One of the most important health insights from the last decade is the role of the gut microbiome. The gut microbiome corresponds to all microorganisms such as bacteria, viruses and fungi that are living in your gastrointestinal tract. In mice, some studies have shown that depletion of your gut microbiome with antibiotics leads to suppression of EAE, which is the mice equivalent of MS. Other studies have shown that germ-free mice (only enviable when it comes to COVID-19) do not develop EAE unless their gut is recolonised with the microbiome of a pwMS. The underlying hypothesis is that the bacteria of the gut microbiome carry protein sequences (epitopes) that are similar but not identical to some of the protein sequences present in your brain. Recognition of the gut microbiome epitopes by the immune system might shift the immune system towards a more pro-inflammatory state and could potentially trigger brain inflammation. In addition, some studies in small groups of pwMS found that some gut bacteria are more or less common compared to healthy controls. However, mice are not humans, and correlation is not causality – whatever your gut feeling tells you.
A new study included 33 pwMS, 18 people with CIS and 32 healthy controls, and showed that in people with advanced MS, bacteria are less frequently coated with IgA antibodies. IgA is an immunoglobulin/antibody found in the linings of the respiratory tract and digestive system as well as in saliva, tears, and breast milk. The equivalent in the blood is IgG. Second, the study showed that some gut bacteria are not detected by IgA-antibodies, but do elicit a serological response when IgG in their blood is measured. So when we analyse the type of IgG’s present in the blood, we notice that some of them are directed at some of the gut microbiome bacteria without these bacteria being detected in the gut itself by IgA.
The problem is we do not have a clue what the findings in this study mean for pwMS and how we should interpret these data. Is this lack of IgA coating relevant? Why would it matter that some bacteria are not recognised by IgA but are recognised by IgG? Is this unique to the gastro-intestinal system? To be honest, I owe you the answer. Irrespective of this study, there are several hurdles when doing research on the gut microbiome that preclude firm conclusions anno 2021:
Problem 1: There are over 1000 bacterial species present in the gut microbiome. Although not all of them are equally frequent, this still implies that you need large study cohorts to draw conclusions about the frequency and relative abundance of certain species. Illustratively, the biggest studies in MS to date included all less than 100 individuals. From a logistical point of view, collecting stool samples is definitely more difficult than obtaining blood samples. In addition, we moved on from bacterial cultures towards genetic sequencing of bacterial genomes. The problem is that the genetic mapping of all these bacterial families requires expensive and extensive sequencing of the microbiome (bad combination) and complicated bioinformatic analyses. Nothing your monthly data plan could handle.
Problem 2: Is the microbiome stable? The microbiome is known to vary over time, and especially sensitive to the use of antibiotics and dietary changes. Microbiota namely fluctuate according to nutrient availability: forgot to extend your Hello Fresh deliveries and only had fast-food this week?, accepting the challenge for a ‘Tournée Minérale’?, trying out intermittent fasting? The influence of such environmental triggers is unclear. An analysis of the faecal microbiota of 37 individuals found that ~60% of bacterial strains remained stable for up to five years. Other studies documented that there is a stable core of microbacteria but that their relative abundance fluctuates over time and throughout the day. Anyway, this susceptibility to environmental triggers is a hurdle to correctly interpret cross-sectional findings originating from a one-off measurement.
Problem 3: Chicken or the egg story. If your microbiome is perturbed, is this the cause or consequence of for example a more severe MS disease course. If people with advanced MS have a different microbiome composition, is this due to the higher frequency of constipation in this subgroup which is known to perturb the gut ecosystem? People with advanced MS tend to use more antibiotics to treat for example urinary tract infections? Are pwMS more frequently trying out diets to influence their disease course? Or is the gut dysbiosis driving the ever increasing prevalence of obesity and is this, in turn, linked with a pro-inflammatory state of the immune system and thus incidence of MS?
Overall, we do not sufficiently understand the connection between the diet, the gut microbiota, and brain inflammation and this limits the interpretation of microbiome studies in pwMS. Admittedly, the association between the microbiome and brain inflammation is less apparent than the link between the microbiome and obesity. It is much more conceivable that the gut microbiome has an impact on the absorption, breakdown, and storage of nutrients and thus energy expenditure. In genetically identical twins who were discordant in terms of body weight, the microbiome showed significantly less diversity in the overweight versus lean ones. Hence, the gut microbiome is an important ecosystem impacting on general health but it is way too early for pwMS to get their microbiome “fingerprint” measured or to get your guts up for a fecal transplant.
Disclaimer: Please note that the opinions expressed here are those of Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Neurol Neuroimmunol Neuroinflamm. 2021 May 11;8(4):e997.doi: 10.1212/NXI.0000000000000997. Print 2021 Jul.
Delphine Sterlin 1, Martin Larsen 1, Jehane Fadlallah 1, Christophe Parizot 1, Marina Vignes 1, Gaëlle Autaa 1, Karim Dorgham 1, Catherine Juste 1, Patricia Lepage 1, Jennifer Aboab 1, Savine Vicart 1, Elisabeth Maillart 1, Olivier Gout 1, Catherine Lubetzki 1, Romain Deschamps 1, Caroline Papeix 1, Guy Gorochov 2
- PMID: 33975914
- PMCID: PMC8114833
- DOI: 10.1212/NXI.0000000000000997
Objective: Based on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS.
Methods: We investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing.
Results: We show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = -0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001).
Conclusions: Gut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.