1Student Research Committee, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran 2Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Science, Shiraz, Iran 3Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

1. 4Department of Internal Medicine, Gastroenterology Ward, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
2. 5Department of Epidemiology, School of Public Health, Shiraz University of Medical Sciences, Shiraz, Iran 6Center for Cohort Study of Shiraz University of Medical Sciences Employees’ Health, Shiraz University of Medical Sciences,

Shiraz, Iran Correspondence should be addressed to Seyed Jalil Masoumi; [email protected] Received 2 June 2024; Accepted 13 February 2025 Academic Editor: Eric Gumpricht

Copyright © 2025 Donya Firoozi et al. Journal of Nutrition and Metabolism published by John Wiley & Sons Ltd. Tis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Background: Depression and anxiety are common in UC patients due to gut microbiota dysbiosis and increased proinfammatory markers. Butyrate, a short-chain fatty acid, participates in the regulation of gut microbiota and infammation and has neuroprotective efects in neurodegenerative disease. Terefore, we assessed the efects of sodium butyrate supplementation on the disease severity, infammation, and psychological factors in active UC patients.

Methods: Tis study was a randomized, parallel, double-blind controlled trial. Participants in the intervention (n 18) and control (n 18) groups received 600mg/kg of sodium butyrate or rice starch as a placebo with their main meal, respectively, for 12 weeks. Te partial Mayo score was used to evaluate disease severity, while the Westergren method was employed to assess the erythrocyte sedimentation rate (ESR). NLR and PLR were determined using an automated analyzer (XS-500i, Sysmex). Moreover, the psychological factors were assessed by the hospital anxiety depression scale (HADS) and the general health questionnaire (GHQ).

Results: In comparison with placebo, sodium-butyrate supplementation signifcantly decreased the ESR level (−6.66±1.56 vs. 3.00 ±2.11, p 0.01), NLR ( 0.24±0.1 vs. 0.33 ±0.23, p 0.02), Mayo score ( 2.33±0.41 vs. 0.22 ±0.40, p <0.001), HADS anxiety score (−2.77± 0.64 vs. 0.94±0.63, p 0.001), HADS depression score (−2.38±0.47 vs. 0.61±0.33, p<0.001), and GHQ total score (−12.11±1.48 vs. 3.55±1.39, p<0.001).

Conclusion: Butyrate could serve as an efective adjuvant treatment for reducing disease severity and alleviating psychological symptoms. Tis trial was registered on the Research Ethics Committee of Shiraz University of Medical Sciences, with the reference number IR.SUMS.SCHEANUT.REC.1400.037.

Trial Registration: Iranian Registry of Clinical Trials: IRCT20211214053401N1 Keywords: anxiety; depression; infammation; short-chain fatty acids; sodium butyrate; ulcerative colitis

Ulcerative colitis (UC) is a chronic infammatory bowel disease (IBD) marked by an alternating period of relapse (active infammation) and remission in the large intestine [1]. Te symptoms of UC include infammation, bloody diarrhea, cramps, and discomfort in the abdomen [2]. Additionally, mental symptoms such as depression and anxiety are common in UC patients [3], which have been linked to a decline in life quality, lower adherence to treatment, and higher morbidity and mortality [4]. According to a meta-analysis study, an estimated 32.6% of UC patients sufer from anxiety, and 23% sufer from depression. During the active phase of the disease, these amounts rise to 70.8% and 41.3%, respectively [5]. IBD has a bidirectional relationship with depression and anxiety through several mechanisms such as gut microbiome dysbiosis, increased proinfammatory cytokines, signaling from the vagal nerve, and changes in the brain morphology [6]. Moreover, immune-infammatory responses happen in depression similar to IBD with common marker production, including an increase in the levels of proinfammatory cytokines such as interleukin (IL)-6, IL-1, IL22, IL-17, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and T-17-inducing cytokines [6, 7]. On the contrary, the production of transforming growth factor beta (TGF-β) and antiinfammatory cytokines such as IL-10 decreased in both IBD and depression [8]. Additionally, the gut microbiome afects function and behavior due to communication with the brain, which directly impacts mental disorders. Tis communication occurs through the gut–brain axis, the hypothalamic–pituitary–adrenal (HPA) axis, immune system activation (mainly microglia in the brain), and the infammatory response system [9]. Additionally, the microbiota of the gut produces neurotransmitters such as dopamine, γ-aminobutyric acid (GABA), and serotonin, which impact mood [10–12].

On the other hand, UC dysbiosis is associated with a reduction in gut bacteria that produce short-chain fatty acid (SCFA)-like clostridium and faecalibacterium, which are linked to both infammation and depressive disorder [13, 14]. SCFAs (butyrate, acetate, and propionate) are produced from nondigestive carbohydrates via fermentation by gut microbiota in the lower intestine [15]. Tey play a pivotal function in the microbiota–gut–brain axis involved in IBD and depression’s pathophysiology [16]. Also, SCFAs have anti-infammatory and neuroprotective efects via complex biological mechanisms [17].

Butyrate is a crucial SCFA and the primary energy source of the colon. Its amount decreased in the intestine and stool of UC patients due to the dysbiosis described above [18]. Butyrate has the ability to modulate the dysbiosis occurring in gut microbiota [19] and antiinfammatory efects through several pathways including suppression of nuclear factor kappa B (NF-κB), reducing the proinfammatory cytokine expression [20], activating the regulatory T-cells, and increasing the antiinfammatory cytokines [21]. Moreover, butyrate exhibits

neuroprotective efects by crossing the blood–brain barrier (BBB) in neurodegenerative disorders such as depression and anxiety [22]. It achieves these efects by reducing the activation of microglia and lipopolysaccharides [22, 23], acting as a HDAC inhibitor [24], increasing the level of brain-derived neurotrophic factor (BDNF) [25], promoting epigenetic modifcations in the central nervous system (CNS) [22], causing neuroendocrine alterations [22], and having protective efects against chronic cerebral hypoperfusion (CCH) and neuroinfammation [26].

According to previous studies, approximately one-third of UC patients experiencing depression and two-thirds experiencing anxiety remain undiagnosed. On the other hand, the majority of UC patients with psychological disorders do not obtain a sufcient and efective treatment [27]. Terefore, assessing and treating depression and anxiety in UC patients are important for achieving better treatment responses and improving their quality of life. Te aims of this research were to assess the efects of sodium butyrate supplementation on reducing disease severity and infammation (as the sign of disease severity) and improving psychological factors including depression and anxiety in patients with active UC.

1. 2.1. Study Design. Te current parallel randomized doubleblind, placebo-controlled clinical trial was conducted based on the Declaration of Helsinki for a 12-week period. Eligible patients were chosen from the IBD clinic located at Shahid Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. All participants provided informed consent, prior to their enrollment. Ethical approval of this study was obtained from the Research Ethics Committee of Shiraz University of Medical Sciences, with the reference number IR.SUMS.SCHEANUT.REC.1400.037.
2. 2.2. Participants. 36 participants (18 people in each butyrate and placebo group) were recruited for this trial according to the sample size estimation which was thoroughly explained in our previous study [28]. Inclusion criteria for this study were active UC patients with mild to moderate disease severity, confrmed based on histological and endoscopic assessments at least three months prior to the study’s start. Additionally, patients had a body mass index (BMI) ranging from 18.5 to 30 kg/ m2 and were between ages of 18 and 60. Te exclusion criteria for this study included patients with any gastrointestinal, renal, autoimmune, cardiovascular diseases, cancer, and diabetes; use of anti-TNF-α, corticosteroids, and anti-infammatory medications; use of any supplements such as multivitamin-mineral, pro-/pre-/syn-/ postbiotics, omega 3, and antioxidants in the last three months; changes in dose or type of medications and disease severity or relapse during the study; alcohol and tobacco use during enrollment; COVID-19 infection two months prior to or during the trial; and pregnancy and lactation.

1. 2.3. Randomization, Allocation Concealment, and Blinding. UC patients meeting eligibility criteria were randomly assigned to either the sodium butyrate or placebo based on block randomization with an allocation ratio of 1:1 and a block size of 4. A random number generator found at https://www.sealedenvelope.com/simplerandomiser was used for this assignment. Tis procedure was carried out by a statistician who was not involved in any other part of the trial. Te randomization numbers were inserted into opaque, sequentially numbered envelopes by the third party to preserve allocation secrecy. When participants were admitted to the trial, these envelopes were opened sequentially. Tus, the participants, researchers, laboratory personnel, and result evaluators were blind to the allocated group until the database was opened. Notably, the butyrate and placebo capsules were packed in similar bottles labeled A and B, and they had the same color, size, and shape. Additionally, a tiny amount of butyrate was included in each placebo bottle to create a similar scent.

1. 2.4. Intervention. Patients in the intervention group received 600mg of sodium butyrate capsules, while those in the control group received 600mg of rice starch capsules as a placebo, once daily with their main meals for 12weeks. Te sodium butyrate supplements were provided by Body Bio Company (Body Bio, USA). Each capsule contains 600mg of butyric acid and other ingredients such as medium-chain triglycerides (MCT), hydroxypropyl methylcellulose, and sodium hydroxide. Sodium butyrate dosage was determined according to the recommendation guidelines of the manufacturer, which have been demonstrated as safe with no side efects based on prior studies [29]. Moreover, at the beginning of the trial, dietary recommendations specifc for IBD were provided to participants according to their usual dietary routines.
2. 2.5. Demographic, Anthropometric, and Dietary Assessments. At the beginning of the study, participants’ general information, such as age, sex, medical history, disease extent and duration, marital status, alcohol consumption, and smoking, was collected through a questionnaire. At the start and end of the study, body weight measurements were taken by a Seca scale (Seca, Germany) with a 100 gr precision, while participants were wearing light clothing and barefoot. Height was measured with a wall-mounted height rod, with a precision of 0.1cm, and participants were measured barefoot at the beginning of the study. Te BMI was determined by dividing the weight in kilograms by the height in meters squared. Dietary intakes were assessed by a 3-day analog food recall (two regular and a weekend day) at the start and end of the trial. Nutritionist IV software (First Databank, San Bruno, CA, USA) modifed for Iranian food was used for the determination of daily calorie and nutrient intake.

1. 2.6. Disease Severity Assessment. Te partial Mayo scoring index was utilized for assessment of UC severity at the start and end of the trial. Tis questionnaire contains three questions about frequency of stool, bleeding from the rectum, and the physician’s overall assessment. Each question is scored between 0 and 3, with the overall score classifed as follows: 0-1 represents remission, 2-4 represents mild disease, 5-6 represents moderate disease, and 7-9 represents severe disease. Te study included participants with mild to moderate active UC based on their scores, which varied from 2 to 7 [30].
2. 2.7. Blood Sampling and Biochemical Assessment. Fifteen milliliters of venous blood were taken from each participant at the start and end of the study after overnight fasting (10–12h). Te level of the erythrocyte sedimentation rate (ESR) was measured by the Westergren method. For the determination of the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR), a Sysmex XS-500i automated analyzer (Sysmex, Japan) was used. Te NLR was computed by divided count of neutrophil to count of lymphocyte, and the PLR was computed by divided count of platelet to count of lymphocyte.
3. 2.8. Psychological Assessment. To screen for depression and anxiety, the Iranian validated version of the Hospital Anxiety and Depression Scale (HADS) was used at the baseline and end of the study by face-to-face interview. Tis questionnaire comprises seven questions for assessing anxiety and seven questions for assessing depression. Each question is scored between 0 and 3, with higher scores indicating a greater level of anxiety and depression, and the total score higher than 7 is considered as a cut-of point. Additionally, psychological distress among patients was assessed using the Iranian validated version of General Health Questionnaire-28 (GHQ-28) at the baseline and end of the study by faceto-face interview. Tis questionnaire consists of 28 items that evaluate symptoms related to anxiety, depression, social dysfunction, and loss of confdence. Each item is scored between 0 and 3 based on Likert scoring, with higher scores indicating higher levels of distress, and the total score of 23 is set as the cut-of point [31].
4. 2.9.ComplianceAssessment. Patients received weekly phone calls to monitor their compliance with supplement consumption. Furthermore, a visit was scheduled in the sixth week to check for general health status or any side efects and distribute the second round of supplements for the following 6weeks. To assess the compliance rate, participants were requested to return any remaining capsules they had not consumed at the sixth and twelfth weeks. Participants were deemed compliant if they consumed at least 85% of the supplements provided.

1. 2.10. Statistical Analysis. Te Statistical Package for Social Sciences (SPSS) software (version 20.0, SPSS Inc., Chicago, IL, USA) was used for analysis of data based on the intention-to-treat (ITT) method. Te qualitative and quantitative variables were reported as the number (percentage) and mean±standard error, respectively. Normality of quantitative data was determined by the Shapiro–Wilk test and skewness and kurtosis statistics. Appropriate functions, such as logarithm (log10) and square root, were used to transform non-normally distributed data. An independent sample t-test was utilized to evaluate baseline patient characteristics and changes in nutritional intake between the two groups. Additionally, suitable methods such as Chisquare or Fisher’s exact were employed for categorical data. Te paired t-test was used for within-group comparisons. Te mean diference (after-before) was computed for the between-group comparison variables, and the independent t-test was used to examine the mean diferences between the two groups. Te signifcance level was considered equal or less than 0.05.
2. 3. Results

1. 3.1. Participant Enrollment. In this clinical trial, which was conducted between January 2022 and February 2023, 201 patients were assessed for eligibility. Ultimately, 36 patients (20 men and 16 women) in the active phase with severity of mild to moderate met the inclusion criteria and were randomly assigned into either the intervention (n 18) or placebo (n 18) groups. During the trial, four patients dropped out in the placebo group due to worsening the disease (n 2) and gastrointestinal complaints (n 2), while two patients dropped out in the sodium butyrate group due to COVID-19 infection (n 1) and a low rate of compliance (n 1). However, based on the ITT principle, total of 36 participants were included for fnal analysis (Figure 1).
2. 3.2.DemographicandBaselineCharacteristicsofParticipants. According to Table 1, there were no signifcant diferences between demographic and baseline characteristics of the patients in terms of age, sex, marital status, education, smoking habit, alcohol drinking, disease duration, current treatment, BMI (kg/m2), weight (kg), SBP, DBP, WBC, platelet count, ESR, hs-CRP, NLR, PLR, GHQ total, HADS depression, HADS anxiety, and partial Mayo score in the control and intervention groups. Furthermore, Table 2 shows that energy and nutrient intakes did not signifcantly difer between the two groups.
3. 3.3. Te Impact of Sodium Butyrate on the Infammatory Markers. In this research, infammatory markers including the ESR, NLR, and PLR as well as the partial Mayo score were evaluated for disease severity. Additionally, in our previous research, the level of calprotectin and hs-CRP were also assessed [28]. According to within-group analysis, the level of the ESR (p <0.001) and the NLR (p 0.02) as well as the Mayo score (p <0.001) signifcantly decreases in the sodium butyrate group before and after treatment, without

any signifcant changes in the placebo group (Table 3). Te between-group analysis revealed signifcant decreases in the levels of the ESR (p 0.01), NLR (p 0.02), and Mayo score (p <0.001) in the sodium butyrate group compared with the placebo group. Additionally, while the PLR exhibited a decreasing pattern, it did not reach statistical signifcance

1. (Table 3).

Te present study performed on UC patients revealed the benefcial efect of sodium butyrate on disease severity, infammatory biomarkers, and physiological factors. Te remarkable infuence of sodium butyrate was mainly observed in the decrease of the ESR and the NLR but not the PLR. It also reduced the partial Mayo score as an indicator of disease severity. Interestingly, sodium butyrate improves HADS anxiety and HADS depression indicators. In addition, sodium butyrate was closely associated with GHQ score reduction in somatic, anxiety, and total subcategories.

Our results support the fndings from experimental studies that report anti-infammatory activity of sodium butyrate. In this regard, Chen et al. have shown that sodium butyrate improved intestinal epithelium barrier integrity and infammatory reaction by preventing AKT signaling pathways and NF-κB in the colitis mice model [32]. According to the animal model of UC, sodium butyrate administration ameliorated mucosa lesion and reduced the infammatory response and leukocyte (neutrophil and eosinophil) infltration [33]. Tese fndings are consistent with the previous report by Liu et al. in the mice model with lipopolysaccharide-induced acute lung injury, which showed downregulation of NF-κB, toll-like receptor 4 (TLR4), IL1β, IL6, and TNF-α gene expression [34]. Similarly, in a diabetic-induced model in mice, oral butyrate supplementation attenuated infammatory cytokines such as MCP-1, TNF-α, and IL-1β. Also, gut microbiome composition and gut epithelial barrier integrity were restored [35]. Moreover, oral administration of butyrate in patients with mild to moderate Crohn’s disease induces clinical remission through ESR, NF-κB, and IL-1β reduction [36]. Furthermore, in a clinical trial by Roshanravan et al., hs-CRP and

Enrollment

Assessed for eligibility (n = 201)

Randomized (n = 36)

Allocated to intervention (n = 18)

Received sodium butyrate (600 mg/d)

Lost to follow-up (give reasons) (n = 2) Infection with COVID-19 virus (n = 1), low compliance rate (n = 1)

Allocation

Follow-up

Allocated to intervention (n = 18)

Received placebo (600 mg/d starch)

Lost to follow-up (give reasons) (n = 4) Gastrointestinal complain (n = 2), worsen UC state (n = 2)

Analysis

Intention-to-treat analysis (n = 18) Intention-to-treat analysis (n = 18)

Figure 1: CONSORT fow diagram of participants during the trial.

MDA biomarkers decreased signifcantly in participants with diabetes type 2 who receive sodium butyrate [37]. Additionally, a recent randomized clinical trial demonstrated that a butyrate-based formula improved the fatty liver index (FLI) and plasma lipid profles in individuals with liver steatosis and metabolic syndrome [38]. In contrast, in a prospective observational study, there was no signifcant efect of sodium butyrate on the ESR and CRP; however, faecal calprotectin diminished remarkably in UC patients [39]. Moreover, elevated PLR and NLR values were reported in active UC patients [40], and a recent study showed reduction of the NLR family protein expression by sodium butyrate [41]. Te PLR and NLR have been explored as an inexpensive, simple, and efective method for capturing infammation [42], and based on our fndings, both the PLR and NLR had decreasing trend in the sodium butyrate group; however, PLR changes were not signifcant. Similarly, a study in patients with COVID-19 revealed that the PLR and NLR can serve as a reliable predictor of survival/ mortality [43]. Another study introduced NLR as an independent indicator of poor clinical outcomes [44].

Te potential mechanisms explaining the protective efect of sodium butyrate in UC patients include direct and indirect pathways. Since sodium butyrate is a main fuel of the colonic mucosa, it modulates intestinal permeability and tight junctions [45, 46]. On the other hand, sodium butyrate

promotes hepatic production of glutamine, whose immune modulating efects confrm its anti-infammatory properties [47, 48]. Previously, it was also demonstrated that butyrate can prevent oxidative stress induced by LPS in mesangial cells [49]. It is important to mention that UC is accompanied by gut dysbiosis and a reduced gut microbial diversity [50]. Evidences reported that sodium butyrate could reconstruct the composition of the gut microbial profle [19, 51], thereby ameliorating UC symptoms. In addition, butyrate interferes in gene expression and chromatin release that reduces proinfammatory cytokine production, including IL1b, TNF, and IL6 [52]. Also, butyrate down-regulates infammation through inhibiting availability of oxygen in the gut, stimulating anaerobic bacterial dominance, and decreasing pathobionts growth [53].

We found that the prevalence of anxiety and depression was reduced after oral supplementation with sodium butyrate in comparison to the control group. Although depression aspect of the GHQ score did not change signifcantly, somatic, anxiety, and total values were improved by sodium butyrate intake. Tere is evidence that the prevalence of mental illnesses including anxiety and depression is higher in UC patients compared to the general population, which can lead to quality of life reduction in UC patients [4]. Tis makes it necessary to introduce treatment solutions for this condition. A study by Qiu et al. investigates

Table 1: Demographic and baseline characteristics of participants.

Groups

Age (years) 41.16± 2.58 38.16±2.91 0.44a Sex n (%) 0.73b

p value Sodium butyrate (n=18) Placebo (n=18)

Female 7 (38.90) 9 (50.00) Male 11 (61.10) 9 (50.00)

Marital status n (%) 0.17b Married 13 (72.20) 8 (44.4) Single 5 (27.80) 10 (55.55)

Education n (%) 0.49b Postdiploma 6 (33.33) 8 (44.44) Diploma or less 12 (66.67) 10 (55.56)

Smoking habit n (%) 0.42b Yes 5 (27.77) 3 (16.66) No 13 (72.22) 15 (83.33)

Alcohol drinking n (%) 0.63b Yes 3 (16.66) 2 (11.11) No 15 (83.33) 16 (88.88)

Ulcerative colitis duration (years) 5.66±0.98 4.02±0.76 0.24a Current treatment n (%) 0.73b

BMI (kg/m2) 24.19 ±1.01 24.34±1.12 0.96a Weight (kg) 68.77±3.04 69.16±3.28 0.95a SBP (mmHg) 106.77±2.26 106.44±2.17 0.91a DBP (mmHg) 75.77±1.67 76.88±1.78 0.65a WBC count (109/L) 8.29±0.62 7.69±0.53 0.53a Platelet count (109/L) 340.83±18.61 314.72±21.44 0.35a ESR (mm/h) 22.66±3.71 17.94±2.67 0.31a hs-CRP (mg/L) 4.36±1.69 4.31±0.88 0.28a NLR 2.10 ±0.24 1.97±0.17 0.66a PLR 154.75±16.76 144.74±14.03 0.65a HADS depression 9.11 ±0.97 9.77±0.79 0.60a HADS anxiety 10.61 ±0.84 11.27±0.91 0.59a GHQ total 30.44±1.60 30.33±1.34 0.95a Partial Mayo score 3.55±0.30 3.66±0.22 0.66a

Asacole plus aminosalicylate 9 (50.00) 11 (61.10) Aminosalicylates 9 (50.00) 7 (38.90)

Note: Te data were reported as mean±standard error and frequency (%) for quantitative and qualitative data. p values of ≤ 0.05 were considered statistically signifcant. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; ESR, erythrocyte sedimentation rate; GHQ, general health questionnaire; HADS, hospital anxiety and depression scale; hs-CRP, high-sensitivity C-reactive protein; NLR, neutrophil/lymphocyte; PLR, platelet to lymphocyte ratio; SBP, systolic blood pressure; WBC, white blood cell. aObtained from the independent sample t-test for quantitative variables. bObtained from Chi-square or Fisher’s exact test for qualitative variables.

Table 2: Mean diferences in dietary intake of participants during 12weeks of intervention.

Energy (kcal/d) −55.57 (482.07) −37.42 (447.41) 0.90 Carbohydrate (g/d) −16.10 (73.37) −25.02 (79.68) 0.73 Protein (g/d) 7.59 (35.80) 11.00 (29.85) 0.76 Total fat (g/d) −3.03 (35.21) 1.00 (31.98) 0.72 Total dietary fber (g/d) −0.14 (7.81) −1.5 (10.03) 0.65

Note: Te data were reported as mean±standard error. p values of ≤ 0.05 were considered statistically signifcant. aObtained from independent sample t-tests.

the efect of sodium butyrate administration in the mice model for 10days, and the results indicated that sodium butyrate is such an agent that could be used to prevent depression onset and progression based on the forced swimming test, tail suspension test, and sucrose preference

test [23]. Tis result was consistent with the previous experiment, which claimed that the treatment efect of sodium butyrate on depression was through reduction of neuroinfammation genes [54]. Based on the results of another animal study, sodium butyrate was introduced as a mood

Table 3: Comparisons within and between groups of infammatory markers and Mayo scores after an intervention of 12weeks.

Pre 22.66±3.71 17.94±2.67

Post 16.00±2.66 20.94±3.73 Change 6.66±1.56 3.00±2.11 p valuea < 0.001 0.34

ESR (mm/h)

0.01

Pre 2.10±0.24 1.97±0.17

Post 1.86±0.25 2.31±0.31 Change −0.24±0.10 0.33±0.23 p valuea 0.01 0.27

NLR

0.02

Pre 154.75±16.76 144.74±14.03

Post 136.07±12.43 165.00±20.21 Change −18.67±10.54 20.26±17.42 p valuea 0.1 0.29

PLR

0.06

Pre 3.55±0.30 3.66±0.22

Post 1.22±0.24 3.88±0.38 Change −2.33±0.41 0.22±0.40 p valuea < 0.001 0.59

< 0.001

Partial Mayo score

Note: Te data were reported as mean±standard error. p values of ≤ 0.05 were considered statistically signifcant. Abbreviations: ESR, erythrocyte sedimentation rate; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio. aObtained from the paired sample t-test. bObtained from independent sample t-tests.

Table 4: Within and between-group comparisons of psychological factors at baseline and after 12weeks of intervention.

Pre 10.61 ±0.84 11.27±0.91

Post 7.83±0.60 12.22±0.77 Change −2.77±0.64 0.94±0.63 p valuea < 0.001 0.27

HADS anxiety

0.001

Pre 9.11 ±0.97 9.77±0.79

Post 6.72±0.73 10.38±0.74 Change −2.38±0.47 0.61 ±0.33 p valuea < 0.001 0.34

< 0.001

HADS depression

Pre 12.16 ±0.47 10.77±0.40

Post 5.10 ±0.54 12.05±0.86 Change −7.00±0.66 1.27±0.64 p valuea < 0.001 0.06

GHQ scores

< 0.001

Somatic

Pre 9.88±0.87 9.27±0.61

Post 6.05±0.33 10.66±0.82 Change −3.83±0.80 1.38±0.65 p valuea < 0.001 0.06

< 0.001

Anxiety

Pre 5.77±0.62 6.50±0.54

Post 5.33±0.45 6.22±0.53 Change −0.44±0.28 −0.27±0.13 p valuea 0.13 0.59

Social

0.12

Pre 2.61 ±0.14 3.77±0.53

Post 2.38±0.20 4.11±0.59 Change −0.22±0.10 0.33±0.25 p valuea 0.12 0.21

Depression

0.10

Pre 30.44±1.60 30.33±1.34

Post 18.94±0.95 33.05±2.14 Change −12.11 ±1.48 3.55±1.39 p valuea < 0.001 0.06

< 0.001

Total

Note: Te data were reported as mean±standard error. Change calculated as follows: (after-before intervention) in each study group. p values of ≤ 0.05 were considered statistically signifcant. Abbreviations: GHQ, general health questionnaire; HADS, hospital anxiety depression scale. aObtained from the paired sample t-test. bObtained from independent sample t-tests.

stabilizer and reversed the manic-like and depressive-like behaviors [24]. Even more, sodium butyrate demonstrated antidepressant efects in chronic mild stress-treated rats and could be related to its infuence on the neurochemical pathways attributed to depression such as tricarboxylic acid cycle and mitochondrial respiratory chain complex enzymes [55]. Tis suggests that sodium butyrate has a protective efect in the brain by neutralizing free radicals [56].

Tese fndings emphasize the potential of sodium butyrate supplements as an adjunct in the treatment of UC. Sodium butyrate as a kind of HDAC inhibitor exhibits neuroprotective and anti-infammatory efects against behavioral defcits [57]. Furthermore, based on the Sun et al. study, the sodium butyrate antidepressant efect seems to increase brain serotonin (5-HT) concentration, BDNF expression, and BBB modifcation in mice exposed to mild stress [58]. In addition, sodium butyrate is able to reverse the mitochondrial complex damage [55]. In line with our fndings, proinfammatory cytokines upregulate by sodium butyrate, which may be a potential mechanism for its antidepressant efects [23, 59]. Additionally, gut microbiome disruptions have been associated with several neuropsychiatric disorders, especially depression. Recent studies suggest the microbiota–gut–brain axis as a bidirectional communication pathway in pathogenesis of various mental complications [60]. Butyrate may play a protective role against gut microbiota dysbiosis via remodeling gut bacterial composition. Also, butyrate can mediate the gut–brain axis through GLP-1 secretion by G protein-coupled receptor activation in the distal small intestine and colon, which has neuroprotective efects and inhibits neuroinfammation [61].

1. 4.1. Strengths and Limitations. To our best understanding, this study is the frst clinical trial that provides evidence for the benefcial efect of sodium butyrate on the psychological factors and infammatory markers such as the NLR and PLR in UC patients. Te study’s limitations include a small sample size of UC patients, the lack of analysis of gut microbiota composition and fecal butyrate levels, and the omission of key infammatory cytokines such as IL-6 and TNF-α as well as some potential diagnostic biomarkers for depression such as BDNF. Tese constraints primarily stem from insufcient funding.
2. 5. Conclusion

To sum up, the results of the present study indicated that sodium butyrate supplementation improved disease severity, infammatory biomarkers, and psychological symptoms in some aspects. In this regard, we suggest that sodium butyrate could be used in UC patients to improve life quality and modulate disease activation and progression. A further study with a larger sample size is warranted.