Inulin supplementation improves some inflammatory indices, clinical outcomes, and quality of life in rheumatoid arthritis patients

Abstract

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that causes joint dysfunction and is associated with changes in serum levels of some biomarkers. The present study investigated the effect of inulin supplementation on pain intensity, clinical outcomes, and quality of life in patients with RA.In a randomized, triple-blind, parallel clinical trial, 60 patients over 18 years of age with RA were randomly assigned to receive either 10 g of inulin or maltodextrin per day for 8 weeks. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were assessed using biochemical kits at the beginning and end of the study. Clinical outcomes were also evaluated, including morning stiffness and pain intensity measured by the Visual Analog Scale (VAS), hand grip measured by a sphygmomanometer (Seca), disease activity assessed using the Disease Activity Score 28 (DAS-28), and overall quality of life determined by the Health Assessment Questionnaire (HAQ).The number of swollen joints, tender joints, pain intensity, and DAS-28 significantly decreased in both groups. However, hand grip, morning stiffness, ESR, CRP, and HAQ improved significantly only in the intervention group. After the intervention, in the intervention group compared to the control group, serum CRP levels significantly decreased (P = 0.02), while serum ESR levels showed no significant reduction (P = 0.45). The number of tender joints (P = 0.002), the number of swollen joints (P = 0.04), DAS-28, HAQ, morning stiffness, and hand grip strength (P = 0.02) significantly improved, but pain intensity did not change (P = 0.11).Inulin appears to benefit inflammatory status, disease activity, and clinical outcomes in patients with rheumatoid arthritis. Incorporating it into their treatment protocol could be valuable for managing their condition.

Trial registration: Our study was approved in the Iranian Registry of Clinical Trials (www.irct.ir) on 10/5/2023, with the registration number IRCT20230506058098N1.

Introduction

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease associated with changes in non-articular manifestations such as fatigue, cardiovascular disease, pulmonary disorders, biological markers, and joint disorders^1–3. The prevalence of this disease is 0.46 percent worldwide^4,5. The most common symptom of RA is pain, which begins before other signs. Pain is often associated with psychological problems and sleep disorders that can limit the patient’s physical activity and affect the quality of life⁶. The studies have shown that the quality of life in patients with rheumatoid arthritis is significantly lower compared to the general population⁷. Some factors, such as genetic, age, environmental, and gender factors, have been suggested to contribute to the development of arthritis^8,9. Numerous studies have shown that RA is associated with increased inflammatory biomarkers^10,11. On the other hand, serum levels of acute-phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) typically increase during the active stages of the disease. These markers are valuable in diagnosis and follow-up. CRP or ESR, and disease activity score-28 (DAS-28) are used to assess disease activity in RA patients^10,12.

There is still no definitive cure for RA, and medication management is generally for symptom relief¹³. Long-term prescription of steroids and non-steroidal anti-inflammatory drugs in the treatment of rheumatoid arthritis is associated with harmful side effects such as gastric ulcer, liver damage, kidney damage, headache, dizziness for non-steroidal drugs, and increased likelihood of weight gain, decreased bone density, and increased risk of infection for steroid drugs. Consequently, integrating complementary treatments with drug therapy will be crucial in managing the symptoms of the disease¹⁴.

Treatments that alter the gut microbiota significantly affect the preclinical stage of arthritis because dysbiosis occurs before clinical arthritis¹⁵. Recent studies propose that patients with RA have considerable changes in intestinal microbiota compared with healthy individuals¹⁶. The characteristics and understanding of gut microbiota have recently increased, indicating a broad field of research, especially in autoimmune diseases. The gut microbiota is the main source of microbes that may have beneficial and disease-causing effects on human health¹⁷. Also, the quantity of Bifidobacterium species and lactic acid bacteria is reduced significantly in RA subjects¹⁶. Diet is the main environmental factor that affects gut microbiota. A diet rich in prebiotics and probiotics may be beneficial¹⁸. Recent studies have demonstrated that consuming probiotics, prebiotics, and symbiotic products can reduce inflammation, improve gut microbiota, and may impact on disease severity and symptoms^18–20.

Inulin-type fructans (ITFs), including oligofructose, inulin, and fructooligosaccharides, are indigestible, soluble, and fermentable food components that have been identified as prebiotic properties and are recognized as functional foods²¹. Beneficial effects of ITF intake on improving metabolic parameters, maintaining the integrity and function of the intestinal mucosal barrier, and modulating immune system responses have been reported^19,22. Inulin fructans; oligo or polymeric, composed of D-fructose units that are ultimately a glucose unit. These compounds are found in celery, chicory, garlic, onions, wheat, bananas, soybeans, artichokes, and asparagus²³. According to the degree of polymerization (DP), these compounds are divided into oligofructose (DP < 10), inulin enriched with oligofructose (a mixture of inulin and oligofructose), and inulin (DP = 10–65). Among prebiotics, inulin fructans play a special role in increasing the level of bifidobacteria and lactobacilli. The prebiotic effects of these compounds are observed in amounts of 5–10 g per day^24–26. Also, a series of clinical studies have been reported that show that up to 20 g/day of inulin and/or oligofructose is well-tolerated²⁷. The intervention period of 60 days has been considered based on the effective dose of ITFs to exert significant bifidogenic effects on the intestinal microbiome and at the same time with minimal gastrointestinal side effects^26,27.

Recent research has found that functional food intake is effective in health promotion, prevention, and treatment of some chronic diseases. Clinical evidence of the effect of inulin supplementation on improving rheumatoid arthritis symptoms in humans has not been reported, and its impact has only been reported in mice^28,29. As regards the lack of research on the influence of inulin supplementation in human studies, we decided to investigate the effect of inulin supplementation on inflammatory indices, clinical outcomes, and quality of life in patients with rheumatoid arthritis.

Methods

Study participants

A minimum sample size of 25 patients per group was determined, providing an 80% statistical power to detect a standardized effect size of 0.8 in CRP as the main study outcome at a 5% significance level³⁰. The estimated sample size was increased to 30 patients per group to accommodate a potential dropout rate of up to 20%. Three hundred and nine patients with RA from October 2023 to July 2024 with the active phase of the disease (DAS-28 > 3·2)¹⁶ were diagnosed by a rheumatologist based on the American College of Rheumatology (ACR) criteria³¹ and referred to participate in our study. The ACR criteria consist of four factors: the number of affected joints, serology tests such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), the levels of acute phase proteins (ESR and CRP), and the duration of symptoms. The inclusion criteria included disease diagnosis for at least 6 months and age above 18. Patients with chronic renal failure, liver dysfunction, pregnant or lactating women, those with symptoms or a history of cardiovascular diseases (CVD) or diabetes mellitus, individuals consuming antihyperglycemic agents including metformin, taking antibiotics, synbiotics, probiotics, any anticoagulants like warfarin, antioxidants, contraceptives, or supplements (apart from the regular supplements provided for RA) during the previous three months, and patients with overt hand deformities were not included in the study. Finally, sixty patients were included in our study. The patients who consumed less than 80% of the prescribed supplements or were concurrently diagnosed with both rheumatoid arthritis and fibromyalgia were excluded from the study. Finally, informed consent was obtained from all subjects. The study protocol was registered in the Iranian Registry of Clinical Trials on 10/5/2023 (http://www.irct.ir: IRCT20230506058098N1) and was approved by the research ethics committee of Isfahan University of Medical Sciences (IR.MUI.RESEARCH.REC.1401.394).

Study design, randomization, blinding, and procedures

The current study is a triple-blind, parallel-assigned, randomized clinical trial for 8 weeks. At first, participants were stratified based on used drugs (Disease-modifying antirheumatic drugs [DMARDs] and Corticosteroids/DMARDs, Corticosteroids, and nonsteroidal anti-inflammatory drug [NSAIDs]) and body mass index (BMI > 25 kg/m² and BMI < 25 kg/m²) and then randomly allocated into two groups using permuted random blocks of size 4 (https://www.sealedenvelope.com/simple-randomiser/v1/lists) for the intake of either inulin supplements (n = 30) or the placebo (n = 30). Inulin supplements as an intervention and maltodextrin as a placebo in 10-g sachets are delivered to the patients alongside their usual prescribed medical treatment. High-performance inulin (HPI) type inulin supplement, with a DP higher than or equal to 22, (Frutafit ® TEX, Sensus/Netherlands) containing higher or equal to 99.5% inulin and less than or equal to 0.5 percent of fructose, glucose, and sucrose (Razavi Pharmaceutical Services Institute) and maltodextrin (Osina Chemi Foodchem® ) with the same appearance ( taste, smell, and color) were delivered to participants to use it with a main meal. Someone outside the study coded both inulin supplement sachets and placebo (codes A and B). The codes were hidden from participants, researchers, and statisticians (concealment). All patients were asked to return the unused packs at each visit to ensure compliance with the intake of supplements or placebo. Additionally, participants were monitored by phone every week to emphasize consumption and inquire about any complications.

Assessment of dietary intake and physical activity

Three-day food records (2 working days a week and one day off) were completed in three sessions during weeks 1, 5, and 8 of the intervention. To find macronutrient and micronutrient intakes of participants using the modified Nutritionist IV software based on Iranian foods (Version 4.1, First Databank, San Bruno, CA, USA). Physical activity records were completed for all participants during weeks 1 and 8 of physical activity using the short form of the International Physical Activity Questionnaire (IPAQ)^32,33. Patients of both groups were requested not to change their routine diet or physical activity or to take supplements that might affect their nutritional status.

Evaluation of disease activity and clinical outcomes (pain intensity, hand grip strength, morning stiffness)

The disease activity was evaluated using the validated DAS-28 quantitative tool. DAS-28 is a composite index that measures disease activity in patients with rheumatoid arthritis by assessing 28 joints in the body³⁴. It is widely approved for clinical trials in conjunction with the European League Against Rheumatism (EULAR) response criteria³⁵. The DAS-28 score was calculated online using a formula considering the number of tender and swollen joints out of the 28 joints assessed, acute phase reactants like ESR or CRP, and the patient’s overall health³⁶. A DAS-28 value of ≤ 2.6 signifies remission, a score between 2.6 and 3.2 indicates mild disease activity, a score from 3.2 to 5.1 indicates moderate disease activity, and a score over 5.1 reflects high disease activity³⁷.

Pain intensity was recorded using VAS. VAS is one of the commonly used pain rating scales. It is often used in epidemiological and clinical research to measure the intensity or frequency of various rates of pain³⁸. The patient’s pain level ranges from none to severe on a scale³⁹.

Handgrip strength was measured to determine muscle strength in a fixed position while sitting on a chair. A sphygmomanometer (Seca) was used to assess hand grip strength^40,41. The patient performed this three times with the dominant hand, and the average of the three maximum efforts was recorded as the hand grip strength in mmHg⁴².

The degree of morning stiffness was measured on a VAS scale from 0 to 100, with 0 representing no morning stiffness and 100 indicating the highest severity⁴³.

Assessment of quality of life

The Health Assessment Questionnaire (HAQ) was used to evaluate functional disability in patients with RA⁴⁴. The questionnaire consists of eight components that assess functional disability and personal health: dressing, standing up, eating, walking, hygiene, hand stretching, gripping, and activity. Each question is evaluated on a scale from 0 to 3, where higher scores indicate a greater severity of disability. The total HAQ score ranges from 0 to 28.

Biochemical assessment

Venous blood samples were collected from patients and centrifuged at 4000 revolutions per minute for 8 min to separate the serum. The Westergren (manual) technique was used to determine the amount of ESR. CRP was measured by spectrophotometry using the Mindray BS800-m automatically. We used the Biorad kit to evaluate quantitative CRP.

Demographic and anthropometric assessments

Each participant completed a general demographic questionnaire at the beginning of the study to gather data on their age, gender, disease duration, education level, medical history, occupation, and use of supplements and drugs. Socioeconomic status (SES) was obtained by use of an Iranian valid and reliable questionnaire⁴⁵. A trained staff member recorded weight, height, and waist circumference using a non-elastic measuring tape at the beginning and end of the study in minimal clothing. BMI was calculated using height and weight measurements (weight (kg)/ (height (m)2).

Statistical methods

Qualitative data were presented as counts (percentages), whereas quantitative variables were presented as means ± standard deviations. Using a Q-Q plot chart and the Shapiro–Wilk test, the normality of the distribution of the quantitative variables was evaluated. The chi-square and independent samples t-test were used to examine the distribution of basic qualitative and continuous characteristics of study participants between the two groups. Nutrient intake was compared between the two groups using an independent samples t-test or a non-parametric Mann–Whitney U test. Paired t-tests or non-parametric Wilcoxon signed-rank tests were used for within-group analysis. While covariance (ANCOVA) analysis was used for between-group comparisons in terms of study outcome variables. ANCOVA was used to adjust for potential confounders’ effects, including baseline values of outcomes, energy intake, and total fiber. SPSS software version 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp) was used to analyze the data at a significant level of P < 0.05.

Results

Sixty patients with a mean age of 55.59 ± 11.68 years were included in this study. One patient in the placebo group was excluded due to failure to follow up, so statistical analysis was performed on fifty-nine participants. Figure 1. No side effects were reported following the administration of inulin in RA patients throughout the study. The baseline characteristics are reported in Table 1. There were no differences in age, marital status, sex, menopausal status, socioeconomic status, physical activity, and intake of drugs between the intervention and placebo groups (P > 0.05). A comparison of dietary intakes revealed significant differences in selenium (P < 0.05) and carbohydrates (P = 0.05) and a marginal difference in energy intake (P = 0.07) and total dietary fiber (P = 0.07) between the two groups Table 2.

Fig. 1.

Patient enrolment and randomization are shown in the CONSORT flow chart.

Table 1.

General characteristics of study participants in two study groups.

Variable	Group		P
	Inulin (n = 30)	Placebo (n = 29)
Age (year)	53.63 ± 10.74	57.62 ± 12.43	0.19
Weight (Kg	71.00 ± 14.56	68.04 ± 15.11	0.45
BMI (Kg/m2)	28.19 ± 5.86	27.66 ± 5.26	0.72
Waist circumference (cm)	91.42 ± 10.57	95.00 ± 13.40	0.26
Female, n (%)	25 (83.30)	25 (86.20)	0.76
Menopause, n (%)	18 (66.70)	18 (72.00)	0.68
Physical activity levels (MET-minute/week) Low Medium High	24 (80.00) 4 (13.30) 2 (6.70)	25 (86.20) 4 (13.80) 0 (0.00)	0.37
Socioeconomic status Low Medium High	8 (26.70) 16 (53.30) 6 (20.00)	9 (31.00) 8 (27.60) 12 (41.40)	0.1
Disease duration (year)	8.70 ± 8.96	8.96 ± 8.67	0.91
Medications, n (%) DMARDs and Corticosteroids DMARDs, Corticosteroids, and NSAIDs	23 (76.70) 7 (23.30)	21 (72.40) 8 (27.60)	0.71

Data are expressed as mean ± SD or Number (%)—comparison of quantitative and qualitative variables performed by independent samples t-test and Chi-square test respectively.

P < 0.05 was considered statistically significant.

BMI body mass index, MET the metabolic equivalent of the task, DMARDs disease-modifying antirheumatic drugs, NSAIDs nonsteroidal anti-inflammatory drugs.

Table 2.

Dietary intakes of study participants throughout the study in two study groups.

Nutrients	Group		P a
	Inulin (n = 30)	Control (n = 29)
Energy (kcal/day)	1589.18 ± 518.67	1312.35 ± 243.75	0.07
Carbohydrates (g/day)	200.50 ± 68.34	165.29 ± 37.66	0.05
Protein (day)	59.91 ± 20.32	50.87 ± 9.45	0.28
Fat (g/day)	64.50 ± 23.44	53.47 ± 12.24	0.10
Cholesterol (mg/day)	210.64 ± 84.33	214.63 ± 124.67	0.78*
SFA (g/day)	15.15 ± 5.51	12.60 ± 3.97	0.12
MUFA (g/day)	23.72 ± 8.72	19.73 ± 4.34	0.09
PUFA (g/day)	16.86 ± 7.42	13.68 ± 3.35	0.09
Total dietary fiber (g/day)	22.48 ± 9.02	18.94 ± 5.68	0.09
Vitamin A (RAE)	387.56 ± 254.20	280.70 ± 128.32	0.22*
Vitamin C (mg/day)	102.81 ± 50.68	86.20 ± 38.84	0.29
Vitamin E (mg/day)	22.10 ± 9.78	18.92 ± 5.27	0.25
Selenium (mg/day)	71.86 ± 28.90	59.75 ± 17.42	0.02

Values indicate average nutrient intake at the study’s beginning, middle, and end and are presented as mean ± standard deviation (SD).

a Obtained from independent samples t-test or Mann–Whitney U test as indicated with *

SFA Saturated fatty acids, MUFA Monounsaturated fatty acids, PUFA Polyunsaturated fatty acids, RAE Retinol activity equivalent.

As shown in Table 3, ESR levels after intervention reduced significantly only in the inulin group (P = 0.005), and the difference between the two groups was significant after adjustment for baseline values (P = 0.04). The difference between the two groups was insignificant after adjusting for baseline values, energy intake, and total fiber. (P = 0.13). CRP levels after intervention were reduced significantly only in the intervention group (P = 0.004), and the difference between the two groups was significant after adjustment for baseline values (P = 0.005) and other covariates (P = 0.02). The pain intensity, swollen joints, and tender joints in the inulin and placebo groups showed a significant decrease at the end of the intervention period. After adjusting for baseline values and other covariates, a more significant reduction in swollen joints and tender joints was seen in the inulin group. The reduction in pain intensity was marginally significant after adjusting for baseline values (P = 0.08) and there was no significant difference between the two groups after adjusting for all covariates (P = 0.11). The mean score of DAS-28 showed a significant decrease in the two groups at the end of the intervention period (P < 0.001). Also, after adjusting for baseline values, and all covariates, the mean score of DAS-28 more significantly decreased in the inulin group than placebo (P = 0.002, P = 0.02 respectively). HAQ score and morning stiffness only changed significantly in the inulin group (P < 0.001) and their difference between groups was significant after adjusting for baseline values (P < 0.001, P = 0.005 respectively), and all covariates (P = 0.02). Hand grip strength increased significantly only in the inulin group (P < 0.001) and this increase was significantly higher in the inulin group after adjusting for baseline values, and all covariates (P = 0.005, P = 0.02 respectively).

Table 3.

Comparison of clinical and biochemical parameters before and after intervention in each group and between groups.

Variables	Inulin (n = 30)				Control (n = 30)				P b	P c
	Baseline	End of trial	Change	P a	Baseline	End of trial	Change	P a
Tender joint count (0–28)	13.20 ± 4.09	5.10 ± 4.89	-8.10 ± 0.97	< 0.001	11.93 ± 3.87	9.07 ± 5.65	-2.86 ± 0.92	0.04	0.001	0.002
Swollen joint count (0–28)	6.00 ± 3.87	2.53 ± 2.80	-3.47 ± 0.59	< 0.001	5.38 ± 3.02	3.59 ± 3.04	-1.79 ± 0.46	0.01	0.03	0.04
Pain intensity (mm)	73.67 ± 10.33	56.33 ± 18.29	-17.33 ± 2.83	< 0.001	74.14 ± 10.86	64.14 ± 15.70	-10.00 ± 3.54	0.01	0.08	0.11
DAS-28	6.08 ± 0.64	4.50 ± 1.05	-1.57 ± 0.19	< 0.001	5.71 ± 0.76	5.04 ± 1.03	-0.67 ± 0.15	< 0.001	0.002	0.02
HAQ score	0.96 ± 0.60	0.62 ± 0.50	- 0.34 ± 0.07	< 0.001	0.92 ± 0.56	0.95 ± 0.60	0.03 ± 0.05 0.05 (-0.60,0.90)	0.60*	< 0.001	0.02
Hand grip strength	76.13 ± 58.20	103.05 ± 55.95	26.91 ± 4.50	< 0.001	65.03 ± 33.00	69.36 ± 47.11	4.33 ± 6.86 -1.36 (-41.67,171.67)	0.53*	0.005	0.02
Morning stiffness (mm)	5.13 ± 2.93	3.17 ± 2.95	-1.97 ± 0.42	< 0.001	5.48 ± 3.52	5.03 ± 3.08	-0.45 ± 0.46 0.00 (-9.00.7.00)	0.34*	0.005	0.02
ESR (mm/h)	33.23 ± 17.58	24.60 ± 10.98	-8.63 ± 2.80	0.005	27.62 ± 19.21	26.93 ± 19.88	-0.69 ± 1.57 -2.00 (-19.00,15.00)	0.66*	0.04	0.13
CRP (mg/L)	18.32 ± 23.08	6.60 ± 5.67	-11.72 ± 3.80	0.004	9.75 ± 13.21	11.36 ± 13.70	1.61 ± 1.88 2.40 (-24.10, 24.30)	0.40*	0.005	0.02

Data are expressed as mean ± SD or mean ± SE (for changes) and median (minimum, maximum).

a Obtained from paired-samples t-test or Wilcoxon signed rank test (indicated as *) for differences before and after the intervention in each groups.

b Obtained from ANCOVA with adjustment for baseline values.

c Obtained from ANCOVA with adjustment for baseline values, energy intake, and total fiber.

VAS visual analogue scale, DAS-28 disease activity score of 28 joints, HAQ health assessment questionnaire, ESR erythrocyt.

Discussion

The current study examined the impact of inulin supplementation on inflammatory indices, clinical outcomes, and quality of life in patients with RA. Our findings suggest that an 8-week regimen of 10 g of inulin supplementation can significantly improve disease activity, HAQ, hand grip strength, morning stiffness, and CRP levels compared to placebo. Despite these positive results, we observed no significant changes in pain intensity or ESR levels. The observed effects were independent of the potential confounders. To our knowledge, no study examining the impact of inulin alone on patients with RA was available, so we had to review similar studies. To support our findings, in a randomized clinical trial (RCT) by Zamani et al., it was declared that synbiotic supplementation containing 800 mg inulin for 8 weeks among 54 patients with RA had beneficial effects on high-sensitivity C-reactive protein (hs-CRP) in patients with RA¹⁶. In an animal study, combining B. coagulans and inulin significantly improved inflammatory factors and clinical parameters in induced RA²⁵. A recent RCT by Vajdi et al. revealed that daily supplementation with 10 g of inulin for 12 weeks had beneficial effects on serum hs-CRP in women with migraines⁴⁶. In a double-blind RCT, it was mentioned that L. casei supplementation improved the inflammatory status including hs-CRP and inflammatory cytokines in patients with RA⁴⁷. According to another randomized controlled study, taking probiotic supplements by patients with RA had a beneficial effect on hs-CRP levels⁴⁸. In contrast, in a prospective clinical trial on patients with RA observed no significant difference in end-of-study hs-CRP levels compared to baseline levels⁴⁹. Consistent with the previous study, a cross-over intervention study in Finland revealed that the intake of synbiotic supplements did not significantly impact serum CRP levels among men with low serum enterolactone (Organic compound derived from the digestion of plant lignans) concentrations⁵⁰. A recent RCT by Valentini et al. on healthy individuals showed that adding probiotic supplements to diet significantly reduced ESR levels in the intervention group⁵¹. In contrast, a recent systematic review and meta-analysis by Wu et al. about the effects of microecological regulators on RA showed that supplementation with intestinal microecological improved levels of inflammatory cytokines but had no significant impact on ESR⁵². Consistent with the results of a previous study, no significant difference in end-of-study ESR levels compared to baseline levels was observed in the study of Esmaeili et al.⁴⁹.

Another interesting result of our study was the improvement in disease activity including DAS-28, swollen joint counts, tender joint counts, and ESR. Consistent, Alipour et al. have investigated that L. casei supplementation among patients with RA had significantly reduced DAS-28, tender, and swollen joint counts⁴⁷. In addition, the positive effects of probiotic and synbiotic supplementation on DAS-28 have been proven in other studies^16,52. Also in Zamani et al.'s investigation on 60 patients with RA, it is mentioned that taking probiotic supplements reduced DAS-28 significantly, but had no impact on tender, and swollen joint counts⁴⁸ Contrary to previous studies, significant reduction of DAS-28, tender, and swollen joints with synbiotic supplementation has not been proven⁴⁹. A recently published clinical trial on 46 children with juvenile idiopathic arthritis in India declared that probiotic consumption for 12 weeks had no significant reduction in swollen joint counts and early morning stiffness but had a marginally significant decrease in tender joint counts⁵³.

In our study, pain intensity did not change significantly. In contrast, a recent investigation documented that synbiotic supplementation had significantly reduced pain intensity¹⁶. Inconsistently, some recent research declared that probiotic and synbiotic supplementation did not significantly decrease pain intensity in patients with RA^48–50.

Hand grip strength and quality of life in our study improved significantly. Fortuna et al. have investigated that prebiotic fiber can significantly increase hand grip strength in adults with obesity and osteoarthritis⁵³. Also, a meta-analysis done by Wu et al. mentioned that supplementation with intestinal microecological regulators leads to significant improvements in HAQ results⁵². Inconsistently, some investigations showed supplementation with synbiotics and probiotics in patients with active RA did not result in significant changes in hand grip strength, inflammatory cytokines, and HAQ^54–56.

Different findings in various studies might be due to the study’s duration, the different doses of the supplement, or individual variations in response to inulin supplementation.Data on inulin supplementation usage for improving inflammatory status is limited. Some previous research on prebiotic consumption and its effects on inflammation has yielded inconsistent results.

Some mechanisms were suggested for these findings. Firstly, probiotics modify the gut microbiota and impact the preclinical stage of arthritis ^15,18. Inulin has been introduced as a potential prebiotic that can alter microbiota, intestinal permeability, and anti-inflammatory properties^24–26,57. It has shown that prebiotics might be more effective than probiotics in enhancing the quality and quantity of beneficial microorganisms in the colon⁵⁵. The second mechanism suggested that ITFs can reduce intestinal and systemic inflammation by boosting the production of SCFAs and increasing the abundance of beneficial bacteria like Bifidobacterium and Lactobacillus^{58,21,59–62}. It is also indicated that ITF intake can modulate immune system responses by improving metabolic parameters and maintaining the integrity and function of the intestinal mucosal barrier^19,21. In a recent RCT by Russo et al., pasta enriched with inulin significantly decreased the excretion rate of lactulose-mannitol in the urine and the level of serum zonulin (intestinal permeability indicators), which indicates the improvement of the function of the intestinal mucosal barrier⁶³. Also, it is declared that according to the urine lactulose-mannitol test, supplementation with inulin was associated with a relative improvement in intestinal permeability in children with type 1 diabetes⁶⁴. Finally, human and animal studies have revealed that ITFs can also affect mineral absorption, particularly calcium and magnesium, and improve bone mineral density^65,66. However, it’s important to apply caution when interpreting and applying findings from animal studies.

This research had some limitations and strengths. One of the most important limitations of this study is not assessing dietary inulin intake in patients due to insufficient data about the quantity of this substance in nutritional databases. The second limitation is the lack of assessment of the composition of the intestinal microbiome and failure to assess the permeability of the intestinal mucosal barrier at the beginning and end of the study by determining the rate of lactulose-mannitol in the urine and the level of serum zonulin, to confirm the modulatory effects of inulin on the intestinal microbiome. A significant strength of this study is that it is the first to examine the impact of inulin supplementation on inflammation status, disease severity, and clinical outcomes in patients with rheumatoid arthritis. Additionally, this study is noteworthy as it evaluates these factors in moderate and severe cases within a triple-randomized clinical trial.

To confirm the present study’s findings, further evaluation of additional parameters related to inflammation is suggested. This includes levels of anti-inflammatory and pro-inflammatory cytokines, analysis of the gut microbiome at the beginning and end of the study, and assessment of intestinal mucosal barrier permeability. These evaluations should be conducted through extensive clinical studies using different doses of inulin in patients with rheumatoid arthritis.

Conclusions

In conclusion, inulin had beneficial effects on inflammatory indices, clinical outcomes, and quality of life in patients with rheumatoid arthritis. However, it had no significant impact on pain intensity or ESR.

Abbreviations

RA

Rheumatoid arthritis

ESR

Erythrocyte sedimentation rate

CRP

C-reactive protein

VAS

Visual analog scale

DAS-28

Disease activity score 28

HAQ

Health assessment questionnaire

ITFs

Inulin-type fructans

DP

Degree of polymerization

ACR

American college of rheumatology

RF

Rheumatoid factor

ACPAs

Anti-citrullinated protein antibodies

CVD

Cardiovascular diseases

DMARDS

Disease-modifying antirheumatic drugs

BMI

Body mass index

HPI

High-performance inulin

IPAQ

International physical activity questionnaire

EULAR

European league against rheumatism

SES

Socioeconomic status

ANCOVA

Analysis of covariance

RCT

Randomized clinical trial

hs-CRP

High-sensitivity C-reactive protein

Author contributions

AT, AG, MS, AF, and MK contributed to the conception, design, data collection, data interpretation, manuscript drafting, and approval of the final version of the manuscript, and agreed on all aspects of the work.

Funding

The financial support for conception, design, data analysis, and manuscript drafting comes from the Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. (no.3401685).

Data availability

The data supporting this study’s findings are available from the corresponding author upon reasonable request.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study procedure was performed according to the Declaration of Helsinki checklist. All participants provided informed written consents, and the local Ethics Committee of Isfahan University of Medical Sciences approved the study protocol (IR.MUI.RESEARCH.REC.1401.394).