Multiple sclerosis (MS) is a heterogeneous chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) (Reich et al., 2018). The origins of the inflammatory and demyelinating processes in MS are not fully understood, with both inside-out and outside-in hypotheses proposed (Lassmann, 2013). It is clear, however, that interactions between genetic and environmental factors play a crucial role in the development of MS (Lassmann, 2013; Mahad et al., 2015; Popescu and Lucchinetti, 2012). Various environmental risk factors have been recognized to increase the risk for MS development, including low vitamin D, smoking cigarettes, exposure to certain infections (e.g., Epstein-Barr virus), and obesity (Thompson et al., 2018; Munger et al., 2013; Bjornevik et al., 1979). Interestingly, the incidence of MS has markedly increased in recent years (Walton et al., 2020), possibly reflecting changes in the incidence of risk factors (Koch-Henriksen et al., 2018). Additionally, obesity (defined as body mass index (BMI) above 30 kg/m2) is a rapidly growing epidemic that affects about one-third of adults in the United States and has doubled or tripled in several countries worldwide (Blüher, 2019). The rise in obesity across all age groups may contribute to the increased incidence of MS (Koch-Henriksen et al., 2018). Understanding the mechanisms linking obesity to MS may provide better insight into its pathophysiology and offer additional therapeutic opportunities for people with MS (pwMS).

The gut microbiota has become an increasingly important area of investigation in many neurological diseases, including MS, and may provide a link between obesity and increased MS risk (Cryan et al., 2020). Alterations in gut microbiota, known as gut dysbiosis, have been implicated in the pathogenesis of obesity, as demonstrated by several studies (Ley et al., 2006; Ridaura et al., 2013; Turnbaugh et al., 2006; Turnbaugh et al., 2008). Similarly, emerging evidence suggests a potential role of gut dysbiosis in MS pathogenesis (Berer et al., 2017; Cantoni et al., 2022). By examining the experimental autoimmune encephalomyelitis (EAE) model, researchers have discovered that germ-free (GF) mice were protected against neuropathology, highlighting the significance of the gut microbiota in MS (Berer et al., 2011; Lee et al., 2011). Both human and animal studies have also provided evidence indicating that gut microbiota plays a crucial role in the pathogenesis of obesity. Specific patterns of gut microbiota alterations have been observed in individuals with obesity, further supporting this link (Ley et al., 2006; Ridaura et al., 2013; Turnbaugh et al., 2006; Turnbaugh et al., 2008). Moreover, a recent review showed a resemblance between the proinflammatory gut microbiota profiles in individuals with MS and obesity (Huitema and Schenk, 2018). In this review, we summarize current evidence linking both obesity and MS to gut microbiota alterations. We also highlight clinical studies linking obesity to increased MS susceptibility and disease progression and experimental mechanistic studies investigating the link between MS and obesity.