Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) where an individual’s immune system attacks the myelin sheath surrounding nerve cells [1]. Such breakdown causes inflammation of the CNS, leading to progressive paralysis [1]. Two types of pro-inflammatory T cells (Th1 and Th17) mediate the inflammation observed in MS, triggering macrophages and other cells involved in the inflammatory response, which results in neurodegeneration [2]. However, the microbiota (community of microorganisms) within the gut is also known to influence the immune response and levels of pro/anti-inflammatory cytokines [3]. When imbalanced this can increase the risk of inflammatory disease such as MS [3], illustrating the importance of the gut in disease.

Overview of The Gut in MS – Mice Models

In a review, Zoledziewska (2019) [4] argues that mice models have demonstrated the importance of the gut and microbiota in multiple sclerosis. In particular, increased levels of interleukin-17 (IL-17) in the gut induces Th17 cytokines in the CNS which contributes to the development of autoimmune disease including MS [4]. Changes in the gut microbiota can alter the immune state in the gut, exacerbating experimental autoimmune encephalomyelitis (EAE), whereby T cells attack the myelin sheath surrounding the neurons in the CNS [4]. Specifically, Berer et al. (2017) [5] found it is the transfer of A. muciniphila and Acinetobacter calcoaceticus monocolonisation from MS patients to germ-free mice that caused severe EAE exacerbation as well as decreases in anti-inflammatory IL-10 producing T cells. These findings therefore emphasise the influence of the gut on immunity and CNS function, demonstrating a need for further investigation.

Gut Microbiota and Long Chain Fatty Acids – The Links Between Obesity and MS

Long chain fatty acids (such as oils, fish and dairy products) increase the risk of obesity and reduce the diversity of the microbiome in the gut (Mielcarz & Kasper, (2015) [6]. In this review paper, Mielcarz and Kasper (2015) [6] suggest numerous studies using mice have demonstrated that high fat diets, which lead to excessive fat in the body, altered gut microbiota (free fatty acids) and exacerbated EAE. Specifically, they outline that there is an association between increases “in pro-inflammatory plasma free fatty acids” and exacerbations in EAE, leading to the argument that obesity could therefore be implicated in the progression of MS (page 6) [6]. However, it is crucial to acknowledge that further research utilising clinical trials is required to confirm the benefits of a low-fat diet in relapsing or progressive MS [6].

That said, in another review, Huitema and Schenk (2018) [7] found similarities between gut microbiomes in MS patients and obesity. Specifically, they suggest adults considered obese had less diversity of bacteria in the gut alongside increased leptin, a hormone involved in immunity. Together, this could increase an individual’s susceptibility to MS. In MS, increased leptin was found to cause more pro-inflammatory cytokines/responses [8] while decreasing anti-inflammatory cytokines [7]. Leptin also plays a role in metabolism, but too much can contribute to weight gain and further increase pro-inflammatory responses [7].  Since MS is a chronic inflammatory disease of the CNS, this increased pro-inflammatory and decreased anti-inflammatory response caused by LCFAs and leptin could therefore increase the risk or progression of MS.

To investigate the associations between obesity, gut microbiota and MS, Stampanoni Bassi et al. (2016) [9] conducted a cross-sectional study, recruiting 140 relapsing-remitting (RR) MS patients. Overall, they found that the higher the BMI, the higher the disability score. Additionally, obese patients with RR-MS had increased levels of pro-inflammatory IL-6 and leptin within the cerebrospinal fluid (CSF) and decreased concentrations of anti-inflammatory cytokines [9].  The study concludes that obesity as a consequence of LCFA consumption is associated with inflammation and disability amongst patients with RR-MS [9],  further demonstrating the influence of diet/lifestyle on autoimmune disease such as MS.

Gut Microbiota and Short Chain Fatty Acids – Can Healthier Diets Improve CNS Inflammation?

Short chain fatty acids (SCFAs) are produced from high-fibre foods such as fruit, vegetables and whole grains [10]. SCFAs have anti-inflammatory effects with research demonstrating a link between obesity, gut microbiota and autoimmune/neurological disease. Research has begun to investigate whether diets supporting SCFA production can slow down or even prevent the progression of MS. The most abundant SCFAs are acetate, propionate and butyrate which are produced by members of the phyla Firmicutes, Bacteriodetes and Actinobacteria [11]. They regulate mucus production and protect the intestine from living bacteria by reducing the permeability of the epithelium  [11].  SCFAs also interact with the blood-brain barrier to modulate brain function, however the mechanisms behind this are still not fully understood [11].

In a systematic review, Melbye et al. (2019) [11] discuss that SCFAs suppress inflammation and improves EAE in mice, while excessive body fat caused by LCFAs aggravate such symptoms. Specifically, SCFAs suppressed Th-17 cytokines in mice, demonstrating a potential benefit of high-fibre diets because excessive Th-17 is known to be associated with autoimmune disease [4]. Importantly, however, Melbye et al. (2019) [11] found in a systematic review that there are some inconsistencies amongst the literature regarding the role of SCFAs produced by the gut microbiota from dietary fibre, immunity and autoimmune disease. The inconsistencies could be explained by many of the human studies in the review having a limited sample size, highlighting a need for more in-depth research to establish the true extent to which diet, and in particular SCFAs produced by gut microbes, can suppress inflammation associated with autoimmune disease such as multiple sclerosis.

Despite this, it is worth noting that this review by Melbye et al. (2019) [11]  found that high consumption of SCFAs leads to a reduction in prevotella (a bacterium in the gut supporting metabolism and the defence against pathogens) in patients with untreated RR-MS, compared to healthy controls and treated RR-MS patients. Furthermore, Melbye et al. (2019) [11] found an association between increased microbiota, increased pro-inflammatory responses and decreased SCFA producers in patients with RR-MS. Specifically, patients with either a gut microbiota compositional imbalance or a recent attack had less bacteria in the gut compared to patients in remission [11] . Overall, this systematic review by Melbye et al. (2019) [11] provides initial insight into the role of SCFAs and gut microbiota in autoimmunity and the progression of MS.

Additionally, a review by Grochowska et al. (2019) [12] further summarises the initial findings on the associations between different bacteria in the gut, cytokines (both pro and anti-inflammatory) and MS development, further stressing the importance of diet. However, a crucial aspect of this review is its consideration for how diet may be associated with other symptoms of MS – not just the presence of increased inflammation of the CNS. Specifically, this review suggests that difficulty coordinating movements and increased blurred vision associated with MS could be caused by Clostridium perfringens toxins B and D [12]. Clostridium perfringens toxins, consumed when eating uncooked meat or poultry [13],  cause inflammation of the retina [12] and were undetectable in healthy controls [14],  suggesting the impact of unhealthy diets on many aspects of our health.

Another finding in this review by Grochowska et al. (2019, page 377) [12], was that MS treatment with “probiotics containing Lactobacillus paracasei and L. plantarum suppressed the development of EAE and reduced [the] severity of clinical symptoms”, whereby probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [15]. Such a finding is important as it provides insight into future therapeutic interventions that not only improve neurological symptoms, but also quality of life. It should therefore be stressed that according to Grochowska et al.’s review (2019, page 377) [12], unhealthy diets, including significant consumption of “salt, animal fat and carbohydrates” cause gut microbiota composition and metabolism to deteriorate, worsening MS symptoms. Such findings illustrate the importance for patients, clinicians and researchers to consider diet when assessing MS symptoms and its progression.

Can Probiotic Treatments Support Gut Equilibrium?

Thus far, it has been suggested that certain diets and the absence of excessive body fat can help balance the microbiota in the gut. Therefore, since the findings proposed by Grochowska et al. (2019) [12], research has continued to investigate the efficacy of probiotic supplements in supporting the gut microbiota and symptoms of multiple sclerosis in both animal and clinical studies.

Firstly, Valizadeh et al. (2021) [16] assessed the efficacy of probiotics in EAE by conducting a systematic review and meta-analysis on fifteen animal studies. They found that EAE was significantly lower in mice that were given probiotics, whereby “Enterococci was associated with a significantly shorter duration of EAE” [16] . Furthermore, Valizadeh et al. (2021, page 409) [16] found that there was a significant reduction in mortality risk in experimental groups, but this was only for female mice. While the long-term effects of probiotics were not considered, this meta-analysis provides insight into the potential efficacy of probiotics on the gut and symptoms of MS, illustrating a need for human research.

Subsequently, in an attempt to extend these findings, research has looked at probiotic intake in humans. Specifically, Mirashrafi et al. (2021, page 10) [17] assessed whether probiotic supplements impact relapsing-remitting MS progression, depression and general health using a systematic review and meta-analysis of clinical trials. They found that while body mass index and weight did not statistically change, probiotic supplements (whereby more than one type was taken per day for 12 to 24 weeks) improved “disease disability, depression, and general health” [17]. These findings extend that of Valizadeh et al. (2021) [16]  who assessed probiotic use with animal models, further highlighting the potential benefits of probiotic supplements to impact disease progression in individuals with RR-MS.

These findings have been supported by other systematic reviews assessing the efficacy of probiotic and commensal gut microbial therapies in treating MS [18]. A total of six human and thirty-one animal studies were assessed in this review, finding various types of bacteria could be successfully used for probiotic therapy as a treatment for MS [18]. Specifically, these included: “VSL#3, Lactobacillus paracasei, Bifidobacterium animalis, E. coli Nissle 1917, and Prevotella histicola”(page 1) [18].  Similarly, reviews by Jiang et al. (2021) [19] found (from three randomised control trials and twenty-two pre-clinical studies) that probiotic consumption can reduce the prevalence, severity and progression of MS, improve motor function and alter the inflammatory markers and microbiome compositions in MS patients. Such findings are encouraging, demonstrating the potential efficacy of probiotic consumption in ameliorating the symptoms of MS. However, it is crucial to recognise that due to the recency of this research many of these reviews not only include the same studies of both preclinical and clinical trials, but also studies that are yet to be replicated. Therefore, definitive conclusions about the benefits of the consumption of specific probiotics (single strains or multi strain combinations) and other supplements are yet to be deciphered.

Moreover, although there is developing evidence on the potential benefits of specific probiotic strains or cocktails in treating (RR)MS, it is crucial to assess whether high consumption of probiotics and probiotic supplements can interact with other drugs and diets in individuals living with MS. Petersen et al. (2021) [20] conducted a systematic review of one hundred and twenty-nine studies to assess this and found that few studies have investigated the possible interactions between drugs and probiotics. In fact, at the time of this review, no clinical data was available and only one study by Matuskova et al. (2011) [21] with rats found that Lactobacillus casei decreased the expression of CYP1A1 mRNA in the intestine, indicating a possible risk for combined probiotic and conventional drug use. However, given the nature of this study, definitive conclusions regarding the interaction between drugs and probiotics in MS cannot be made.

That said, Petersen et al. (2021, page 3623) [20]  briefly discusses how several trials have investigated the immunomodulatory effects of probiotics for individuals living with MS and found “no reported adverse effects”. According to Petersen et al. (2021) [20] , these studies identify benefits of probiotics in the context of NSAIDs; analgesic medication used by those living with MS to manage discomfort and painful sensations. Specifically, Petersen et al. (2021, page 3623) [20] concludes that probiotics were found to protect against intestinal damage that was caused by repeated NSAID use, suggesting that there are “no significant risks associated with using probiotics as a supplement to MS medication”. Note, however, that interactions with other MS medications are yet to be investigated, so this claim cannot be generalised to all prescribed medications in MS. A trained healthcare professional should be consulted to minimise harm and risks before diets are altered.

Finally, it is important to consider the feasibility of dietary changes as a treatment option for individuals with MS. In addition to that above, Petersen et al. (2021, page 3610) [20]  found that there were also no significant interactions “between conventional MS drugs and ginger, cranberry, vitamin D, fatty acids, turmeric, or glucosamine”, highlighting that there are many common drugs, foods/flavourings and vitamins which individuals with MS are often consuming that do not (as far as the research suggests) interact with their prescribed medication. Thus, dietary changes and supplements such as probiotic therapy could be a highly accessible treatment for many people living with MS if the promising initial observations translate from bench to bedside.

Conclusion

Overall, there is considerable evidence from animal models that long chain fatty acids and excessive body fat are associated with alterations in gut microbiota composition, particularly reduced diversity. This change subsequently impacts the reactivity of the immune system, increasing the risk of autoimmune disease such as multiple sclerosis. Based on such evidence, research has investigated the importance of diet on health, demonstrating that a diet high in fibre that favours short chain fatty acid production could improve gut diversity and minimise inflammation, while probiotics could be a useful intervention (particularly for RR-MS). These findings therefore highlight a potential method for preventing the onset or progression of multiple sclerosis.

It is important, however, to recognise that there are numerous limitations to the research thus far. Firstly, research predominantly utilises animal models to assess the role of short and long chain fatty acids on the gut and multiple sclerosis, meaning the true efficacy of healthier diets in supporting individuals with multiple sclerosis is still largely unknown. Additionally, research into short and long chain fatty acids alone does not provide a holistic view of the relationship between the gut, immune system and multiple sclerosis; nor does it fully account for the risk factors associated with multiple sclerosis and its progression. As for research into the use of probiotics to treat multiple sclerosis, the field is still in its early stages and thus there is currently a significant lack of study replication, hindering the reliability of current findings.

Consequently, future research should firstly prioritise the use of human clinical trials to better establish the influence of healthier diets on the progression of multiple sclerosis; and secondly investigate how other dietary/lifestyle choices could be interacting with gut microbiota and the immune system in individuals with multiple sclerosis to establish a more holistic approach. Finally, future research should prioritise study replication to not only establish the reliability of current findings, but to also guide future research, identifying errors and thus areas of improvement. However, that said, research thus far certainly shows promise for the future in combatting autoimmune diseases such as multiple sclerosis.

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