Non-pharmacological therapies are often used for the management of axial spondyloarthritis (axSpA). This randomized controlled trial aimed to investigate the effect of probiotic supplementation, compared with high-intensity interval training (HIIT), in patients with non-radiographic axSpA.
Materials and methodsIndividuals with non-radiographic axSpA were recruited and allocated to a probiotic supplementation group or to an online-delivered strength training program for 12 consecutive weeks. The online program was delivered synchronously in small groups under professional supervision. The primary outcome was functional disability, assessed with the Bath Ankylosing Spondylitis Functional Index (BASFI). Secondary measures included disease activity (the Bath Ankylosing Spondylitis Disease Activity Index), spinal mobility (the Bath Ankylosing Spondylitis Metrology Index, and the Ankylosing Spondylitis Quality of Life Questionnaire). Measures were collected one week before randomization (baseline) and at 6, 12, and 24 weeks after baseline. For statistical analysis, a linear mixed model for repeated measures was used. Both statistical significance and clinical relevance (based on the minimum clinically important difference thresholds) were analyzed. Analyses were conducted under the intention-to-treat principle.
ResultsTwenty patients were initially included. Of those, 8 participants discontinued intervention. No adverse events were reported. There was a non-significant time effect or time*group interaction for the mean changes in the BASFI score after baseline. Lack of significant differences between groups was observed for the secondary measures. However, more than half of participants in both groups achieved clinically relevant improvements in the BASFI score at follow-up assessments.
ConclusionThese preliminary results should be interpreted with caution, as they are exploratory and hypothesis-generating rather than confirmatory. Both interventions showed potential benefits but require further testing in larger, adequately powered trials.
Las terapias no farmacológicas se utilizan con frecuencia para el manejo de la espondiloartritis axial (EspAax). Este ensayo aleatorio y controlado tuvo como objetivo investigar el efecto de la suplementación con probióticos, con entrenamiento interválico de alta intensidad (HIIT), en pacientes con EspAax no radiográfica.
Materiales y métodosSe reclutaron individuos con EspAax no radiográfica y se les asignó a un grupo de suplementación con probióticos o a un programa de entrenamiento de fuerza impartido en línea durante 12 semanas consecutivas. El programa en línea se impartió de forma síncrona en pequeños grupos bajo supervisión profesional. La variable principal fue la discapacidad funcional, evaluada con el Índice Funcional de Espondilitis Anquilosante de Bath (BASFI). Las secundarias incluyen la actividad de la enfermedad (Índice de Actividad de la Enfermedad de Espondilitis Anquilosante de Bath), la movilidad espinal medida (Índice de Metrología de la Espondilitis Anquilosante de Bath) y el Cuestionario de Calidad de Vida en la Espondilitis Anquilosante. Las mediciones se realizaron una semana antes de la aleatorización (línea base) y a las 6, 12 y 24 semanas después de la línea base. Para el análisis estadístico, se utilizó un modelo mixto lineal para medidas repetidas. Se analizaron tanto la significación estadística como la relevancia clínica (basada en los umbrales del minimum clinically important difference). Los análisis se realizaron según el principio de intención de tratar.
ResultadosInicialmente, se incluyeron veinte pacientes. De estos, 8 participantes interrumpieron la intervención. No se reportaron eventos adversos. No se observaron efectos significativos del tiempo ni interacciones tiempo*grupo en los cambios medios de BASFI después de la línea base. Tampoco se encontraron diferencias significativas entre grupos en las medidas secundarias. Sin embargo, más de la mitad de los participantes en ambos grupos lograron mejoras clínicamente relevantes en la puntuación BASFI durante las evaluaciones de seguimiento.
ConclusiónEstos resultados preliminares deben interpretarse con cautela, ya que son exploratorios y generadores de hipótesis más que confirmatorios. Ambas intervenciones mostraron beneficios potenciales, pero requieren una evaluación adicional en ensayos de mayor tamaño y con suficiente potencia estadística.
Probiotics and high-intensity interval training showed comparable effects on functional disability in non-radiographic axial spondyloarthritis.
More than half of participants achieved clinically meaningful improvements in BASFI scores.
Both interventions are exploratory, hypothesis-generating non-pharmacological strategies.
Moderate adherence and acceptable safety profiles were observed in both groups.
Findings support further adequately powered randomized trials targeting microbiota and exercise modulation.
IntroductionAxial spondyloarthritis (axSpA) is a chronic inflammatory immune disease with a global prevalence ranging from 20 to 160 cases per 10,000 individuals [1]. The prevalence cited refers to overall axSpA, whereas non-radiographic axSpA is estimated at approximately 40–50% of all cases. The pathogenesis of axSpA is complex and involves genetic and environmental factors, including gut inflammation and the occurrence of dysbiosis (imbalance of gut microbiota) [2]. Various factors, such as a less biodiverse microbiota [3], together with the inability of some organisms to adapt to a pathogen-rich environment [4,5], have been related with the increasing prevalence of autoimmune diseases in the general population. There are two forms of clinical presentation for axSpA (radiographic and non-radiographic), determined by the presence or absence of radiographic sacroiliitis [6]. In early disease stages, the sacroiliac joints are most often affected, while more severe structural changes in the spine usually occur at later stages [7]. Around 78% of individuals with axSpA suffer from at least one peripheral musculoskeletal manifestation: peripheral joint disease, enthesitis and dactylitis. Hip and shoulder involvement are found in 34% of patients [8]. AxSpA is caused by inflammation in the axial skeleton and is characterized by joint pain and stiffness, increased fatigue, and limited function [8], resulting in a substantial physical, psychological, and socioeconomic burden [9]. The strongest evidence for exercise interventions supports improvements in BASDAI and BASFI scores, while effects on the Bath Ankylosing Spondylitis Metrology Index (BASMI) and the Ankylosing Spondylitis Quality of Life questionnaire (ASQoL) remain moderate.
The clinical management of axSpA often combines both pharmacological and non-pharmacological interventions to reduce inflammation and enhance health-related quality of life [10,11]. Pharmacological therapies, i.e., non-steroidal anti-inflammatory drugs and biological disease-modifying antirheumatic drugs, can be beneficial. However, these interventions come with substantial costs and associated adverse events, thus there is a need for complementary and alternative options. Among non-pharmacological treatments, exercise therapy, education, and changes in lifestyle are highly recommended [10]. Exercise therapy has shown positive effects on disease activity, pain intensity, and spinal mobility and function in individuals with axSpA [12]. A combination of strength and resistance training has been suggested as the best exercise approach, although the optimal dose remains to be elicited [13]. In addition, engaging in regular exercise can help to modify the composition and diversity of the microbiota, thereby contributing to modulate the inflammatory response [14]. Overall, current evidence for the impact of exercise in this population is still low to moderate [15].
Probiotics are defined ‘as live microorganisms that confer a health benefit when administered in an adequate amount’ [16]. The specific probiotic strains and daily dose (2×109CFU/day) were selected based on prior studies demonstrating immunomodulatory and gastrointestinal benefits in chronic inflammatory conditions. These can exert immunomodulatory effects [8,16], such as regulation of microbiota and increase of neurotransmitters [17], and reduce inflammatory factors, as demonstrated in individuals with different types of inflammatory arthritis [16]. Scarce research has investigated the impact of probiotics in patients with spondyloarthritis [18,19]. Thus, more studies are needed to assess their efficacy in those with chronic inflammatory diseases [20].
This study aimed to determine the effect of probiotic supplementation for 12 weeks, compared with an online-delivered strength training program, on functional disability in patients with non-radiographic axial spondyloarthritis. As a secondary aim, we compared the effects of probiotic supplementation and exercise therapy on disease activity, spinal mobility, and quality of life, as well as on planned biochemical measures. We hypothesized better outcomes in the probiotics group.
Materials and methodsStudy designThis was an exploratory, two-armed, parallel-group, and single-blinded pilot randomized controlled trial. Outcome assessors and data analysts were blinded to group allocation. The study protocol conformed to the Consolidated Standards of Reporting Trials (CONSORT) guidelines and was conducted according to the ethical principles of the Helsinki Declaration. The study received approval by the Institutional Review Board (on February 2, 2021, Camilo José Cela University, Madrid, Spain: 26012021) and was prospectively registered at ClinicalTrials.gov (Identifier: NCT05666115).
ParticipantsEligible individuals were recruited from the Region of Madrid, Spain, using advertisement and informative sessions organized in collaboration with the Spanish Coordinator of Spondyloarthritis Associations. Participants were required to be18 years of age or older and have a confirmed diagnosis of non-radiographic axSpA in accordance with the 2009 Assessment of the SpondyloArthritis International Society classification criteria [21], which are widely used for research purposes, although not diagnostic per se. In this study, the diagnosis had already been established by each participant's rheumatologist prior to study enrollment. Exclusion criteria were: any systemic disease or comorbidity that could severely impair exercise capacity [22], a high-sensitivity C-reactive protein level exceeding the upper limit of normal (2.87mg/L) [23], changes to medical treatment within the previous 2 months, and ongoing active peripheral arthritis; this was excluded to ensure the homogeneity of axial involvement and avoid confounding factors in functional outcome assessments. All participants received detailed information about the study, including potential risks and benefits, and provided oral and written informed consent before commencing. Baseline physical activity levels were collected and described to consider potential variability between groups that might influence response to interventions.
Randomization and blindingRandomization was executed using a computer-generated block randomization approach (randomized.com), with a block size of ten. An external researcher safeguarded the sequence for those directly engaged in the study and it was kept concealed in sealed opaque envelopes to preserve the evaluator's blindness to the outcomes. Researchers who collected or analyzed data remained unaware of the study aims and group allocation to ensure blinding of outcome assessors. Participants were not blinded due to the nature of the interventions. The therapists responsible for the interventions were not involved in symptom evaluation or outcome data collection.
InterventionsParticipants in the probiotics group received probiotic supplementation for 12 weeks. During the first 4 weeks, patients were instructed to take two capsules of Enterelle plus (Bromatech lab, Manno, Switzerland) during morning time (before or after breakfast). Enterelle plus contains specific strains, i.e., S. boulardii MTC5375 and SP92, E. faecium UBEF-41, and L. acidophilus LA-14, that contribute to reduce the mycotic flora and modulate the gastrointestinal transit. For the next 8 weeks, participants were told to ingest two capsules of Adomelle (Bromatech lab, Manno, Switzerland) at night, during or right after dinner. Adomelle contains three specific strains, Bifidobacterium breve B-3, L. acidophilus LA-14 and L. plantarum LP-115, which have been associated with improvements in abdominal symptoms, such as bloating, gas, and bowel irregularities. The strains and administration schedule were selected based on prior literature supporting their immunomodulatory properties and gut health effects in chronic inflammatory contexts.
The exercise group engaged in a 12-week online-administered Tabata protocol (20-s work bouts interspersed with 10-s rest), as a form of high-intensity interval training (HIIT). This type of intervention has demonstrated efficacy in individuals with various chronic conditions [24], including axSpA [12]. The exercise program included a combination of high knees, lunges, basic burpees, plank, skipping, mountain climbers, and jump squats. The exercise regime was conducted three times per week, with each session lasting approximately 8min (comprising 2 sets of 4min, with a 10-s rest interval). All sessions were individually tailored and supervised by a senior professional with a degree in Physiotherapy and Sciences of Physical Activity and Sport. Participants were advised to continue exercising provided pain remained ≤3/10 on the numerical rating scale. Adherence to the probiotic intervention was monitored weekly via structured phone calls. Adherence was calculated as the percentage of completed sessions or capsules consumed, verified via logbooks and capsule counts, and reported with 95% confidence intervals.
Outcome measuresThe primary outcome was functional disability during routine daily life activities, as evaluated with the Bath Ankylosing Spondylitis Functional Index (BASFI) [25,26]. The BASFI comprises 10 items (where higher scores indicate greater impairment) and is among the recommended core set of instruments for assessing axSpA [27]. The minimum clinically important difference (MCID) for BASFI has been established at 17.5% [28]. This outcome was selected because of its clinical relevance in reflecting the patient's physical limitations, rather than disease activity.
Secondary outcomes included disease activity, spinal mobility, and health-related quality of life. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [29]. The BASDAI explores five different constructs (fatigue, spinal or peripheral joint pain, localized tenderness, and morning stiffness), with lower scores indicating lower disease activity. This tool is easy to use and has demonstrated adequate validity and reliability [30]. The MCID for BASDAI has been established at 22.5% [28].
Spinal mobility was assessed with the Bath Ankylosing Spondylitis Metrology Index (BASMI), a comprehensive index that incorporates measures of lumbar flexion and side flexion (cm), tragus-to-wall and intermalleolar distance (cm), and cervical rotation (degrees). For bilateral measures such as neck rotation, lumbar side flexion and tragus-to-wall distance, the mean value was used. Final scores of the BASMI range from 0 “no mobility limitation” to 10 “severe limitation” [31]. Chest expansion was also evaluated following established guidelines [31]. With the participant in a standing position with both hands placed behind the head, measurements were taken at the fourth intercostal level by calculating the difference between maximal inspiration and expiration (cm) [32]. Health-related quality of life was assessed using the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) [33]. The ASQoL is a valid, feasible and reliable instrument. The final score of the ASQoL ranges from 0 to 18, where higher scores indicate lower quality of life [33]. Primary and secondary measures were collected in the morning (before breakfast) at four distinct time points: 1 week before randomization (baseline) and at 6, 12, and 24 weeks (primary endpoint) after baseline.
Statistical analysisSample size was calculated using the G*power software (Kiel University, Kiel, Germany). The estimation was based on an alpha level of 0.05, a desired power of 80%, a correlation of 0.5 among repeated measures, and a large effect size (η2=0.15) to obtain a clinically meaningful difference between groups in the BASFI (≥17.5%) [30] at the primary endpoint. According to these parameters, twelve participants were necessary to complete this pilot study.
Data were analyzed using the IBM Statistics Package for Social Science, v.26 (IBM Corp, NY, USA), and considering an intention-to-treat (ITT) approach. The Shapiro-Wilk test evaluated the normal distribution of the variables. Data are reported as mean (standard deviation, or 95% confidence interval) or in percentages. The two-sample t-test or χ2 test were used to examine potential differences in baseline values and demographic variables between the two groups. A linear mixed models for repeated measures was used to compare the differences between groups for the mean changes in the primary and secondary measures from baseline to 6, 12, and 24 weeks after baseline. The Bonferroni post hoc procedure was used to compare differences between groups according to time.
Clinical differences were calculated with percentage using the equations: (Baseline−Week 6)×100/Baseline, (Baseline−Week 12)×100/Baseline, and (Baseline−Week 24)×100/Baseline. A p-value <0.05 was considered statistically significant.
ResultsParticipants were enrolled between April and November 2021. Sixty individuals were screened for eligibility and 40 were excluded for different reasons (Fig. 1). A total of 20 patients provided consent to participate and were randomized. Of these, three individuals did not wish to continue taking probiotics, and five participants withdrew from the exercise program. Reasons for dropout included loss of motivation (n=3), schedule incompatibility (n=3), and medical reasons unrelated to interventions (n=2).
Twelve participants completed the final assessment; however, analyses followed an intention-to-treat approach using linear mixed models with all available observations, and participants who discontinued contributed data up to their last completed assessment. This resulted in a dropout rate of 40% (8 out of 20 participants), which is considerable and should be acknowledged as a limitation when interpreting the results. Mean adherence was 83% (95% confidence interval [CI]: 70–96%) in the probiotics group and 78% (95% CI: 63–91%) in the exercise group.
Adverse events were collected according to passive adverse event collection methods, reported weekly by phone. No adverse events were reported throughout the intervention period, and safety was monitored during weekly follow-ups. Adverse events were defined as any unfavorable symptom or medical occurrence temporally associated with the intervention, whether or not causally related, and were recorded via structured weekly phone follow-ups. The baseline clinical, medical, and demographic characteristics of the sample are included in Table 1. Both groups showed similar values for all outcomes (all, p>0.05).
Baseline clinical and demographic characteristics of the sample.
| Probiotics group(n=7) | Exercise group(n=5) | p-Value | |
|---|---|---|---|
| Age (years) | 46.8 (11.1) | 40.6 (8.9) | 0.324a |
| Women [n (%)] | 2 (28.6%) | 2 (40%) | 0.692b |
| Current smoking (>twice per week), yes [n (%)] | 2 (28.6%) | 0 (0%) | 0.210b |
| Self-reported digestive problems, yes [n (%)] | 3 (42.9%) | 2 (40%) | 0.925b |
| Regular physical activity (>twice per week), yes [n (%)] | 4 (57.1%) | 3 (60%) | 0.925b |
| Body composition | |||
| Height (cm) | 174.3 (7.5) | 169.4 (9.9) | 0.352a |
| Weight (kg) | 79.3 (6.9) | 68.8 (14.1) | 0.181a |
| Medication | |||
| NSAIDs, yes [n (%)] | 6 (85.7%) | 5 (100%) | 0.583b |
| TNF-inhibitor, yes [n (%)] | 5 (71.4%) | 4 (80%) | 0.636b |
| Antidepressant drugs, yes [n (%)] | 0 (0%) | 1 (20%) | 0.237b |
NSAIDs, non-steroidal anti-inflammatory drugs; TNF, tumor necrosis alpha. Data from continuous variables are presented as mean (standard deviation). Data for categorical variables are presented as numbers (%). Significance level was set at p<0.05.
Table 2 presents the results for the BASFI across different assessment points. There were no differences between the probiotics and exercise groups in score changes from baseline to 6, 12, and 24 weeks after baseline, with a non-significant time effect (F=0.311; p=0.654) or time*group interaction (F=0.539; p=0.528). The exercise group showed a statistically significant decrease in BASFI score at week 6 compared to week 24 (mean difference: −0.94; 95% CI, −2.01 to 0.13; p=0.041). Clinical changes in BASFI score surpassed the MCID (17.5%) [28] in 60% of participants in the exercise group at weeks 12 and 24 (18.06–50.37%). In the probiotics group, 4 out of 7 participants demonstrated improvements exceeding the 17.5% threshold (17.7–69.70%) at weeks 6, 12 and 24, while one patient improved around 5%, and 2 participants reported worsened BASFI scores (Fig. 2).
Results for the Bath Ankylosing Spondylitis Functional Index (BASFI, 0–10) in the study groups.
| Group | Measurement point | p-Valuea | ||||
|---|---|---|---|---|---|---|
| Baseline | Week 6 | Week 12 | Week 24 | Time | Time*group | |
| Probiotics(n=7) | 4.6 (3.6)[1.2–7.9] | 5.0 (3.5)[1.8–8.2] | 5.2 (3.0)[2.0–7.9] | 5.1 (3.5)[1.9–8.4] | 0.654 | 0.528 |
| Exercise(n=5) | 2.6 (2.5)[0.4–5.6] | 2.8 (1.2)[1.3–4.4] | 2.7 (1.8)[0.4–4.9] | 1.9 (1.8)[0.4–4.2] | ||
Data are presented as mean (standard deviation) with the [95% confidence interval]. Significance level was set at p<0.05.
As regards the secondary measures, there was no statistically significant time effect or time*group interaction for the BASDAI, the BASMI or the ASQoL (Table 3). In the exercise group, within-group changes were statistically significant for the BASMI scores when comparing weeks 6 and 24 (mean difference: 0.34 points; 0.19–0.48; p=0.003). Clinical changes in BASDAI score surpassed the MCID (22.5%) [28] in 2 participants from each group at week 6. This improvement was maintained at week 12, while 4 participants of the probiotics group improved between 42.15 and 100% at week 24. Changes were similar for the BASMI and ASQoL, except that all subjects clinically improved their BASMI score after 6 weeks of exercise (12.5–75%) (Fig. 2). There were no associations between the BASFI, the BASDAI, the BASMI and the ASQoL (p>0.05).
Scores for the BASDAI, BASMI, and ASQoL in the study groups.
| Outcome | Group | Measurement point | p-Valuea | ||||
|---|---|---|---|---|---|---|---|
| Baseline | Week 6 | Week 12 | Week 24 | Time | Time*group | ||
| BASDAI(0–10) | Probiotics(n=7) | 5.4 (3.4)[2.3–8.6] | 4.7 (2.6)[2.3–7.1] | 4.2 (3.1)[1.3–7.1] | 3.7 (3.5)[0.5–7.0] | 0.954 | 0.436 |
| Exercise(n=5) | 4.1 (1.8)[1.9–6.4] | 4.4 (4.1)[0.6–9.5] | 6.3 (2.5)[3.2–9.4] | 5.7 (2.9)[2.0–9.3] | |||
| BASMI (0–10) | Probiotics(n=7) | 1.9 (1.3)[0.7–3.1] | 1.7 (1.1)[0.7–2.8] | 1.7 (0.9)[0.8–2.7] | 2.0 (1.0)[1.1–2.9] | 0.148 | 0.884 |
| Exercise(n=5) | 0.9 (0.4)[0.4–1.5] | 0.7 (0.4)[0.2–1.2] | 0.9 (0.6)[0.2–1.7] | 1.1 (0.4)[0.5–1.5] | |||
| ASQoL (0–18) | Probiotics(n=7) | 8.6 (7.1)[2.0–15.1] | 8.7 (7.9)[1.4–16.1] | 8.6(7.7)[1.4–15.7] | 8.4 (7.5)[1.5–15.4] | 0.780 | 0.794 |
| Exercise(n=5) | 7.4 (5.2)[0.9–13.8] | 6.6 (3.1)[2.8–10.3] | 5.6 (3.8)[0.9–10.3] | 6.2 (3.5)[1.8–10.5] | |||
Data are presented as mean (standard deviation) with the [95% confidence interval]. Significance level was set at p<0.05.
ASQoL, Ankylosing Spondylitis Quality of Life Questionnaire; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASMI, the Bath Ankylosing Spondylitis Metrology Index.
This pilot randomized controlled trial explored the effects of probiotic supplementation compared with an online strength training program in patients with non-radiographic axial spondyloarthritis. No statistically significant differences were observed between groups for functional disability, disease activity, spinal mobility, or quality of life. These findings should be interpreted cautiously, given the exploratory and underpowered nature of the study.
Despite the absence of statistically significant between-group effects, more than half of participants in both interventions achieved clinically meaningful improvements in functional disability, as defined by MCID thresholds. This suggests potential feasibility and clinical relevance of both non-pharmacological strategies.
Clinical implicationsPrevious studies have demonstrated the benefits of exercise therapy in patients with axSpA [12,15]. At the end of both interventions, the authors detected that more than half of participants had clinically relevant improvements in the BASFI score at follow-up assessments. Although these improvements were produced in 60% of participants in the exercise group, there is no consensus on the optimal amount of exercise required to achieve clinically meaningful improvements. While HIIT programs, such as those structured as Tabata, have shown a positive impact in individuals with different chronic conditions [34–36], our specific intervention of three 8-min weekly sessions may have been insufficient in duration or intensity to induce robust anti-inflammatory or functional responses. For example, previous studies showing HIIT benefits used protocols lasting up to 1h per session [36]. This suggests that future protocols may require increased frequency or volume for optimal effects in axSpA populations. Therefore, the lack of response to exercise in the present trial may be attributed to an inadequate exercise dose (intensity, duration and frequency of sessions).
In a previous 12-week study involving 48 patients with axSpA, the use of a synbiotic supplementation, compared to placebo, showed improvements in the IL-17 and IL-23 expression. However, similar to our study, no significant changes were observed in the BASDAI score (or ASDAS-CRP) [37], indicating a lack of effect on functional disability. Another previous trial involving 63 patients with active spondyloarthritis compared the impact of an oral probiotic (S. salivarius K12, B. lactis LAFTI B94, L. acidophilus LAFTI L10) with placebo over a 12-week period. In line with our findings, no significant differences between groups were found for BASDAI or BASFI scores. In fact, a strong placebo effect was noted [18], with both groups demonstrating changes in most outcome measures over the course of the study. Regarding the lack of response to probiotics, it is possible that probiotic supplementation is insufficient per se to achieve noticeable improvements. Additionally, the regular medical treatment prescribed for the patients could interfere with the potential impact of probiotics. It is also possible that participants had severe alterations in their intestinal microbiota that could not be modified within a mere 12-week period of probiotics without dietetic or antibiotic treatment, or even that probiotics should be incorporated earlier in the course of the disease or in a more sustained manner over time. All of this, however, remains a speculation.
Study limitationsThis study presents several important limitations. The small sample size, largely due to the COVID-19 pandemic, limited statistical power and external validity, while a high attrition rate (40%) further reduced analytical robustness. In addition, biochemical and microbiota data could not be analyzed due to failures at the contracted laboratory, preventing the evaluation of key mechanistic outcomes related to probiotic effects.
Baseline variability may have contributed to interindividual response heterogeneity; however, the limited sample size did not allow formal subgroup or sensitivity analyses. Although patients receiving anti-TNF therapy were included – potentially influencing biomarker levels – this decision was necessary to preserve sample representativeness under pandemic-related constraints. These limitations warrant cautious interpretation of the findings; nevertheless, the study provides valuable pilot data to inform future research.
Future studies should explore factorial designs combining probiotic supplementation and exercise interventions, incorporating robust biomarkers (e.g., ASDAS-CRP, fecal calprotectin) and predefined response criteria.
ConclusionsOur findings suggest that probiotic supplementation for a 12-week period had a similar effect to a 12-week online strength training program in terms of functional disability, disease activity, spinal mobility, and quality of life in patients with non-radiographic axSpA. However, these preliminary findings must be interpreted with caution due to the limited sample size, high attrition, and lack of statistical power. More than half of the participants in both groups achieved clinically relevant changes in BASFI scores at week 12, suggesting potential benefits of both non-pharmacological strategies. Therefore, future research should involve larger, adequately powered randomized controlled trials, with extended intervention durations, alternative probiotic strains, and optimized exercise protocols. Moreover, future studies should consider evaluating malabsorption and gut microbiota alterations as key factors influencing treatment response, exploring the potential synergistic effects of combining microbiota modulation and exercise.
Institutional review board statementThe study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Camilo José Cela University (protocol code 26012021 and 02/02/2021).
Informed consentInformed consent was obtained from all subjects involved in the study.
Declaration of generative AI and AI-assisted technologies in the writing processDuring the preparation of this work the author(s) used ChatGPT in order to improve language. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
FundingThis research was conducted with resources of Camilo José Cela University.
Conflicts of interestThe authors declare no conflict of interest.
The authors want to sincerely thank the Spanish Coordinator of Spondyloarthritis Associations and all the patients and collaborating external researchers for their contribution.
