The potential effectiveness of probiotics in reducing multiple sclerosis progression in preclinical and clinical studies: A worldwide systematic review and meta-analysis

Abstract

Background and objective: Multiple Sclerosis (MS) is an immune-mediated disease characterized by nerve cell inflammation and demyelination. The effectiveness of probiotics in reducing inflammatory damage in MS. Therefore, the aim of this systematic review and meta-analysis was the potential effectiveness of probiotics in reducing Multiple Sclerosis progression in preclinical and clinical studies.

Methods: PubMed, Scopus, Cochrane, and Google Scholar databases were searched using multiple relevant keywords, and screening was carried out based on the inclusion/exclusion criteria from January 2004 to August 16, 2024.

Results: Based on our criteria, 269 papers were obtained, and after omission of unsuitable articles, 23 full-text articles consisting of 17 animal studies and six human models were selected. It was concluded that in an experimental autoimmune encephalomyelitis (EAE) animal model, probiotics such as Bifidobacterium, Prevotella, and Lactobacillus can decrease the T helper 1 (Th1)/Th17 ratio while inducing interferon gamma (IFN-γ) and interleukin (IL)-17 levels. In all cases, probiotics can modulate immune cells and cytokines and consequently decrease EAE signs and symptoms. In all human studies, single or multiple probiotics decreased the severity of disease and changed the gut microbiota population.

Conclusion: Our results showed that probiotics can control the development of MS by reducing inflammatory conditions, and may have beneficial effects in the prevention and treatment of MS.

Fig 1. Systematic literature review flow diagram.

Fig 2. The forest plots of the effect of probiotics on the level of IFN-γ by ELISA (A) and RT-PCR (B) methods.

It should be noted that these data are from EAE studies. Overall, probiotics decreased IFN-γ production with Std diff in means between probiotics and control groups was -2.492 with ELISA test (A) and -2.453 with RT-PCR test (B).

Fig 3. The forest plots of the effect of probiotics on the level of IL-17 by ELISA (A), RT-PCR (B) and Flow cytometry (C) methods.

It should be noted that these data are from EAE studies. The overall level of IL-17 decreased after probiotic addition in ELISA test (overall Std diff in means = -3.578) (A), but increased following probiotic administration in RT-PCR (overall Std dif in means = 0.504) (B), and flow cytometry (overall Std dif in means = 5.298) (C).

Fig 4. The forest plots of the effect of probiotics on the level of IL-10 by ELISA (A) and RT-PCR (B) methods.

These data are from EAE studies. The level of IL-10 increased after the consumption of probiotics and the overall standard difference in means was 3.712 (A) and 10.627 (B) in ELISA and RT-PCR studies, respectively.

Fig 5. The forest plots of the effect of probiotics on the level of TNF-α by ELISA (A) and RT-PCR (B) methods.

These data are from EAE studies. The probiotics reduced the TNF-α level with an overall standard difference in means between groups of -3.060 in ELISA test (A) and -1.373 in RT-PCR test (B).

Fig 6. The forest plots of the effect of probiotics on the level of T-reg (A) and CD4 CD25 (B).

These data are from EAE studies. Based on the results, the standard difference in means between probiotics-takers and control groups was 3.386 for Treg cells (A) and -0.290 for CD4 CD25 cells (B).

Fig 7. The forest plots of the effect of probiotics on clinical score.

These data are from EAE studies. The clinical score was lower in the probiotic-received group than in the control group, and the overall standard difference in the means between the two groups was -4.975 (95%CIs: -6.469, -3.481) (A). A subgroup analysis of clinical scores based on the method used showed that in all methods, the clinical scores were lower in the probiotic-received group than in the control group, with higher differences detected by ELISA (B).

Fig 8. The publication bias assessment and sensitivity analysis.

The assessment of publication bias was done by drawing the funnel plots of standard error (A) or precision (B) by standard difference in mean as well as using Egger’s regression test (C). The asymmetric distribution of the studies (open circles) over the combined effect size can be observed. The sensitivity assay of publication bias was done by Duval and Tweedie’s trim and fill method which suggests that five studies are missing. These five studies are shown by solid black circles in both funnel plots of standard error (D) or precision (E). The observed and adjusted effect sizes as well as other statistical parameters of the trim and fill method are also shown (F).

Fig 9. The forest plots of the effect of probiotics in human studies on the level of IFN-γ (A), IL-17 (B), and TNF-α (C).

IFN-γ was increased following probiotic administration as the Std diff in means equal to 0.577 (A). The IL-17 and TNF-α were decreased after probiotic administration with the Std diff in means equal to -4.480 and -0.075, respectively (B and C).

Fig 10. Probiotic consumption in people with MS had favorable effects on EDSS.

The overall EDSS was lower in probiotics-received subjects than in controls, with the Std diff in means equal to -1.839.