Re-vitalise your gut

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Gut microbiome

The lions share of the risk (~70%) for developing MS is attributable to environmental risk, while genetics explains bulk of the remaining risk. The environmental risk factors studied in MS have been manifold, ranging from the latitude effect, to viruses, and may well explain some of the heterogeneity that we observe.

For some time now, researchers have been looking at an imbalance in the gut microbiome or their maladaptation in MS cases versus controls. The findings suggest that the interaction between the microbiome and the host (you) may be reciprocal.

Here, a group of investigators have been investigating a particular human gut commensal, Prevotella histicola, a gram negative bacterium. In the past they have found that P. histicola suppresses induction of disease in the mouse model of MS, decreasing the presence of pro-inflammatory T cells (Th1 and Th17), whilst increasing the frequency of the regulatory immune cell population. To further consolidate their findings they have taken this work a step further, asking the question whether targeting P. histicola could be a novel therapeutic strategy in MS? To this effect, they have pitched against glatiramer acetate (aka Copaxone) in a proof of concept battle.

In therapeutic setting P. histicola suppresses PLP91−110-Induced EAE in HLA-DR3.DQ8 transgenic mice similar to therapeutic treatment of Copaxone®. (A) Mice were immunized with PLP91−110/CFA plus pertussis toxin on days 0 and 2 of the disease induction and 1 week later mice were treated with Copaxone®, P. histicola or a combination of both (with treatment administered on alternate days for a total of 14 doses, 7 doses of Copaxone® and 7 doses of P. histicola) for 2 weeks. Clinical scores were assessed daily for the duration of the experiment. (B) Cumulative EAE scores of mice treated as in (A). (C) Mice were treated with Copaxone®, P. histicola or a combination of both after 12 days of immunization. Clinical scores were assessed daily for the duration of the experiment. (D) Cumulative EAE scores of mice treated as in (C).

They found that P. histicola suppresses EAE as efficiently as Copaxone in their model (see figure above). As before, P. histicola alone or in combination with Copaxone increased the regulatory cell population, while at the same time decreasing pro-inflammatory cells, suggesting that P. histicola may be immunomodulatory. However, it would seem Copaxone administration failed to alter the number of Th1/Th17 pro-inflammatory cells, whilst P. histicola had a direct effect (see figure below).

HLA-DR3.DQ8 transgenic mice induced with EAE and treated with P. histicola alone or in combination with Copaxone® show a decrease in inflammatory cytokine-producing cells in the CNS. (A) Mice were immunized with PLP91−110/CFA plus pertussis toxin on days 0 and 2 of the disease induction and 1 week later mice were treated with Copaxone® (7 doses), P. histicola (7 doses), or a combination of both (with treatment administered on alternate days for a total of 14 doses, 7 doses of Copaxone® and 7 doses of P. histicola). Clinical scores were assessed daily for the duration of the experiment. Flow cytometric plots of IL17+– or IFNγ+-expressing mononuclear cells that were isolated from the brain and spinal cord of mice treated with P. histicola alone, Copaxone® alone, P. histicola and Copaxone®, or media. Cells were isolated and stimulated with antigen (PLP91−110) plus Brefeldin A for 12 h. Plots were previously gated on CD4+ cells. (B–D) Quantification of the frequency of CD4+IL17+T cells (B), CD4+IFNγ+ T cells (C), and CD4+IL17+IFNγ+ T cells (D) from mice treated as in (A). Cells were previously gated on lymphocytes, singlets, and CD4+ cells.
*p ≤ 0.05, **p ≤ 0.005, ***p ≤ 0.0005, and “n.s.” indicates not significant when compared to the media-treated group.

So I would say, watch this space. Clearly, this is a novel therapeutic avenue that needs to be trialed in MS, possibly at the early stages of the disease.

ABSTRACT
Front Immunol. 2019 Mar 22;10:462. doi: 10.3389/fimmu.2019.00462. eCollection 2019.

Prevotella histicola, A Human Gut Commensal, Is as Potent as COPAXONE® in an Animal Model of Multiple Sclerosis.
Shahi SK, Freedman SN, Murra AC, Zarei K, Sompallae R, Gibson-Corley KN, Karandikar NJ, Murray JA, Mangalam AK1.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. We and others have shown that there is enrichment or depletion of some gut bacteria in MS patients compared to healthy controls (HC), suggesting an important role of the gut bacteria in disease pathogenesis. Thus, specific gut bacteria that are lower in abundance in MS patients could be used as a potential treatment option for this disease. In particular, we and others have shown that MS patients have a lower abundance of Prevotella compared to HC, whereas the abundance of Prevotella is increased in patients that receive disease-modifying therapies such as Copaxone® (Glatiramer acetate-GA). This inverse correlation between the severity of MS disease and the abundance of Prevotella suggests its potential for use as a therapeutic option to treat MS. Notably we have previously identified a specific strain, Prevotella histicola (P. histicola), that suppresses disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) compared with sham treatment. In the present study we analyzed whether the disease suppressing effects of P. histicola synergize with those of the disease-modifying drug Copaxone® to more effectively suppress disease compared to either treatment alone. Treatment with P. histicola was as effective in suppressing disease as treatment with Copaxone®, whereas the combination of P. histicola plus Copaxone® was not more effective than either individual treatment. P. histicola-treated mice had an increased frequency and number of CD4+FoxP3+ regulatory T cells in periphery as well as gut and a decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4 T cells in the CNS, suggesting P. histicola suppresses disease by boosting anti-inflammatory immune responses and inhibiting pro-inflammatory immune responses. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as efficiently as Copaxone® and may provide an alternative treatment option for MS patients.

About the author

Neuro Doc Gnanapavan

10 comments

  • Copaxone its a very “soft” drug

    Why wouldn’t they try instead with a more potent theraphy?

    Fecal transplant between mouse Eae and wild type mouse induses Eae in the wild type

    Obrigado

    • The reason for picking Copaxone was based on its purported mode of action – suppression of inflammatory T cell responses by inducing the production of Th2 cytokines that are anti-inflammatory. But, in my opinion P. Histicola would be adjunctive treatment rather than standalone.

      In answer to your other question there have been similar studies, including faecal transplants from naive mice led to amelioration of EAE.

  • “So I would say, watch this space.”
    Which is quite frustrating.
    Why not start any treatment that looks promising, and then use “big data” to extract the results?
    Phase 1-2-3 is kind of last century method, and I cannot wait another 10 years.

    • I agree with you, but randomised controlled studies remain the gold standard in science for treatment comparisons to establish equipoise or superiority of one over the other and will remain a requirement for drug licensing. This should be able to enter at at a Phase IIa/b level, as a safety study may not be required…but don’t hold me to it, as the MHRA may require a small pilot to judge this.

      NB, I also have issues with large data sets as there’s junk in them too and it’s difficult to weed these out.

    • FMT is already available, also as an attempt to ameliorate MS. Hopefully this particular strain will be available as a supplement soon. Overall safety of such probiotic bacteria is questioned from time to time but still appears to be high.

  • Hi doctor, speaking about guts, What do you think of this possibility?

    GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

    https://stm.sciencemag.org/content/10/462/eaat4301

    Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

    • Interesting. But not everyone’s T cells seem to react against this antigen, but there were some high responders. Myelin based antigens remain to date the most frequently reported antigens to which the autoimmune response is directed against in MS.

      • And do you know who are those HLA-DRB3*–positive patients? It is some kind of genetic background? Is it explained anywhere? This is the first time I read about this classification and there is not too much in internet.

  • Confusing picture… It seems the specific strain of _Prevotella_ is important, as well as where they are in the body?

    “Overall results show that P. histicola has immune modulatory activity and can suppress abnormal immune responses, which ultimately prevent autoimmunity. This supports the idea that maintaining a healthy microbial community within our intestines is a potential therapeutic strategy for MS.”

    https://multiplesclerosisnewstoday.com/2017/08/14/human-gut-microbe-may-lead-to-treatment-for-multiple-sclerosis/

    “…at least some Prevotella strains seem to be inflammophilic pathobionts that thrive in an inflammatory environment…”

    “…only certain strains may exhibit pathobiontic properties…”

    “Intriguingly, some Prevotella species could have evolved immune escape mechanisms, including induction of neutrophil dysfunction that may lead to chronic inflammation due to defective clearance.”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506432/

    • Yes, pretty much all of the publications in MS refer to Prevotella histicola that is found in the upper GI tract mainly (but also nasopharyngeal, genito-urinary lining). P. Melanogenica in one study isolated from those with coeliacs disease doesn’t appear to suppress inflammation. So all subspecies are not made equal.

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