Effectiveness of Fecal Microbiota Transplantation in Nociplastic Pain Management: A Systematic Review

Abstract

Nociplastic pain, commonly observed in conditions such as Fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome, arises from altered central pain processing and involves complex mechanisms, including interactions between the gut–brain axis and immune dysregulation. Conventional therapies often fail to address this type of pain effectively, leading to interest in alternative approaches such as fecal microbiota transplantation. This technique has been proposed to restore gut microbial balance and modulate systemic inflammation, neuroinflammation, and neurotransmitter signaling. This systematic review, conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and registered in the International Prospective Register of Systematic Reviews (CRD42024611939), evaluated 13 studies with n = 409 participants, including clinical trials, case reports, and retrospective analyses. A quality assessment was performed using appraisal tools such as Cochrane RoB 2, ROBINS-I, NOS, and CARE. The results suggest that fecal microbiota transplantation may reduce pain intensity and improve fatigue and quality of life, particularly in patients with Fibromyalgia and irritable bowel syndrome. However, outcomes for Chronic Fatigue Syndrome and psoriatic arthritis were inconsistent and limited by methodological flaws, small sample sizes, and variability in protocols and donor selection. Although adverse events were minimal, the current evidence is insufficient to support widespread clinical use. High-quality, standardized studies are needed to confirm the efficacy of fecal microbiota transplantation. Until then, its application should remain experimental and interpreted with caution.

1. Introduction

Nociplastic pain is a complex chronic pain condition characterized by altered central pain processing and increased sensitivity, often in the absence of detectable tissue damage or ongoing inflammation [1,2,3]. This type of pain is prevalent in conditions such as Fibromyalgia [4,5], Chronic Fatigue Syndrome (CFS) [6,7], neuropathy [8], and irritable bowel syndrome (IBS) [9,10], profoundly impacting patients’ quality of life and posing a substantial burden on healthcare systems due to its persistent and treatment-resistant nature. Conventional therapies, often aimed at symptomatic relief, have demonstrated limited success, as they fail to adequately address the underlying pathophysiological drivers of nociplastic pain, including central sensitization, immune dysregulation, and gut–brain axis interactions [11,12].

The gut microbiota, a key modulator of systemic inflammation and neuroimmune pathways, has gained recognition for its role in influencing nociplastic pain [13,14]. Dysbiosis—an imbalance in the gut microbial ecosystem—may worsen nociplastic pain by triggering inflammatory responses and disrupting immune regulation, contributing to both central and peripheral sensitization [15,16,17]. This highlights the gut–brain axis as a promising therapeutic target, with the potential to mitigate chronic inflammation and alter pain perception through the restoration of microbial balance [18,19]. In this context, therapies aimed at modifying the gut microbiota, such as fecal microbiota transplantation (FMT), have garnered growing interest [20,21].

FMT involves transferring processed stool from a healthy donor to a recipient with dysbiosis to restore microbial balance and diversity (eubiosis) [22]. This intervention requires meticulous donor screening, careful preparation and preservation of beneficial microorganisms [23], and precise administration via colonoscopy [24], nasogastric tube [25], or encapsulated formulations [26]. While FMT has shown significant efficacy in treating recurrent Clostridium difficile infections by re-establishing microbial equilibrium, its potential application to manage nociplastic pain remains a novel and emerging area of exploration [27].

Preliminary evidence from human studies suggests that FMT may offer a therapeutic approach for reducing nociplastic pain by directly targeting gut dysbiosis. Restoration of a balanced microbiota has been associated with the modulation of immune responses and reductions in systemic inflammation, both critical contributors to nociceptive and nociciplastic pain [28,29]. For instance, studies on individuals with irritable bowel syndrome and Fibromyalgia have reported decreased levels of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, following FMT [30,31].

Additionally, improvements in visceral hypersensitivity have been observed in irritable bowel syndrome, highlighting its potential role in addressing nociplastic pain mechanisms [32]. Changes in neurotransmitter synthesis, including serotonin and dopamine, as well as neuroactive tryptophan metabolites, have also been documented in human studies, further supporting the potential of fecal microbiota transplantation to influence gut–brain axis signaling pathways [33]. This biochemical modulation, mediated by shifts within the gut–brain axis, suggests that FMT can address the root causes of nociplastic pain rather than merely alleviating symptoms [34].

Despite preliminary promising findings, there remains a notable gap in understanding FMT’s full therapeutic potential in managing nociplastic pain, with limited existing evidence necessitating further research into its mechanisms, safety, efficacy, and long-term outcomes. This systematic review aims to synthesize current knowledge on the impact of FMT in modulating nociplastic pain, focusing on its influence on immune and inflammatory responses, pain modulation, microbiota composition, and patient-centered outcomes such as pain reduction and quality of life.

2. Materials and Method

2.1. Data Sources and Search Strategy

A systematic review of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [35]. The protocol for this systematic review was pre-registered with the PROSPERO database CRD42024611939. The search was performed from 10 November 2024 to 10 December 2024 to identify all available studies examining the efficacy of FMT in addressing nociplastic pain syndrome in various conditions across the following databases: MEDLINE (PubMed), ELSEVIER (Scopus), EBSCOhost, Cochrane Library, and Web of Science (WOS). The strategy used in MEDLINE (PubMed) was as follows: (“faecal microbiota transplant” [Title/Abstract] OR “fecal microbiota transplantation” [Title/Abstract] OR “fecal transplantation” [Title/Abstract] OR “faecal transplant” [Title/Abstract] OR “gut microbiota” [Title/Abstract]) AND (“nociplastic pain” OR “chronic pain” OR “pain sensitization” OR “central sensitization” OR “gut-brain axis” OR “pain modulation”).

Two independent researchers (N.H.G. and H.A.L. conducted the search, and a blinded investigator (U.R.C.) evaluated all retrieved articles by title and abstract, followed by a full-text assessment to determine eligibility. In the event of discrepancies, a fourth author (S.M.P.) acted as an arbitrator. Table S1 outlines the detailed search strategy.

2.2. Inclusion and Exclusion Criteria

This review considered studies that met the following criteria: clinical trials (randomized and non-randomized) and observational studies as case series and case–control studies. Eligible publications were required to be (1) published between 1 January 2014 and 30 November 2024 and (2) available in full-text format in (3) English, Spanish, French, Portuguese, or Arabic. The focus was on (4) adult populations undergoing FMT with an emphasis on its (5) therapeutic impact on nociplastic pain and conditions characterized by central sensitization. These included chronic inflammatory states such as Fibromyalgia, IBS, CFS, neuropathic pain syndromes, and other disorders where nociplastic pain is a critical component. Eligible studies assessed outcomes related to (6) pain modulation, physical and psychological symptoms, immune and inflammatory markers, safety profiles, or quality of life improvements following FMT.

Studies were excluded if they did not match the specified (1) study types or (2) were published outside the defined timeframe. Publications (3) without full-text access or (4) those not available in English, Spanish, French, Portuguese, or Arabic were also excluded. Further exclusions (5) applied to studies involving non-adult populations, such as pediatric cases, or studies that did not directly evaluate the therapeutic impact of FMT on conditions involving central sensitization. (6) Abstract-only publications, commentaries, opinion pieces, and conference proceedings were not considered for inclusion.

2.3. Data Extraction

Data extraction was conducted independently by two authors (N.H.G. and H.A.L.), with a third author (U.R.C.) available to resolve any discrepancies. A standardized data extraction template, structured according to the PICO (Population, Intervention, Comparison, Outcomes) framework, was utilized to collect comprehensive details. This included authorship, year and country of publication, study design, study objectives, results, participant characteristics (e.g., disease characteristics, intervention specifics, sample size, gender distribution), details of the intervention and control groups, measured outcomes, and study conclusions. The data extraction process adhered to the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0 [35]. The reliability of the data table was evaluated using a representative sample of studies to ensure consistency and accuracy.

2.4. Methodological Quality Assessment

2.4.1. Randomized Controlled Trials

The Cochrane RoB 2 tool was utilized for randomized controlled trials (RCTs), including double-blind and placebo-controlled designs [36]. This instrument assesses potential biases across several key domains: the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results. Each domain is rated as “low risk”, “some concerns”, or “high risk” of bias, culminating in an overall risk-of-bias judgment for each study. This tool is widely recognized for its rigor and utility in evaluating the internal validity of RCTs, ensuring the methodological integrity and transparency of study findings.

2.4.2. Non-Randomized Clinical Trials

This tool was employed for assessing non-randomized, open-label trials. The ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions) tool [37] evaluates bias across seven distinct domains, including confounding, participant selection, classification of interventions, deviations from intended interventions, missing data, outcome measurement, and selection of the reported result. Studies are categorized as presenting a “low”, “moderate”, “serious”, or “critical” risk of bias. The tool is specifically designed to address biases that arise from non-randomized intervention designs, highlighting areas where study design may impact the reliability of outcomes.

2.4.3. Case Reports

The Consensus-based Clinical Case Reporting Guideline Development (CARE) guidelines [38] were applied for the assessment of case reports. This instrument ensures comprehensive and structured reporting by evaluating key elements such as patient information, clinical findings, diagnostic assessment, therapeutic intervention, timeline, follow-up, and outcomes. Adherence to these guidelines allows for a detailed and transparent presentation of individual patient cases. While case reports inherently lack generalizability and control groups, adherence to CARE guidelines ensures that they provide valuable, high-quality insights into specific clinical scenarios.

2.4.4. Observational Study

The Newcastle–Ottawa Scale (NOS) [39] was used to evaluate the quality of non-randomized studies, particularly retrospective outcome studies. This tool assesses studies across the following three broad categories: selection of study participants, comparability of cohorts, and ascertainment of exposure or outcomes. Studies are rated based on their adherence to methodological rigor, with a “star” system that identifies strengths and potential sources of bias. The NOS is widely used for assessing the methodological robustness of cohort and case–control studies, providing a reliable framework for evaluating study quality and minimizing the impact of potential biases.

3. Results

3.1. Study Selection

The selection process for publications commenced with an extensive search across multiple academic databases, resulting in the identification of a total of 1837 studies. The contributions from individual databases were as follows: MEDLINE (PubMed) (n = 412 studies), ELSEVIER (Scopus) (n = 523 studies), EBSCOhost (n = 387 studies), Cochrane Library (n = 200 studies), and Web of Science (WOS) (n = 315 studies).

Following the removal of 423 duplicate entries, a total of 1414 unique articles were retained for the screening phase. During this phase, the titles and abstracts of these articles were evaluated for their relevance to the research question, resulting in the exclusion of 1067 articles for reasons such as a lack of relevance to the study’s scope, a focus on non-target populations, or the absence of primary data. Consequently, 347 articles were selected for a detailed full-text eligibility review.

Among the 347 articles assessed at the full-text stage, 335 were excluded for various reasons, including differing study designs that did not fit the inclusion criteria (e.g., systematic or narrative reviews) (n = 131), interventions outside the defined scope of interest (n = 85), the absence of relevant outcome measures (n = 60), publications in non-target languages (n = 33), and articles with access restrictions or limited data (n = 26). Ultimately, 13 studies were selected for qualitative synthesis. Figure 1 illustrates the PRISMA 2020 flowchart for the study selection process.

Figure 1. The PRISMA 2020 flowchart shows the systematic review process. Out of n = 1837 identified records, n = 423 duplicates were removed, leaving n = 1414 articles screened by title and abstract, excluding n = 1067. From n = 347 full-text assessments, n = 334 were excluded due to reasons such as differing study designs, irrelevant interventions, or access issues. A total of 13 studies were included in the final qualitative synthesis, comprising clinical trials, case reports, and retrospective studies. Source: own work.

3.2. Characteristics of Included Studies

The 13 included studies focused on clinical trials involving Fecal Microbiota Transplantation (FMT). Of these, 7 were randomized, double-blind, placebo-controlled trials [40,41,42,43,44,45,46], 2 were open-label, randomized trials [47,48], 3 were case reports [49,50,51], and 1 was a retrospective outcome study [52]. The included studies examined populations with different nociplastic pain conditions such as IBS [40,42,43,45,48,50,52], Fibromyalgia [47,50], Chronic Fatigue Syndrome [46,50,52], psoriatic arthritis [44], rheumatoid arthritis [51], systemic sclerosis [41], and diabetic neuropathy [49], totaling a diverse sample.

Patient groups varied widely, including 60 Fibromyalgia patients in a Chinese open-label trial [40], 11 CFS patients in a Finnish pilot study [41], and smaller cohorts, such as individual case reports for RA and diabetic neuropathy [45,51]. Interventions typically involved FMT delivered via colonoscopy [40,42,45,47,49,50,51], gastroscopy [44,45,50], or rectal catheterization [48], with follow-up periods ranging from 4 months [45] to over a year [43]. Comparators included placebo groups using autologous stool or continued standard treatment. Outcomes varied, encompassing symptom reduction (e.g., pain and fatigue) engraftment rates [42], gut microbiota composition changes [46], quality of life improvements [49,50], and adverse events [44,46].

Notable findings included significant symptom relief in some cases [40,45], while other studies reported limited or no efficacy compared to placebo [41,44], emphasizing the need for further research. Geographically, the studies were conducted in countries such as China [40,45,51], Finland [47,51], Denmark [34], Norway [46,49,50], India [42], Belgium [43], the United Kingdom [48], and Germany [52]. More details in Table 1 below.

Table 1. Characteristics of the included studies.

Irritable Bowel Syndrome
Year, Author, and Country	Study Design	Participants	Intervention	Comparison	Outcomes	Conclusion
Singh et al. (2022) [48] India	Randomized, placebo-controlled, single-center study	N = 44 (Irritable Bowel Syndrome-d patients mean age ~ 39 years, ~50% female)	Dose: FMT alone or with antibiotic pretreatment. Route: Colonoscopy. Follow-up: 10 weeks.	Placebo	Primary Outcomes (Bacterial Engraftment): o Median engraftment rates: ▪ FMT group alone: 15.5%. ▪ R-FMT group: 5% (p = 0.04 vs. FMT alone). ▪ CM-FMT group: 2.4% (p = 0.002 vs. FMT alone). o Antibiotic pretreatment significantly reduced engraftment compared to FMT alone. Secondary Outcomes (Week 10): IBS-SSS (symptom severity): o Mean change: ▪ FMT alone group (−32.3). ▪ R-FMT group (−85.3). ▪ CM-FMT group (−114). ▪ Placebo group (−93.4) (p = 0.55). IBS-QoL (quality of life): o Mean change: ▪ FMT alone (+15.4). ▪ R-FMT (+19.3). ▪ CM-FMT (−1.2). ▪ Placebo (+9.4) (p = 0.61). o No statistically significant differences in symptom relief or quality of life between FMT and placebo. Adverse Events: Mild, unrelated events: urinary tract infections, nasal congestion, and headaches.	FMT alone may provide better microbiota engraftment for IBS-D
Holvoet et al. (2021) [42] Belgium	Randomized, placebo-controlled trial	N = 62 (Irritable Bowel Syndrome patients with bloating)	Dose: Single nasojejunal administration of 300 mL donor stool. Route: Nasojejunal tube. Follow-up: 12 weeks (up to 1 year).	Autologous stool (placebo)	Primary Outcomes (12 weeks): Symptom improvement: o 56% in FMT group vs. 26% in placebo (p = 0.03) Bloating reduction: o Median improvement 19% (FMT group) vs. no significant improvement (placebo group) Significant response difference by gender: o Women (69%) responded better than men (29%) (p = 0.01). Secondary Outcomes: Abdominal discomfort: o Mean reduction of 19% (p = 0.001). Abdominal pain: o Mean reduction of 26% (p = 0.001). Quality of life: o Mean improvement of 16% (p = 0.03). Microbiota Analysis: o Responders had higher baseline microbial diversity than non-responders (p = 0.04). Long-term Effects: o Sustained response in 21% of initial responders at 1 year. o Retransplantation success rate: 67% for patients who initially responded but lost the effect. Adverse Events: None significant.	FMT effective for IBS, but long-term effects vary
Lahtinen et al. (2020) [45] Finland	Randomized clinical trial	N = 49 (Irritable Bowel Syndrome)	Dose: 30 g donor stool. Route: Colonoscopy. Follow-up: 12 weeks.	Autologous FMT (placebo)	Primary Outcomes (12 weeks) IBS Symptom Severity Score [IBS-SSS], Responders (≥50%-improvement) o FMT group: 11/23 (48%). o Placebo group: 11/26 (42%) p = 0.68. Secondary Outcomes: Quality of life (15D and IBS-QoL): o No significant changes at any time point between groups. Depression (BDI) and anxiety (BAI): o No significant differences within or between groups. Microbiota composition: o FMT group donor-like microbial changes sustained up to 52 weeks. o Placebo group showed no significant microbiota alterations. Stool consistency (dry weight): o FMT group ▪ Significant reduction in stool water content at: ▪ 26 weeks (p = 0.005). ▪ 52 weeks (p = 0.001). Adverse Events: o FMT group: 30% mild events (diarrhea, bloating).Placebo group: 39% mild events (including 4 cases of transient fever, p = 0.045).	FMT provided transient symptom relief, but not a sustained improvement over placebo, limiting its clinical use.
El-Salhy et al. (2019) [40] Norway	Randomized, double-blind, placebo-controlled study	N = 165 (Irritable Bowel Syndrome)	Dose: 30 g or 60 g fecal microbiota suspension (from a superdonor). Route: Gastroscope. Follow-up: 12 weeks.	Placebo (own stool)	Primary Outcomes IBS Symptom Severity Score [IBS-SSS], Responders (≥50%-improvement) o Placebo group: 23.6% responders. o 30 g FMT group: 76.9% responders (p < 0.0001 vs. placebo). o 60 g FMT group: 89.1% responders (p < 0.0001 vs. placebo, p = 0.004 vs. 30 g FMT). Secondary Outcomes: Fatigue (FAS): o Significant reductions in FMT groups compared to placebo at 3 months (p < 0.05). Quality of Life (IBS-QoL): o Significant improvement in both FMT groups (p < 0.0001). Microbial Diversity: o Increased abundance of beneficial bacteria (e.g., Alistipes spp., Lactobacillus spp.). Adverse Events: o FMT group: Mild and transient (nausea, abdominal pain, diarrhea, constipation). Placebo group: No significant adverse events.	FMT is effective for IBS, showing a dose-dependent response with emphasis on donor selection.
Johnsen et al. (2019) [43] Norway	Double-blind, randomized, placebo-controlled trial	N = 90 (non-constipated Irritable Bowel Syndrome patients)	Dose: 50–80 g of donor feces (fresh or frozen). Route: colonoscopy. Follow-up: 6 months.	Placebo (own stool)	Primary Outcomes (6 months): IBS-Quality of Life (QoL): o Responders (≥14-point improvement): ▪ FMT group: 85%. ▪ Placebo group: 61%. ▪ OR: 3.8 (95% CI 1.3–11.0), p = 0.011. ▪ No significant differences at 12 months. Fatigue Impact Scale (FIS): o Responders (≥20-point improvement): ▪ FMT group: 35%. ▪ Placebo group: 11%. ▪ OR: 4.4 (95% CI 1.2–16.5), p = 0.02. ▪ No significant differences at 3 or 12 months. Secondary Outcomes: Fatigue subgroup:  o FMT group effects on QoL and fatigue were more sustained in subgroups without functional comorbidities or self-reported depression. Depression subgroup: o Sustained fatigue improvement for FMT group at 12 months (p = 0.001). QoL o Subdomains most improved: activity interference, body image, and relationships. Adverse Events: No serious adverse events; mild transient events reported in both groups.	QoL and fatigue improved in select IBS patients
Chronic Fatigue Syndrome
Salonen et al. (2023) [46] Finland	Randomized, double-blinded, placebo-controlled pilot study	N = 11 (Chronic Fatigue Syndrome patients, 10 female, 1 male, mean age 42.2 years)	Dose: Universal donor stool. Route: Colonoscopy. Follow-up: 1 and 6 months.	Placebo (autologous FMT)	Primary Outcomes Visual Analog Scale (VAS)-Fatigue: o CFS group: ▪ Baseline: 62.4 (±22.4). ▪ 1 month: 60.0 (±21.8), p = 0.88. ▪ 6 months: 72.8 (±13.6), p = 0.45. o Placebo group: ▪ Baseline: 76.0 (±3.6). ▪ 1 month: 73.7 (±4.9), p = 0.41. ▪ 6 months: 69.5 (±9.7), p = 0.20. o Conclusion: No significant changes between groups or over time. Modified Fatigue Impact Scale (MFIS): o Physical subscale: ▪ CFS group: ▪ Baseline (29.4 ± 2.4). ▪ 1 month (26.2 ± 2.8, p = 0.08). ▪ 6 months (27.4 ± 4.6, p = 0.42). ▪ Placebo group: ▪ Baseline (30.0 ± 6.2). ▪ 1 month (29.5 ± 4.8, p = 0.88). ▪ 6 months (25.7 ± 7.9, p = 0.32). o Total: ▪ CFS group: ▪ Baseline (59.6 ± 9.2), 1 month (53.5 ± 9.9, p = 0.45). ▪ 6 months (58.6 ± 11.9, p = 0.79). ▪ Placebo group: ▪ Baseline (61.0 ± 8.3). ▪ 1 month (62.0 ± 9.8, p = 0.85). ▪ 6 months (56.2 ± 20.3, p = 0.61). o Conclusion: No significant differences between or within groups. 15D and EQ-5D-3L (Quality of Life): o Profiles showed no significant changes in either group at any time point. Adverse Events: None reported.	FMT was safe but did not improve QoL for CFS patients
Thurm et al. (2017) [50] Germany	Case report and literature review	N = 1 (58-year-old male with Fibromyalgia, Irritable Bowel Syndrome with Chronic Fatigue Syndrome)	Dose: Self-administered FMT (six consecutive enemas using stool from a screened donor). Route: Enema. Follow-up: 9 months.	No formal comparison	Primary Outcomes: Symptom resolution: o Total improvement in fatigue, depression, insomnia, and cognitive impairment (e.g., memory loss, concentration deficit). o Physical examination showed no Fibromyalgia tender points. Occupational status: Returned to full-time employment after years of disability. Microbiota Analysis (before vs. after FMT group): Streptococcus: Decreased from 26.39% to 0.15%. Bifidobacterium: Increased from 0% to 5.23%. Bacteroidetes phylum: Increased from 0.42% to 39.82%. Firmicutes phylum: Decreased from 99.35% to 36.17%. Adverse Events: None reported.	FMT may help complex functional disorders, though randomized trials are needed
Kenyon et al. (2019) [52] United Kingdom	Retrospective outcome study	N = 42 (Chronic Fatigue Syndrome, 30 with Irritable Bowel Syndrome)	Dose: 10 rectal FMTs from different donors. Route: Rectal catheter. Follow-up: Not specified.	Standard oral approaches	Primary Outcomes Symptoms (% Improvement): o FMT Group: Median improvement 70%. o Oral Group: Median improvement 30%. o Statistical significance: Mann–Whitney U = 111.5, p = 0.003. Secondary Outcomes: FMT led to complete resolution of IBS in a majority of patients. Sustained energy level improvements in FMT recipients compared to marginal benefits in oral group. Adverse Events: o FMT: 1 patient developed diarrhea, leading to treatment discontinuation; another tolerated only half the implants. No severe adverse events reported.	FMT appears less effective for some CFS patients; further trials recommended
Fibromyalgia Syndrome
Fang et al. (2024) [47] China	Open-label, randomized, non-placebo-controlled study	N = 60 (Fibromyalgia Syndrome)	FMT vs. continued standard treatment.	Standard treatment	Primary Outcomes: Symptoms (% Improvement): o FMT significantly improved IBS symptoms compared to placebo. o Response Rate: 59% in the FMT group versus 36% in the placebo group. Secondary Outcomes: Quality of Life: o Enhanced health-related quality of life, particularly related to gastrointestinal well-being. Safety: o Adverse events were generally mild and transient. Adverse Events: Most common side effects were temporary abdominal bloating and diarrhea.	FMT may relieve Fibromyalgia symptoms by modulating gut microbiota. Further research is needed for confirmation.
Psoriatric arthritis
Kragsnaes et al. (2021) [44] Denmark	Randomized, double-blind, placebo-controlled trial	N = 31 (Psoriatic arthritis)	Dose: Single stool donation (50 g). Route: Gastroscopy (Duodenum). Follow-up: 26 weeks.	Sham (Placebo)	Primary Outcomes Treatment Failure: o FMT group: 60% experienced failure (9/15). o Placebo group: 19% experienced failure (3/16). o Risk ratio: 3.20 (95% CI 1.06–9.62), p = 0.018. Secondary Outcomes: HAQ-DI Score: o FMT group: Mean change: −0.07 (95% CI −0.22 to 0.09). o Placebo group: Mean change: −0.30 (95% CI −0.44 to −0.15). o Difference: 0.23 (95% CI 0.02–0.44), p = 0.031. ACR20 Response: o FMT group: 47% (7/15). o Placebo group: 50% (8/16), not significant. Change in Enthesitis Index (SPARCC): o FMT group: −1.9 (95% CI −3.5 to −0.3). o Placebo group: −4.3 (95% CI −5.8 to −2.8). o Difference: 2.3 (95% CI 0.1–4.5), p < 0.05. Adverse Events: o FMT: 93% reported mild AEs (e.g., abdominal discomfort, flatulence). o Placebo: 88% reported mild Aes. No serious adverse events reported.	FMT appears less effective than placebo for PsA symptoms
Rheumatoid arthritis
Zeng et al. (2021) [51] China	Case report	N = 1 (20-year-old female with rheumatoid arthritis)	Dose: 300 mL of fecal microbiota suspension (from an 8-year-old healthy donor). Route: Colonoscopy. Follow-up: 4 months.	No comparison	Primary Outcomes Disease Activity Score (DAS28): o Baseline: 6.6. o Day 42: 1.9. o Day 78: 1.4. o Improvement: −5.2 points (clinically significant reduction). Health Assessment Questionnaire Disability Index (HAQ-DI): o Baseline: 1.4. o Day 7: 0.05 (sustained until day 78). Rheumatoid Factor Titer (IU/mL): o Baseline: 314. o Day 42: 158. o Day 78: 135.9. Adverse Events: None reported.	FMT shows potential for RA but requires further research
Systematic sclerosis
Fretheim et al. (2020) [41] Norway	Double-blind, placebo-controlled randomized pilot trial	N = 10 (patients with systemic sclerosis)	Dose: Commercial anerobic human intestinal microbiota (ACHIM). Route: Gastroduodenoscopy. Follow-up: 16 weeks with two FMT sessions in weeks 0 and 2.	Placebo	Primary Outcomes Symptom Improvement: o UCLA GIT 2.0 score improvement in 3/5 FMT patients vs. 1/4 placebo patients at week 4 and week 16. o Improvements more pronounced for bloating, diarrhea, and fecal incontinence in FMT group. Adverse Events: o FMT group: ▪ Mild and transient (bloating, nausea, diarrhea, constipation). o Placebo group: ▪ 2 serious procedure-related events (laryngospasms, duodenal perforation). Microbiota Changes: o FMT group increased microbial diversity at week 16 (p < 0.02). o Relative abundance of Ruminococcaceae, Lachnospiraceae, and Eggerthellaceae increased in FMT group. Secondary Outcomes: o No significant changes in systemic markers (CRP, ESR) or lung function (FVC, DLCO).	FMT reduced GI symptoms but had procedural risks
Diabetic neuropathy
Cai et al. (2018) [49] China	Clinical case report	N = 1 (female, diabetic neuropathy)	Dose: Two FMTs over 3 months. Route: Colonoscopy. Follow-up: 3 months.	No explicit comparison group	Primary Outcomes: Visual Analog Scale (VAS): o Decreased from 7.2 (severe pain) to 2.5 (mild pain). Glycemic control: o Fasting plasma glucose improved from 8.7 mmol/L to 4.5 mmol/L. HbA1c: o Reduced from 7.5% to 6.3%. Neuropathy symptoms: o Significant reduction in limb pain and paresthesia. No need for painkillers post-treatment. Electromyogram: o Improved motor conduction velocity in tibial nerve, although sensory dysfunction persisted. Adverse Events: Mild nausea, vomiting, and diarrhea post-FMT, resolved within days.	FMT may offer therapeutic benefits for diabetic complications

Abbreviation: ACR20 (American College of Rheumatology 20% Improvement Criteria), CFS (Chronic Fatigue Syndrome), CRP (C-reactive Protein), DAS28 (Disease Activity Score for 28 Joints), DLCO (Diffusing Capacity of the Lung for Carbon Monoxide), EQ-5D-3L (EuroQol-5 Dimension-3 Level Questionnaire), FMT (Fecal Microbiota Transplantation), FVC (Forced Vital Capacity), GI (Gastrointestinal), HAQ-DI (Health Assessment Questionnaire Disability Index), HbA1c (Glycated Hemoglobin), HRQOL (Health-related Quality of Life), IBS (Irritable Bowel Syndrome), IBS-D (Diarrhea-predominant Irritable Bowel Syndrome), IBS-QoL (Irritable Bowel Syndrome Quality of Life), IBS-SSS (Irritable Bowel Syndrome Symptom Severity Score), MFIS (Modified Fatigue Impact Scale), QoL (Quality of Life), RR (Risk Ratio), UCLA GIT 2.0 (University of California, Los Angeles Gastrointestinal Symptom Rating Scale 2.0), VAS (Visual Analog Scale).

3.3. Methodological Quality Assessment

3.3.1. Randomized Controlled Trials

For the randomized controlled trials, including those with double-blinding and placebo controls [40,41,42,43,44,45,46] the Cochrane Risk of Bias (RoB) 2 tool was used. These studies generally exhibited strong methodological rigor, demonstrating robust random sequence generation and allocation concealment. However, concerns were noted in some studies regarding the blinding of outcome assessment and selective reporting, which may have affected the reliability of specific outcomes.

3.3.2. Open-Label Trials

The open-label trials [47,48] were evaluated using the ROBINS-I tool (Risk of Bias in Non-randomized Studies of Interventions). This assessment revealed a moderate risk of bias predominantly arising from the open-label nature of the studies, which may introduce potential performance and detection biases that could affect the interpretation of the results.

3.3.3. Case Reports

Case reports [49,50,51] were evaluated according to the CARE (Case Report) guidelines. All reports adhered well to structured presentation standards and offered detailed patient data. However, they were inherently limited due to the absence of control groups, small sample sizes, and restricted generalizability. Notably, Thurm et al. (2017) [50] presented a unique combination of case reports and literature review, providing insights into complex functional disorders treated with self-administered FMT, though the findings underscore the necessity for randomized trials.

3.3.4. Retrospective Outcome Study

The retrospective outcome study [52] was assessed using the Newcastle–Ottawa Scale (NOS) for non-randomized studies. This evaluation indicated moderate quality, with primary concerns related to cohort selection and comparability, which could influence outcome interpretations. In summary, while many studies demonstrated a sound methodological basis, further rigorous trials with larger, more diverse samples are warranted to validate findings and bolster evidence for the efficacy of FMT across various conditions. For further details, refer to Table 2 below.

Table 2. Methodological Quality Analysis.

Study	Design	Methodological Quality Tool	Final Score	Observed Biases
El-Salhy et al. (2019) [40]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	High	Open-label design leading to potential performance and detection biases.
Fretheim et al. (2020) [41]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	Moderate	Concerns with blinding of outcome assessment and selective reporting.
Holvoet et al. (2021) [42]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	Low	Open-label nature affecting blinding and performance outcomes.
Johnsen et al. (2019) [43]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	High	Appropriate randomization and effective blinding; potential unclear risk from missing data handling and selective reporting.
Kragsnaes et al. (2021) [44]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	Moderate	Issues with selective reporting noted.
Lahtinen et al. (2020) [45]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	Moderate	Limited by lack of comparative data and generalizability.
Salonen et al. (2023) [46]	Randomized, double-blind, placebo-controlled	Cochrane RoB 2	Moderate	Limited by small sample size and short follow-up.
Fang et al. (2024) [47]	Open-label, randomized	ROBINS-I	Moderate	Potential blinding bias.
Singh et al. (2022) [48]	Open-label, randomized	ROBINS-I	Moderate	Issues with selection bias and comparability between cohorts.
Cai et al. (2018) [49]	Case report	CARE	Good	Minor concerns regarding selective reporting.
Thurm et al. (2017) [50]	Case report	CARE	Good	Minimal concerns noted.
Zeng et al. (2021) [51]	Case report	CARE	Good	Inherent limitations due to case report’s nature.
Kenyon et al. (2019) [52]	Retrospective outcome study	NOS	Moderate	Detailed patient outcomes but limited generalizability and need for controlled trials.

This table presents the methodological quality analysis of the included studies. The table evaluates key domains such as risk of bias, study design, intervention classifications, and outcome measurements to ensure a comprehensive assessment of methodological rigor and potential limitations across all included studies. This analysis underscores the strengths and limitations of each study, providing critical insight into the reliability and validity of the findings.

3.4. Main Results

3.4.1. Severity of Nociplastic Pain Following FMT

Fibromyalgia and CFS are conditions characterized by chronic nociplastic pain, often stemming from central sensitization. Fang et al. (2024) [47] conducted an open-label randomized trial on 60 Fibromyalgia patients, demonstrating significant reductions in pain intensity and fatigue following FMT compared to standard treatment, suggesting that FMT may impact nociplastic pain through gut microbiota modulation.

Conversely, Salonen et al. (2023) [46] evaluated 11 CFS patients in a double-blind, placebo-controlled pilot study, finding no significant improvements in fatigue or quality of life. Similarly, Kenyon et al. (2019) [52], in a retrospective study of 42 patients with CFS and IBS, found limited efficacy of FMT compared to standard treatments, highlighting the complexity of nociplastic pain in CFS. Notably, Thurm et al. (2017) [50] reported significant improvement in a patient with Fibromyalgia, IBS, and CFS following self-administered FMTs, pointing to potential benefits of gut microbiota modulation in complex nociplastic pain syndromes, though further randomized trials are needed.

Irritable bowel syndrome is a functional gastrointestinal disorder often associated with nociplastic pain due to disrupted gut–brain communication. In this sense, Singh et al. (2022) [48] conducted a randomized, placebo-controlled study on IBS patients, noting improved microbiota engraftment with FMT, but no significant impact on symptom severity. This suggests that while FMT may modify gut microbiota, its influence on nociplastic pain symptoms in IBS can be limited. Holvoet et al. (2021) [42] and Lahtinen et al. (2020) [45] observed initial symptom relief in IBS patients receiving FMT, but effects diminished over time, indicating challenges in achieving sustained modulation of nociplastic pain pathways. However, Johnsen et al. (2019) [43] and El-Salhy et al. (2019) [40] highlighted improvements in fatigue and quality of life among IBS patients, showing FMT’s potential to impact nociplastic pain-related symptoms, particularly where gut dysbiosis is implicated.

Psoriatic arthritis and rheumatoid arthritis present a combination of inflammatory and nociplastic pain. Kragsnaes et al. (2021) [44] found FMT less effective than a placebo for psoriatic arthritis symptoms in a double-blind, placebo-controlled trial, underscoring the difficulty of modulating nociplastic pain through gut interventions in autoimmune conditions. Conversely, Zeng et al. (2021) [51] reported significant improvements in a young RA patient following FMT, including reduced pain and inflammatory markers, suggesting that gut microbiota may influence nociplastic pain pathways in RA, though more robust evidence is needed.

In systemic sclerosis and diabetic neuropathy, nociplastic pain often coexists with other symptoms. Fretheim et al. (2020) [41] found FMT effective in reducing gastrointestinal symptoms in systemic sclerosis patients, though procedural risks were noted. This underscores the potential role of gut interventions in modulating nociplastic pain within complex chronic conditions. Similarly, Cai et al. (2018) [49] reported pain relief and improved glycemic control in a diabetic neuropathy patient following FMT, indicating potential therapeutic benefits for conditions with nociplastic pain features.

3.4.2. Functionality and Quality of Life of Nociplastic Pain Following FMT

Several studies evaluated the impact of FMT on physical functionality, particularly in conditions with chronic pain or inflammatory components. Fang et al. (2024) [47] examined Fibromyalgia Syndrome patients and observed significant reductions in pain intensity, fatigue, and other physical symptoms, suggesting potential improvements in physical functioning through gut microbiota modulation.

Similarly, Zeng et al. (2021) [51] reported a notable reduction in physical symptoms for a rheumatoid arthritis patient, with the Health Assessment Questionnaire Disability Index (HAQ-DI) score dropping from 1.4 to 0.05 and a reduction in disease activity score (DAS28) from 6.6 to 1.4, indicating enhanced physical functionality and decreased disability.

Kragsnaes et al. (2021) [44] explored FMT’s effects on psoriatic arthritis, finding a lesser improvement in the HAQ-DI score among the FMT group compared to placebo, reflecting limited benefits for physical functionality. In systemic sclerosis patients, Fretheim et al. (2020) [41] found that 80% of those receiving FMT experienced reductions in gastrointestinal symptoms, potentially contributing to overall physical functionality improvements, albeit with risks associated with the procedure.

For IBS patients, physical functionality improvements were reported inconsistently. Holvoet et al. (2021) [42] found symptom improvement, including bloating relief, which could enhance daily functioning. However, effects diminished over time, reflecting variability in long-term outcomes.

Psychological functionality and QoL were also evaluated across several studies. Salonen et al. (2023) [46] examined CFS patients but found no statistically significant improvements in fatigue or QoL after FMT, suggesting limited psychological benefits in this cohort. Conversely, Johnsen et al. (2019) [43] and El-Salhy et al. (2019) [40] observed improvements in QoL and reductions in fatigue in IBS patients, indicating a positive psychological impact from FMT. Moreover, they highlighted a dose-dependent response in QoL improvement, emphasizing the role of donor stool quantity.

Moreover, Kenyon et al. (2019) [52] assessed CFS patients, noting that FMT was less effective compared to standard oral approaches for symptom management and failed to improve psychological outcomes for most patients. In a case study, Thurm et al. (2017) [50] reported significant improvement in psychological functionality, with reduced fatigue and enhanced overall well-being following self-administered FMT for a patient with Fibromyalgia, IBS, and CFS.

In addition, Fang et al. (2024) [47] and Zeng et al. (2021) [51] showed potential combined benefits of FMT on both physical and psychological functionality in Fibromyalgia and rheumatoid arthritis patients, respectively, through reduced symptom severity and improved daily functioning. Furthermore, Fretheim et al. (2020) [41] also suggested potential combined improvements in systemic sclerosis, albeit with procedural risks. Lahtinen et al. (2020) [45] and Singh et al. (2022) [48], however, noted that while there might be initial symptom relief or microbiota changes, the sustained impact on physical and psychological functionality was limited, emphasizing the need for further, larger-scale trials.

3.4.3. Other Effects in Nociplastic Pain Following FMT

In addition to physical and psychological functionality, several studies highlighted other variables influenced by FMT interventions. Microbiota composition changes were a common outcome across studies, with Fretheim et al. (2020) [41] observing quantitative changes in IgA- and IgM-coated bacteria among systemic sclerosis patients, while Singh et al. (2022) [48] reported varying rates of engraftment in IBS-D patients. These findings underscore the role of microbiome alterations in therapeutic outcomes.

Adverse events were also documented, ranging from none in some studies [46,49] to serious events like laryngospasms and duodenal perforation in Fretheim et al. (2020) [41]. Engraftment rates and donor stool characteristics emerged as variables of interest, influencing the degree of symptom relief, as evidenced by El-Salhy et al. (2019) [40], who noted a dose-dependent response in IBS patients.

4. Discussion

4.1. Severity of Nociplastic Pain Following FMT

Nociplastic pain, a hallmark of conditions such as Fibromyalgia and CFS, arises from altered nociceptive processing and heightened central sensitization [1,2,3,53]. The gut–brain axis, a bidirectional communication network linking the gut microbiota with the CNS, is increasingly recognized as pivotal in modulating pain pathways [54]. FMT may influence nociplastic pain through neurophysiological and biochemical mechanisms by restoring gut microbiota balance, potentially modulating systemic inflammation [55], neuroinflammation [56], and neurotransmitter signaling [57].

A primary mechanism involves the modulation of pro-inflammatory cytokines and immune signaling. Chronic nociplastic pain is associated with elevated levels of inflammatory markers such as interleukin-6, tumor necrosis factor-alpha, and C-reactive protein [58,59]. Evidence suggests that FMT may reduce systemic inflammation by promoting the growth of anti-inflammatory commensal bacteria, which can downregulate these mediators [60,61]. For instance, Fang et al. (2024) [47] reported significant reductions in pain intensity among Fibromyalgia patients, potentially attributable to decreased neuroinflammatory signaling that otherwise sustains central sensitization and pain hypersensitivity.

The gut microbiota also plays a relevant role in the production and metabolism of neurotransmitters that regulate pain perception, including serotonin, dopamine, GABA, and tryptophan metabolites. Neuroactive tryptophan metabolites—including xanthurenic acid, quinolinic acid, and 3-indoxyl sulfate—have been recognized for their contribution to the pathogenesis of functional pain [62,63]. These metabolites are key modulators of neuroinflammation and central sensitization, underscoring FMT’s potential to influence these pathways. By restoring a healthy gut microbiome, FMT may enhance serotonin biosynthesis and regulate tryptophan pathways, thereby modulating nociceptive and neuroinflammatory processes [64,65]. More details in Figure 2.

Figure 2. Mechanisms and analgesic effects of fecal microbiota transplantation in nociplastic pain management. Source: own work.

Despite these promising mechanisms, the efficacy of FMT in relieving symptoms of nociplastic pain remains inconsistent. For example, Salonen et al. (2023) [46] reported no significant improvements in fatigue or quality of life in CFS patients, underscoring the variability in individual microbiota profiles and host-specific factors. As noted by Hartikainen et al. (2024), this variability may reflect the influence of individual microbiota profiles or host-specific factors on neurotransmitter biosynthesis and signaling [66].

Another critical mechanism involves the modulation of microglial cells, the resident immune cells of the CNS. Microglial activation, often driven by systemic inflammation and gut-derived metabolites, contributes to neuroinflammation and heightened pain sensitivity [67]. By altering the gut microbiota, FMT may reduce pro-inflammatory microglial activation, thereby alleviating central sensitization [68]. Evidence from studies on Fibromyalgia patients suggests symptom improvement following FMT [69,70], although further research is needed to confirm the impact of microbiota transplantation on neuroimmune interactions.

4.2. Functionality and Quality of Life in Nociplastic Pain Following FMT

Improvements in physical and psychological functionality following FMT may be attributed to its impact on neuroendocrine signaling pathways and systemic immune modulation. Zeng et al. (2021) [51] reported significant reductions in disease activity and improvements in physical functionality in a rheumatoid arthritis patient post-FMT. These outcomes likely result from a decrease in systemic inflammation mediated by changes in gut microbiota composition, reducing peripheral nociceptive signaling and central sensitization.

That FMT may also influence the hypothalamic–pituitary–adrenal (HPA) axis is also relevant, as dysregulation of the HPA axis is common in nociplastic pain syndromes, leading to altered stress responses, increased cortisol levels, and exacerbated pain perception [71]. By restoring gut microbiome balance, FMT may recalibrate HPA axis activity, mitigating stress-related amplification of pain signals [72]. This mechanism may partly explain improvements in fatigue and quality of life observed in IBS patients [40,43].

On the other hand, psychological improvements following FMT, including enhanced mood and reduced anxiety, can be linked to gut microbiota’s ability to synthesize and modulate neurotransmitters such as GABA, which exerts inhibitory effects on neural excitability and stress responses [73]. Enhanced GABAergic signaling, along with increased production of short-chain fatty acids (SCFAs) like butyrate [74,75], may stabilize the blood–brain barrier (BBB), reduce neuroinflammation, and promote resilience to nociplastic pain triggers [76]. However, inconsistent outcomes, as noted by Kenyon et al. (2019) [52], suggest variability in individual responses based on baseline gut microbiota composition and other host factors.

4.3. Other Physiological and Biochemical Effects of FMT on Nociplastic Pain

Beyond its impact on nociceptive signaling and neurotransmitter modulation, FMT can alter the gut microbiome’s production of key metabolites, such as SCFAs (e.g., butyrate, propionate, and acetate) [77]. SCFAs exert anti-inflammatory and neuroprotective effects by modulating immune cell activity, reducing oxidative stress, and promoting gut barrier integrity [78]. By mitigating systemic inflammation and enhancing intestinal permeability, FMT may decrease the translocation of bacterial endotoxins (e.g., lipopolysaccharides) [79] that trigger neuroinflammation and worsen nociplastic pain.

Microbial metabolites such as tryptophan-derived kynurenine also play a role in pain modulation and neuroinflammation [80]. Dysregulation of the kynurenine pathway can lead to neurotoxic metabolite accumulation, contributing to heightened pain sensitivity and depression in nociplastic pain syndromes [81]. FMT may restore a balanced microbial metabolite profile, reducing neurotoxicity and improving pain outcomes. Fretheim et al. (2020) [41] observed changes in IgA- and IgM-coated bacteria, indicating shifts in mucosal immunity that may further modulate systemic and neuroinflammatory responses [82,83].

While adverse events such as those reported by Fretheim et al. (2020) [41] highlight potential risks associated with FMT, optimizing donor selection, engraftment protocols, and microbiota composition can enhance therapeutic outcomes while minimizing complications. Collectively, these neurophysiological and biochemical pathways underscore FMT’s complex and multifaceted role in modulating nociplastic pain, necessitating a precision-medicine approach to maximize its therapeutic potential.

4.4. Implications for Practice

FMT presents considerable promise in the management of nociplastic pain—a chronic pain state marked by altered pain processing and central sensitization, prevalent in disorders such as Fibromyalgia, IBS, and CFS. Current evidence suggests that FMT can alter gut microbiota composition, thereby modulating systemic inflammation, gut–brain communication, and immune responses implicated in nociplastic pain. This modulation may reduce pain intensity, alleviate fatigue, and improve gastrointestinal symptoms. However, the quality of evidence remains limited, with studies often having small sample sizes and variable methodologies, leading to mixed outcomes.

At present, FMT should be considered a complementary or alternative intervention to conventional pharmacological therapies, which frequently show limited effectiveness and significant side effects. Despite the promising results, the scientific community lacks high-quality, large-scale RCTs to definitively establish FMT’s efficacy and safety in managing nociplastic pain. Thus, the clinical use of FMT in pain management should be approached with caution, especially as more robust evidence is required.

In clinical settings, incorporating FMT into nociplastic pain management strategies could transform treatment paradigms by offering a natural and potentially sustainable means of symptom alleviation through microbiome restoration. By attenuating systemic inflammation and enhancing gut barrier integrity, FMT may reduce reliance on conventional pain medications, thereby mitigating risks such as opioid dependence and associated adverse effects. Furthermore, its potential to modulate neuroinflammatory pathways could lead to significant improvements in both physical and psychological patient well-being.

To achieve consistent therapeutic outcomes, the establishment of standardized protocols for donor selection, preparation, and FMT administration will be essential. Future studies should focus on improving the quality of the data, with larger sample sizes, long-term follow-ups, and rigorous methodological designs. Ultimately, FMT may not only provide symptomatic relief but also target the underlying mechanisms of pain sensitization, offering a transformative opportunity in the care of patients with nociplastic pain.

4.5. Implications for Research

Future research on the role of FMT in managing nociplastic pain presents several critical opportunities. First, refining and standardizing FMT protocols is essential. This includes establishing not only a context for developing more robust study designs but also optimal donor selection criteria, improving preparation techniques, and determining the most effective delivery routes tailored specifically to nociplastic pain conditions. Investigating how FMT influences the gut–brain axis, modulates immune responses, and interacts with pathways involved in central sensitization could provide profound insights into its therapeutic potential and inherent limitations in chronic pain syndromes.

To ensure consistency and comparability across studies, it is imperative to incorporate FDA-approved endpoints in future research. Standardizing these endpoints alongside FMT protocols will not only enhance the reliability of study results but also pave the way for regulatory approval and wider clinical adoption. This alignment with regulatory standards will strengthen the credibility of findings and facilitate the integration of FMT into evidence-based practice for nociplastic pain management.

Furthermore, longitudinal studies are necessary for evaluating the long-term safety and efficacy of FMT across diverse patient populations affected by nociplastic pain. Understanding inter-individual variations in treatment response—shaped by factors such as microbiota composition, genetic predispositions, and other patient-specific variables—is vital for optimizing personalized care strategies. Furthermore, expanding research beyond gastrointestinal disorders to explore the neurobiological and immune-mediated dimensions of nociplastic pain could further elucidate the broader applicability and therapeutic value of FMT.

Additionally, assessing FMT as an adjunctive therapy for conditions like Fibromyalgia, IBS, and related disorders offers an exciting opportunity to develop comprehensive, multi-targeted treatment strategies. By addressing the root causes of nociplastic pain through microbiota modulation, FMT holds great promise for significantly improving clinical outcomes and providing renewed hope for individuals experiencing chronic, refractory pain conditions.

5. Conclusions

This systematic review underscores the potential of FMT in managing nociplastic pain, characterized by altered pain processing and central sensitization. Evidence indicates that FMT may influence systemic inflammation, gut–brain signaling, and neuroimmune pathways, showing promise in conditions such as Fibromyalgia, CFS, IBS, and autoimmune disorders. However, results vary widely, reflecting the complexity of nociplastic pain and the multifactorial factors affecting outcomes. Further research is necessary to standardize protocols, improve study designs, and better define FMT’s role in chronic pain management.