Humans as “supra-organisms” – this is the picture that takes shape when considering the countless microorganisms living within us [1]. Among these, trillions of microbes – including bacteria, viruses, fungi, and archaea – reside in our gastrointestinal tract [2]. The genes of these microorganisms – collectively known as the microbiome – outnumber those in the human genome by more than 150 times [3].
These symbiotic microbes in our gut play a key role in modulating our immune system and maintaining health [4]. When the composition of the commensal gut microbiota is altered, the balance between the body’s inflammatory and regulatory immune responses can be shifted. This imbalance can be associated with different inflammatory conditions [5]. Notably, specific gut microbiome may be linked to the risk, course, and progression of multiple sclerosis (MS) [6].
Risk of developing MS: Beyond genetics
More than 200 loci in the human genome have been linked to the development of MS. Multiple genome-wide association studies (GWAS) have identified 32 independent genetic associations within the major histocompatibility complex (MHC), 200 autosomal variants (not located on sex chromosomes) that increase susceptibility outside the MHC, and one variant on the sex chromosome X [7]. However, genetic heritability accounts for only 20-30% of the overall risk of developing MS [7]. This means that part of the remaining risk can be explained by a combined influence of genes and environment – also known as the ‘effect of nature and nurture’ [7].
Professor Sergio Baranzini, from the University of California San Francisco (UCSF), tells us, “Genetics is an essential component of the risk of developing MS, but it alone does not fully account for the entire risk. This is clear in studies of monozygotic or ‘identical’ twins. If genetics were the only factor, then all monozygotic twins with MS should be concordant. But this is not the case. Only about 40% are concordant [8]. Therefore, we sought to investigate what environmental factors, in addition to genetics, contribute to MS risk. A pioneer study on animals was conducted using SJL mice, with a genetic predisposition to develop experimental autoimmune encephalomyelitis (EAE). Professor Lloyd Kasper demonstrated that treating these mice with wide-spectrum antibiotics, which altered the gut commensal bacteria, protected them against EAE [9]. Gut microbiota appears to be essential to develop the disease in animal models. This study was followed by a seminal paper by the group of Professor Hartmut Wekerle, showing experimentally and in vivo that gut microbiota is required for the spontaneous EAE model [10]. In fact, despite a genetic predisposition to EAE, the mice did not develop the disease when kept under germ-free conditions. However, they developed it when colonised with microbiota from an individual with MS [10].”
Gut bacterial communities contribute to regulate the immune response. They work together with the human genome to maintain a balance between immunoregulatory (Treg) and pro-inflammatory (Th17) T-cells [3]. Throughout a person’s lifetime, the human genome cannot change, whereas the microbiome can. A healthy microbiome can tune a balanced immune response. Diet, antibiotic use, environment, and lifestyle can alter the microbiome’s composition, a condition known as dysbiosis [3]. An increase in pro-inflammatory bacteria or a reduction in anti-inflammatory bacteria can disrupt the balance between Th17 cells and Tregs and eventually lead to autoimmune and inflammatory conditions in animal models [3].
Professor Jennifer Gommerman, from the University of Toronto, explains, “When the microbiome, for example, breaks down components of our diet, it produces different small molecules that become metabolites. These metabolites can enter the intestine and influence the behavior of immune cells that reside in the gut. Among these, short-chain fatty acids are an example of known bacterial metabolites with immunoregulatory effects. The metabolites can also travel beyond the gut and have an impact on the peripheral immune system. They can even have remote effects on the central nervous system (CNS). Moreover, immune cells that ordinarily “live” in the gut and are influenced by the metabolites in that location can themselves migrate to the brain and spinal cord [11].”
Gut microbiota and MS
Evidence indicates that the microbiota of individuals with MS has a more pro-inflammatory profile [12]. Researchers observed an increase in specific bacterial taxa in people with MS, such as Akkermansia muciniphila and Acinetobacter calcoaceticus, which contribute to a proinflammatory environment [12]. Conversely, other bacteria that stimulate anti-inflammatory responses in mice were found to be reduced in MS [12]. When transplanting microbiota from people with MS into germ-free mice, the symptoms of EAE were exacerbated [12]. This suggests a causal role of gut microbiota composition in the pathogenesis of MS. Gut microbiota of individuals with MS can trigger MS-like autoimmune condition in SJL mice [13]. When gut microbiota of monozygotic twins with MS is transplanted in SJL mice it induces autoimmunity more frequently compared to microbiota from the unaffected monozygotic twins [13].
The association of certain microbes – e.g. Akkermansia muciniphila – with EAE severity can vary depending on the composition of the background microbiota [14]. In addition, even when receiving the same microbiota, mice can show different disease courses [14].
Professor Baranzini tells us, “Many confounding factors, including diet, geography, lifestyle, treatment, can murk the waters when one tries to understand the role of gut microbiota in individuals with MS. To overcome these challenges, we started the International Multiple Sclerosis Microbiome Study (iMSMS). This is a large and well-controlled study that recruited 576 individuals with MS and 576 healthy individuals living with them in the same house from the United States, Europe, and South America [6]. We found stable differences between the microbiota of the individuals with MS and that of the healthy controls. Furthermore, we observed that the gut bacteria of individuals with MS can vary from person to person, not only in terms of the types of bacteria present but also in the metabolic pathways those bacteria carry out. Disease-modifying treatments can also modulate microbiome composition, function, and derived metabolites.”
The researchers carefully looked at the specific elements of people’s diets using food questionnaires and calculated a healthy eating index [6]. Some bacteria were found to be more common in people with MS independently of their diet. For example, the bacterium Ruminococcus torques is typically more abundant in individuals who consume less sodium. Although people with MS and their healthy controls ate similar amounts of sodium, this bacterium was still found to be more common in people with MS. Another example is F. prausnitzii, which is enriched in people who eat more fruit. Despite people with MS consuming more fruit than controls, F. prausnitzii remained significantly reduced in their gut microbiota [6].
The gut microbiota changes with age
Chronological age is strongly associated with the clinical course of MS. Older age is a major risk factor for disability accumulation [15] (see also the Spotlight on the impact of ageing on MS). Researchers sought to explore the role of gut microbiota in age-dependent disease progression [16].
Professor Gommerman explains to us, “If you look at the microbiome of aging mice with EAE in an animal facility, you will not see many changes. Moreover, transferring the microbiome of an aged mouse into a young mouse from the same facility has minimal impact on the disease. That’s because the mice live in identical conditions – they have the same diet, sleep cycle, and environment. In humans, however, the microbiome does change with age. Why? Because humans are exposed to a variety of conditions throughout their life, including diet, physical exercise, travels, antibiotics, and medications. To study the ageing microbiome, one approach is to take samples from humans and transplant them into mice – this provides the advantage of studying the impact of human ageing on the microbiome whilst having an animal model system where we can isolate tissues and cells from the CNS at different points in the disease course. This approach can capture the complexities of environmental exposures over a lifetime. In fact, compared to faecal transplants from young human donors, faecal transplants from some aged human donors into young mice were able to induce an aged EAE phenotype in chronologically young mice. To minimise genetic and environmental confounders, we recruited pairs of first-degree relatives sharing the same sex and household. This helped us more reliably identify microbes and their metabolites that may change with age [16].”
The gut: The body’s largest immune reservoir
There is growing interest in exploring dietary interventions and supplements that can help modulate the composition of the gut microbiota.
Professor Yanjiao Zhou, from the University of Connecticut, tells us, “Calorie restriction has the potential to benefit individuals with MS and in a recent study, we observed that it is safe and feasible. After 12 weeks of intermittent caloric reduction in individuals with MS we could reduce the levels of leptin, which has proinflammatory effects [17]. In another study, we showed various alterations in gut microbiota and its fungal component – the mycobiome – of people with MS [18]. Using advanced multi-omics technologies, we could also identify a potential biological network that connects meat consumption to higher levels of meat-related metabolites in the blood, a reduction in bacteria that digest polysaccharides, and increased Th17 cells in people with MS [19].”
The use of prebiotics, probiotics, short-chain fatty acids, and faecal microbiota transplantation in individuals with MS seems promising but is still under investigation [20].
Professor Gommerman observes, “Many factors influence our microbiome, including physical exercise and diet. However, it can be difficult to change the microbiome in a dramatic way, because it develops primarily during the first decade of life. While more research is needed, what we do know is that when studying the immune system in humans, we usually analyse blood because it is the easiest and least invasive method. But, in fact, the gut is the largest reservoir of immune cells in the body. This makes it worthwhile to look at the microbiome in almost any disease – especially in MS that often progresses over time.”
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Written by Stefania de Vito
Special thanks to Professor Sergio Baranzini (University of California, San Francisco – UCSF), Professor Jen Gommerman (University of Toronto) and Professor Yanjiao Zhou (University of Connecticut) for their insights.
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