Beyond its influence in the gastrointestinal milieu, the gut microbiota may influence the development of autoimmune diseases. A recent study, led by Dr. Ashutosh Mangalam, assistant professor of pathology at the University of Iowa Carver College of Medicine in Iowa City (USA), has found that gut microbiota changes may contribute to the disease course of multiple sclerosis.
The researchers aimed to investigate whether gut microbiota may play a role in the pathogenesis of multiple sclerosis (MS), a chronic autoimmune disorder with an aetiology involving both genetic and environmental factors. Detailed faecal microbiome analyses showed that gut microbiota of relapsing-remitting MS (RRMS) patients (n=31) -including both remission RRMS and active RRMS- differed from age- and gender-matched healthy controls (n=36). Specifically, there was an increased abundance of Pseudomonas, Mycoplana, Haemophilus, Blautia, and Dorea genera in MS patients, whereas the control group showed an increased abundance of Parabacteroides, Adlercreutzia and Prevotella genera. Although analysis of species richness showed no differences between RRMS patients and healthy controls, RRMS patients with active disease showed decreased species richness compared to patients in remission and controls, which points out the need to consider MS phase (remission and active phases) when assessing the role of gut microbiota in the disease. These data show that individuals with MS have a distinct gut microbial community profile compared to controls, which suggests a microbial signature in the gut microbiota of MS patients.
Going beyond the observation of an altered gut microbiota in patients suffering from MS, the potential connection between gut microbiota, therapy, and changes in immunity has not been previously studied. Another recent study, led by Prof. Howard L. Weiner from the Department of Neurology at Harvard Medical School in Boston, Massachusetts (USA), found that alterations in the gut microbiota in MS patients correlated with immunomodulatory treatment and changes in the expression of immune-related genes. Faecal samples were collected from MS patients (n=60) and healthy subjects (n=43). All MS patients had relapsing-remitting disease but none had active MS when enrolled at the study. Within the overall cohort of MS patients, both untreated (n=28) and treated (n=32) subgroups were analysed independently. Gene expression profiling and proliferation and cytokine assays in response to specific microbial stimulation were performed on peripheral blood T cells and monocytes from MS patients (n=18) and healthy subjects (n=18). Sera from MS patients (n=45) and healthy subjects (n=16) were collected for capturing serologic activity directed against specific microbes. Finally, breath samples from MS patients (n=41) and healthy subjects (n=32) were collected from a second subject cohort to determine breath methane concentrations.
The overall microbial community structure (calculated by measures of alpha- and beta-diversity) was not different between MS patients and healthy controls. When comparing the relative abundance of microbiota at the phylum level between the entire MS cohort (both treated and untreated) and controls, MS patients had a significantly increased relative abundance of the phyla Euryarchaeota and Verrucomicrobia compared to healthy controls. In addition, relative abundances of the gut microbiota differed between MS (untreated and treated) patients and controls at the genus level. Gut microbiota alterations in MS patients included increases in the relative abundances of Methanobrevibacter, a genus in the phylum Euryarchaeota, and Akkermansia, a genus in the phylum Verrucomicrobia, and decreases in Butyricimonas, which belongs to the phylum Bacteroidetes. Furthermore, these changes correlated with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and nuclear factor-kappa B (NF-kB) signalling pathways in circulating T cells and monocytes. No differences in anti-Methanobrevibacter antibody titres were observed between MS patients and healthy controls.
The researchers also studied whether immunosuppressive medication may skew gut microbiota composition in treated versus untreated MS patients. It was found that treated MS patients had increases in the Prevotella and Sutterella genera, and decreases in Sarcina genus, when compared with untreated MS patients. Prevotella and Sutterella genera were either significantly reduced or showed a trend of reduced populations in untreated patients compared with controls, which suggests that immunomodulatory therapy may normalize some of the MS-related changes in the gut microbiota. As Sarcina levels were similar between untreated patients and controls, it suggests a treatment-associated effect on this genus. Data were also analysed taking into account confounding factors such as age, gender, and body mass index. MS-effect and treatment-effect on the gut microbiota composition remained significant after adjusting for these factors.
In the second smaller cohort of this study, MS patients (n=41) showed elevated breath methane compared with controls (n=32), which was consistent with MS patients’ increased abundance of Methanobrevibacter -the main methane-producing microbe in the human gut.
All together these data show that MS patients have gut microbiota differences that require more investigation. Further studies are needed in order to confirm these findings in a larger patient population and assess whether the observed alterations in the gut microbiota have an active role in, or are a consequence of, changes in immune gene expression or the disease itself. Further research will also help determine whether alterations in gut microbiota or in breath methane levels in MS patients could be used as disease biomarkers.
In a recent review, led by Dr. Justin Glenn and Dr. Ellen Mowry from the Department of Neurology at Johns Hopkins University in Baltimore, Maryland (USA), potential mechanisms by which the gut microbiota could be manipulated for therapeutic benefit are discussed. Those mechanisms may involve altered levels of bacteria; the activity of bacteriophage or bacterial toxins in the human gut may affect the immune system and thus contribute to the development of autoimmune disorders such as MS. Probiotics and phage therapy are proposed as a novel strategies to be explored for MS.
Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016; 6:28484. doi:10.1038/srep28484.
Glenn JD, Mowry EM. Emerging concepts on the gut microbiome and multiple sclerosis. J Interferon Cytokine Res. 2016; 36(6):347-57. doi:10.1089/jir.2015.0177.
Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016; 7:12015. doi:10.1038/ncomms12015.
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