive status in female patients with functional constipation (FC), and to assess the ability of prucalopride as monotherapy and in combination with a multistrain probiotic to influence these parameters.

Materials and methods. The study included 70 female patients with FC, who were randomized into two equal groups: patients of Group FC-P received prucalopride at a dose of 2 mg daily for 8 weeks, and patients of Group  FC-PP received prucalopride at a similar dose together with a multi-strain probiotic (Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus rhamnosus, not less than 1×10⁹ CFU of each strain per capsule), 1 capsule 3 times a day for 8 weeks. At baseline, as well as after 2, 4, and 8 weeks, the groups were assessed for the number of defecations per week, stool form (Bristol Stool Scale, BSS), severity of abdominal bloating and abdominal pain against the background of bloating (Visual Analog Scale, VAS), as well as the presence

of the need for additional straining, sensation of incomplete and difficult defecation. Before and after treatment, all subjects were assessed for levels of interleukin-1β, cortisol, brain-derived neurotrophic factor, tryptophan, kynurenine, kynurenic acid, serum and platelet serotonin, psychoemotional status (Spielberger — Hanin test, STAI), Hamilton Depression Rating Scale (HDRS), Four-Dimensional Symptom Questionnaire (4DSQ)), cognitive status (Brief Assessment of Cognition in Schizophrenia, BACS), quality of life (SF-36), and gut microbiota composition in stool samples (16S rRNA sequencing).

Results. The study was completed by 34 patients in Group FC-P and 30 patients in Group FC-PP. Abdominal bloating directly correlated with the severity of somatization (r = 0.25; p < 0.005) and inversely — with cortisol levels (r = –0.29; p < 0.05). The severity of abdominal pain directly correlated with the levels of state and trait anxiety (STAI), distress, anxiety, and somatization (4DSQ) (r = 0.32, p < 0.05; r = 0.28, p < 0.05; r = 0.31, p < 0.05; r = 0.26, p < 0.05; r = 0.35, p < 0.005, respectively) and inversely — with the indicators of vitality, emotional role functioning, and mental health (SF-36) (r = –0.28, p < 0.05; r = –0.32, p < 0.01; r = –0.30, p < 0.05, respectively). Stool form type inversely correlated with the level of kynurenine (r = –0.27; p < 0.05) and kynurenic acid (r = –0.26; p < 0.05). The sensation of incomplete evacuation correlated with the severity of depression according to HDRS (r = 0.27, p < 0.05) and state anxiety (r = 0.25; p < 0.05), while the sensation of difficult evacuation directly correlated with the level of interleukin-1β (r = 0.25; p < 0.05) and distress (r = 0.27; p < 0.05) and inversely with the ratio of plasma serotonin to kynurenine  (r = –0.27; p < 0.05). The number of defecations per week and the presence of the need for additional straining did not show statistically significant correlations with any of the variables. The age of the subjects, duration of the disease, and cognitive indicators did not demonstrate a reliable correlation with the severity of FC symptoms. When assessing the gut microbiota composition, various correlations with FC symptoms were identified, the most significant of which was a direct correlation between the level of bacteria from the Ruminococcaceae family and the severity of abdominal bloating (r = 0.39; p < 0.05). After randomization, the formed groups did not differ significantly in the assessed clinical, laboratory, and psychometric parameters, quality of life, age, and disease duration (p > 0.05). During treatment, both groups showed significant improvement in all clinical parameters; however, Group FC-P showed a more pronounced reduction in abdominal pain (p < 0.005) and sensation of incomplete evacuation (p < 0.05). Only in Group FC-P was a significant improvement in cognitive function observed, with the total score and the results of the BACS subtests “Semantic and Phonemic Verbal Fluency”, “Digit Sequencing”, and “Tower of London” being significantly higher than in Group FC-PP (p < 0.0001, p < 0.05, p < 0.05, and p < 0.0001, respectively). Quality of life, on the contrary, was significantly higher in Group FC-PP due to the indicators “Vitality” (p < 0.05), “Emotional Role Functioning” (p < 0.001), and “Mental Health” (p < 0.05). A key difference in gut microbiota composition between the groups at the end of treatment was a change in the abundance of representatives of the order Lactobacillales, specifically the family Streptococcaceae, which increased in Group FC-P and decreased in Group FC-PP (p < 0.05). In Group FC-PP, the number of representatives of the Ruminococcaceae family (p < 0.05) and other bacteria capable of synthesizing short-chain fatty acids also increased significantly. No adverse events during therapy were reported in either group throughout the entire observation period.

Conclusion. Disruption of the components of the “microbiota — gut — brain” axis in FC is closely associated with the symptoms of the disease. The efficacy of prucalopride as monotherapy and in combination with a multistrain probiotic regarding the symptoms of FC develops through influence on components of the “microbiota — gut — brain” axis not directly related to the pathogenesis of FC, while these approaches have divergent effects on cognitive function, quality of life, and the abundance of individual representatives of the phylum Firmicutes (Bacillota).

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