Multiple Sclerosis and Related Disorders 59 (2022) 103671 Available online 6 February 2022 2211-0348/© 2022 Elsevier B.V. All rights reserved. Original article Systematic review and meta-analysis of Mycobacterium avium subsp. paratuberculosis as environmental trigger of multiple sclerosis Temitope C. Ekundayo a, b, * , Tosin A. Olasehinde e, h , Ayodeji O. Falade c , Mary A. Adewoyin d , Chidozie D. Iwu f , Bright E. Igere g , Oluwatosin A. Ijabadeniyi a a Department of Biotechnology and Food Science, Durban University of Technology, Steve Biko Campus, Health Services, 121 Steve Biko Rd, Musgrave, Berea, 4001, Durban, South Africa b Department of Biological Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria c Biotechnology, Computational Biochemistry and Phytomedicine Research Group, Department of Biochemistry, University of Medical Sciences, Ondo City, Ondo State, Nigeria d Department of Biological Sciences, Anchor University, Ayobo Road, Ipaja, Lagos e Nutrition and Toxicology Division, Food Technology Department, Federal Institute of Industrial Research Oshodi, Lagos, Nigeria f School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa g Department of Microbiology and Biotechnology, Western Delta University, Oghara, Delta State, Nigeria h Discipline of Microbiology, School of Life Sciences University of Kwazulu-Natal, Westville campus, Durban, South Africa A R T I C L E INFO Keywords: Neuroinfection Autoantibodies Neuroimmune Neuroinfammatory Neurodegeneration Myelin damage Autoimmune disorder ABSTRACT Mycobacterium avium subsp. paratuberculosis (MAP) has been identifed as one of the environmental agents that causes multiple sclerosis (MS). The global prevalence of MS has been upsurging over the years; however, efforts to divulge the role of MAP in MS have been limited. As a result, the present study aimed at assessing the odd ratios (ORs) associated MAP with the risk of MS. MAP-related MS data were obtained from 6 databases using the terms ’multiple sclerosis’ or ’MS’ and ’paratuberculosis’ without regard for time or language restrictions following PRISMA standards. A total of 2,538 participants’ data from 12 studies presenting anti-MAP antibodies and MAP DNA from 4 studies were ftted in random-effects (RE) and fxed-effects (FE) meta-analytic models. Furthermore, the between-study heterogeneity was measured using I 2 -values with a signifcant limit set at an I 2 > 75%. Analytical rigor and publication bias was determined using leave-one-out-analytics, Egger’s tests, and p- curve analysis. In the FE and RE models, anti-MAP antibodies data signifcantly associated MS risk with MAP as 10.71 OR (95%-CI [7.78; 14.74], p-value < 0.0001) and 12.76 OR (95%-CI [8.13; 20.02], p-value < 0.0001) respectively, with an I 2 value of 34.9% (95%-CI [0.0%; 67.2%]; p-value = 0.11). Similarly, the MAP DNA dataset in FE signifcantly present MS risk due to MAP as 5.53 OR (95%-CI [3.54; 8.66], p-value< 0.0001) while, RE showed 5.27 OR (95%-CI [3.22; 8.60], p = 0.0017), with an I 2 -value = 0.0% (95%-CI [0.0%; 84.7%]; p-value = 0.71). Eggers’ test, on the other hand, found publication bias in anti-MAP antibodies data (intercept = 1.61, 95% CI: 0.45 – 2.77, t = 2.72, p = 0.021), but not in MAP DNA dataset (intercept = -5.57, 95% CI: -20.44 – 9.29, t = -0.74, p = 0.54). The robustness of the meta-analyses was demonstrated by all sensitivity analyses. In addition, there is no evidence of p-hacking observed (right-skewness test (P Full < 0.001, P Half <0.001; statistical power ≥ 94% (95%-CI: 72.5%-99%)). In conclusion, the synthesis revealed a strong association between MAP and MS, indicating that MAP is a signifcant environmental agent that may trigger MS. Thus, early screening of MAP in MS cases may assist in the therapeutic approach to its management/treatment. Therefore, future studies should be tailored towards the role of MAP in the severity of MS phenotypes, as well as address global data gaps and low disease surveillance. 1. Introduction Multiple sclerosis (MS) is an autoimmune-mediated chronic infammation, demyelination, and neurological disease characterized by an axonal loss in the central nervous system (Oh et al., 2018). MS causes lesions in the gray and white matter of the spinal cord and the brain that * Corresponding author. E-mail address: cyruscyrusthem@gmail.com (T.C. Ekundayo). Contents lists available at ScienceDirect Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard https://doi.org/10.1016/j.msard.2022.103671 Received 17 December 2021; Received in revised form 27 January 2022; Accepted 5 February 2022