Table 1.
Summary of the major bacteria linked to MS.
| Bacteria | Target TLR | Relationship with EAE | Relationship with MS | Suspected mechanism of action | |
|---|---|---|---|---|---|
| Risk factor | Mycobacterium avium subsp. paratuberculosis | TLR2 (Arsenault et al., 2014; Cossu et al., 2017a) TLR9 (Arsenault et al., 2013; Cossu et al., 2017a) | DNA and antibodies in serum (Cossu et al., 2011, 2014, 2015, 2017b), intrathecal IgG synthesis in CSF (Mameli et al., 2016) | Activation of autoreactive T cells in the periphery by and reactivation in brain (Cossu et al., 2013, 2017a) | |
| Chlamydia pneumoniae | TLR2 (Shimada et al., 2012) TLR3 (Shimada et al., 2012) TLR4 (Shimada et al., 2012) TLR9 (Shimada et al., 2012) | Exacerbation of disease severity (Du et al., 2002) | DNA and antibodies in CSF (Contini et al., 2008; Fainardi et al., 2008; Tang et al., 2009; Ivanova et al., 2015) | Infection of neuronal glial cells and alteration of BBB permeability (MacIntyre et al., 2002) | |
| Mycoplasma pneumoniae | TLR1 (Waites and Talkington, 2004) TLR2 (Waites and Talkington, 2004) TLR6 (Enevold et al., 2010) | Antibodies in serum, intrathecal IgG synthesis in CSF (Bahar et al., 2012) Isolation from brain and urine samples of MS patients (Harbo et al., 2013) | Direct invasion in the brain may cause demyelination (Lindsey and Patel, 2008) | ||
| Clostridium perfringens type B | TLR2 (Abramovitz et al., 1987) | Immunoreactivity to epsilon toxin in PBMCs and CSF (Dorca-Arévalo et al., 2008) Bacterium isolated from feces of MS patients (Dorca-Arévalo et al., 2008) | The neurotoxin affects endothelial cells, myelinated fibers, and oligodendrocytes of the CNS (Sakai et al., 2011) | ||
| Helicobacter pylori | TLR4 (Efthymiou et al., 2017) | Histological presence of infection (Gavalas et al., 2015) Serum antibodies (Efthymiou et al., 2017) | Release of pro-inflammatory mediators and loss of self-tolerance (Kountouras et al., 2015) | ||
| Euryarchaeota, Firmicutes, Proteobacteria (Sutterella) | TLR2 (Schmutzhard et al., 1988) TLR4 (Schmutzhard et al., 1988) TLR5 (Schmutzhard et al., 1988) TLR9 (Schmutzhard et al., 1988) | Exacerbation of disease severity (Carabotti et al., 2015) Increased disease incidence in a spontaneous mouse model (Shahi et al., 2017) | More frequent in MS patient’s microbiota than healthy controls (Colpitts and Kasper, 2017; Shahi et al., 2017; Tremlett and Waubant, 2017) | Pro-inflammatory response and reduced IL10 production (Carabotti et al., 2015) Staphylococcal enterotoxin B (Brocke et al., 1993) | |
| Protective factor | Mycobacterium bovis BCG | TLR2 (Cossu et al., 2017a) TLR4 (Cossu et al., 2017a) | Suppression of disease (Sewell et al., 2003; Lee et al., 2008) | Reduced MRI activity and lower antibody titer in MS patients, compared to control subjects (Cossu et al., 2014, 2017b; Ristori et al., 2014) | Skin vaccination or direct inoculation in brain or gut of mice (Sewell et al., 2003; Lee et al., 2008; Moliva et al., 2017) Antigenic competition, diversion of autoreactive T cells to granulomas (Sewell et al., 2003) |
| Helicobacter pylori | TLR4 (Efthymiou et al., 2017) | Infection reduces disease severity (Cook et al., 2015) | Lower antibody titer in MS patients compare to controls (Yoshimura et al., 2013; Jaruvongvanich et al., 2016; Yao et al., 2016) | Suppression of Th1/Th17 cell responses (Salama et al., 2013) | |
| Firmicutes (Clostridia), Actinobacteria, Bacteroides | TLR2 (Schmutzhard et al., 1988) TLR4 (Schmutzhard et al., 1988) TLR5 (Schmutzhard et al., 1988) TLR9 (Schmutzhard et al., 1988) | Reduced disease susceptibility following oral administration of Bacteroides fragilis PSA (Carabotti et al., 2015) | Less frequent in the microbiota of MS patients than in healthy control subjects (Logsdon et al., 2018) | Anti-inflammatory response (Carabotti et al., 2015) Expansion of CD39(+) Tregs and increased IL10 expression (Carabotti et al., 2015) |