1. Introduction

Multiple sclerosis (MS) is a chronic neuroinflammatory disease with highly heterogeneous outcomes currently affecting approximately 2.8 million individuals globally [1]. There has been a significant rise in its prevalence, with a 30% global increase over the past decade. MS disproportionately affects women, with almost a two-fold greater incidence rate between genders, and is a frequent cause of permanent disability in young adults [2]. Existing evidence indicates the involvement of diverse risk factors in the development of MS, including genetic predispositions, exposure to infections, and elements contributing to pro-inflammatory conditions such as smoking, obesity, and insufficient sun exposure [3]. While significant progress has been made in unraveling the pathophysiology of MS, the exact underlying mechanisms remain elusive [4].

Much of the central nervous system (CNS) damage is believed to result from an immune-mediated processes, involving components of the innate immune system, as well as adaptive immune system activation of certain lymphocyte populations and B cell activation [5]. Some T cell populations, including T-helper (Th1) and Th17 lymphocytes, are associated with a repertoire of pro-inflammatory cytokines, while Th2 lymphocytes and T regulatory (Treg) cells secrete anti-inflammatory cytokines [6]. In people with MS, there is an imbalance between Th1/Th17 and T regulatory subset, resulting in increased Th1 pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF-α). In addition, secretion of Th2 anti-inflammatory cytokines, such as IL-10, is decreased in MS, and this can intensify the destruction of myelin and prevent remyelination [7]. In particular, CD4⁺ T cells contribute to the initiation of the immune response in MS patients, while CD8⁺ T cells, are believed to be the major lymphocytes found in active MS lesions, which have been identified as potential major contributors to MS pathology [8]. Tregs, as key regulators of the immune system, possess the ability to suppress autoimmunity and play a role in promoting tissue regeneration [8].

In addition to the immune-mediated mechanisms, compelling evidence suggests that immune-independent mediators contribute to the pathogenesis of MS [8]. In this regard, adipokines, which are white adipose tissue secretions, are believed to play a key role as immune cell modulators through altering the local and systemic inflammation [9]. Conversely, the function of adipokines is influenced by inflammatory factors released by immune cells. One example is leptin, an adipokine known to contribute to inflammatory mechanisms and neurodegeneration in MS [10]. Additionally, it impacts immune system by regulating the balance between Th1 and Th2 [11]. While current disease-modifying treatments (DMTs) are effective for reducing relapses, disability progression, and lesions [12], they may not optimally modulate the complex balance of pro-inflammatory and protective immune responses [13, 14]. This finding, coupled with the reciprocal interplay between adipokines and the immune system, implies that additional adjunct approaches, including diet [15], may further optimize patient outcomes through modulation of cytokine and adipokine balance in MS.

Diet exerts systemic effects on human metabolism and is involved in immune system modulation and cytokine signaling, rendering it an attractive candidate as a potential environmental mediator in MS [15]. Dietary factors that are able to promote regulatory, as opposed to inflammatory immune cell differentiation and cytokine production hold the potential to have beneficial effects on inflammation in MS [16]. Furthermore, evidence also supports the notion that there are links between specific foods and autoimmune diseases, namely MS [17], and that several specific dietary components are linked to inflammation [18–20]. Accordingly, nutrition research has shifted towards examining the effects of composite dietary patterns as opposed to focusing on individual nutrients [16]. Despite a lack of consistent evidence for any specific therapeutic diet for MS, preliminary trials suggest several dietary patterns may potentially reduce inflammation [18, 21, 22]; however, the specific effect of dietary patterns on inflammatory biomarkers among people with MS is an area with present insufficient amount of data and inconsistency. For example, a randomized control trial showed that adherence to a Mediterranean-style diet significantly decreases inflammatory markers as well as MS fatigue severity [23]. In contrast, Yadav et al. showed that a very-low fat plant-based diet is well tolerated by patients with MS, but had no significant improvement on inflammatory markers, namely hs-CRP [24].

Extensive research has thoroughly investigated the significant link between inflammation and its contribution to MS pathophysiology [25]. The ability of natural food components to modulate cell metabolism, specifically inflammatory and autoimmune processes, makes diet an intriguing prospect for MS therapy [19]. However, the specific effect of dietary patterns, rather than specific dietary components on inflammatory markers in MS, is an area with present inconsistency and an insufficient amount of data, and a systematic review (and meta-analysis) is crucial to consolidate the existing evidence. Exploring the link between dietary interventions and inflammation within the MS community is crucial for providing well-informed, evidence-based dietary recommendations to address a significant gap in current MS management practices. To the best of our knowledge, the current study will be the first to review and combine evidence on how diet affects inflammatory markers in people with MS.

2. Materials and methods

2.4. Data collection and analysis

2.4.1. Study selection.

References from various databases and repositories will be imported into EndNote20 referencing software. Two reviewers will independently review the titles, abstracts, and full-text papers of the identified articles for inclusion, and any duplicates will be removed using EndNote. All searches will follow a two-phase screening strategy:

1. Phase one will assess the eligibility of the title and abstract of every manuscript generated from the electronic and hand-searching against the predetermined inclusion and exclusion criteria. Studies that either do not clearly meet the inclusion criteria or meet at least one exclusion criteria will be excluded at this phase.
2. Once the first round of screening is completed, the full-text paper will be retrieved from articles identified in stage one and will be assessed against the predetermined inclusion and exclusion criteria.

Any conflicts between reviewers relating to study eligibility will be resolved in consensus meetings with a third and fourth reviewer. The results of searches in all databases, along with the selection process, will be displayed using the PRISMA 2020 flow diagram (Fig 1).

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Fig 1. PRISMA flow diagram for identifying, screening, and determining the eligibility and inclusion of studies.

https://doi.org/10.1371/journal.pone.0297510.g001

2.4.2. Data extraction.

Data extraction will be conducted by one reviewer using a pre-piloted data extraction form and independently verified by a different review team member. Study characteristics (i.e., author’s name, year of publication, country, study design), population characteristics (i.e., number of participants, number of participants in the final analysis, age, gender, intervention duration, and type, co-interventions), and outcomes (inflammatory biomarkers/ unit of assessment e.g., measurement tool or method used, results of interventions e.g., mean difference, confidence intervals, P-values, etc.) will be extracted. Any discrepancies will be achieved by discussion during consensus meetings, or, if needed, in consultation with a third and fourth reviewer. The information will be summarized in a “table of characteristics” (S1 Table).

2.4.3. Risk-of-bias analysis.

Two reviewers will independently assess the risk of bias in included studies using the Cochrane Risk of Bias Tool [31]. Risk of bias will be judged as low, high, or unclear for individual elements: 1) random sequence generation (selection bias); 2) allocation concealment (selection bias); 3) blinding of outcome assessment (detection bias) and self-reported outcomes; 4) incomplete outcome data addressed (attrition bias); 5) selective reporting (reporting bias); 6) other bias (other sources of bias that have been detected by the reviewer). Two figures will be generated to demonstrate the risk of bias assessment of individual and overall studies that have been included in the systematic review and meta-analysis.

2.4.4. Credibility of evidence.

The credibility of evidence for each pairwise comparison will be evaluated using the NutriGRADE scoring system [32], which is an extension of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scoring system that is specific to nutrition studies and comprises the following items: (1) risk of bias, study quality, and study limitations; (2) precision; (3) heterogeneity; (4) directness; (5) publication bias; (6) funding bias; and (7) study design for meta-analyses of randomized trials. This scoring system judges the meta-evidence of each pairwise comparison and categorizes scores into 4 classes: high, moderate, low, and very low credibility of evidence.

3. Ethics and dissemination

Ethics committee approval and informed consent from patients will not be required. The planned systematic review and meta-analysis will carry public health significance by offering current evidence regarding the effect of dietary patterns on inflammatory biomarkers among adults with MS. The results of the systematic review and meta-analysis will be submitted to a peer-reviewed journal.

4. Discussion

The objective of this study will be to evaluate the impact of dietary interventions on inflammatory biomarkers among individuals with MS. Multiple studies have consistently pointed toward the significance of the inflammatory processes in driving the pathogenesis and exacerbation of MS [8, 33]. The ability of dietary patterns to improve inflammatory and autoimmune processes makes diet an intriguing prospect for individuals with MS as a potential adjunct therapy [19]. To our knowledge, this systematic review and meta-analysis will be the first to summarize and compare the effects of different dietary approaches on inflammatory markers in people with MS. The findings will add more evidence to the literature on the potential effects of dietary interventions on the inflammatory and immune-regulating biomarkers in the setting of MS. Given improving the inflammatory process and shifting the balance towards anti-inflammatory biomarkers is important for ameliorating the MS symptoms and specific dietary recommendations for individuals with MS are scarce, this systematic review will provide important data regarding the role of diet in inflammatory pathways in MS.

Supporting information

Acknowledgments

The authors would like to acknowledge the following contributor: Heather Healy, a health sciences librarian, for her valuable assistance in developing the search syntax.