Are the decrease in circulating anti-α1,3-Gal IgG and the lower content of galactosyl transferase A1 in the microbiota of patients with multiple sclerosis a novel environmental risk factor for the disease?

Abstract

The etiology of multiple sclerosis (MS), particularly the environmental component of the disease, remains speculative. Recent reports have suggested that alterations in the gut microbiota of MS patients could contribute to the etiology or pathophysiology of the disease. In this Viewpoint, using PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to infer the functional content of the gut microbiota, we show that the gut microbiota of MS patients is characterized by a significant decrease in the relative abundance of the enzyme EC 2.4.1.87, which corresponds to the GGTA1 gene (which codes for the α1,3-Gal epitope and is lacking in humans), against which MS patients also have low levels of IgG antibodies. The decrease in circulating anti-α1,3-Gal IgG and lower content of galactosyl transferase A1 in the microbiota of patients with multiple sclerosis could be a novel environmental risk factor for the disease.

Introduction

The amount and taxonomic composition of the intestinal microbiota affect the host immune response in experimental models (Berer and Krishnamoorthy, 2014). Gut microbiota patterns from patients suffering from multiple sclerosis (MS) differ from those of healthy individuals. MS patients have reduced relative abundances of Bacteroidaceae, Bacteroides, Parabacteroides, Faecalibacterium, Prevotella, Anaerostipes, Collinsella and Slackia (Miyake et al., 2015, Cantarel et al., 2015, Chen et al., 2016a, Jangi et al., 2016), which are believed to affect host immunity (Kamada et al., 2013).

Recently, we reported that MS patients exhibit a decrease in anti-α1,3-Gal IgG blood levels compared with those of age/gender-matched healthy individuals (Le Berre et al., 2017). The α1,3-Gal epitope is lacking in human glycans following the loss-mutation of the glycosyltransferase A1 (GGTA1) gene that controls its synthesis (Padler-Karavani et al., 2008). Anti-α1,3-Gal antibodies, which appear during the first year of life, supposedly due to the immunization against gut microbiota (Cooper et al., 1994), represent a substantial fraction of the total IgG and IgM pool in humans (up to 1 percent of B cells display a B cell receptor committed to α1,3-Gal) (Galili, 2013). The levels of anti-α1,3-Gal antibodies may affect the immune response against GGTA1-positive infectious agents by several mechanisms (Galili, 2016, Soares, 2015) and may also be involved in autoimmune processes (Galili, 2013).

In this Viewpoint, we suggest that the abnormal level of anti-α1,3-Gal antibodies could be related to abnormal amounts of GGTA1 gene-positive microorganisms in the MS patient microbiota, providing a new link to novel alterations in environmental factors in the disease (working hypothesis in Fig. 1A).