bacteria, lipoarabinomannan from mycobacteria, and zymosan from yeast. Interestingly, lipoteichoic acid from a human-derived strain of Lactobacillus paracasei,
acting via TLR2, was shown to correct age-related gut leakiness and inflammation,
and increase mucin production and increase the abundance of a mucin-degrading
bacterium Akkermansia muciniphila, an organism associated with protection from
obesity and diabetes (Wang et al. 2019). Similarly, a TLR2 agonist administered to
mice induced both TLR2 tolerance and attenuation of the autoimmune disorder
Experimental Autoimmune Encephalomyelitis (EAE). This tolerance was accompanied by reduced Th17 cells and an increase in splenic type 1 regulatory T cells
(Anstadt et al. 2016). Moreover, the same authors find that patients suffering from
Multiple Sclerosis have abnormally low circulating levels of a bacterium-derived
TLR2 agonist, when compared to healthy donors (Anstadt et al. 2016).
18.4.5.3 Immunoregulation via TLR9
There is evidence that signals via TLR9 might sometimes exert anti-inflammatory
effects. This intracellular TLR detects unmethylated CpG motifs. These are relatively common in microbial genomes, and they drive an inflammatory response.
However, several workers have identified variants of the CpG motif and other
microbial DNA sequences, that have lost their pro-inflammatory effects, or become
anti-inflammatory (Krieg et al. 1998; Hiramatsu et al. 2014). A recent study found
that the genomes of a large range of Lactobacillus species are rich in these immunosuppressive motifs, when compared to several pathogens (Mazhary et al. 2020).
Lactobacilli are ubiquitous, associated with food and people, but also notably with
flowers, animals, insects, and soil containing fermentable matter such as grass
(silage). We know that at least part of the probiotic effects of lactobacilli require
the presence of TLR9, which is well expressed in the gut and airways (Rachmilewitz
et al. 2004). This raises the possibility that organisms such as lactobacilli breathed in
from the natural environment can exert immunoregulatory effects in this way.
18.4.5.4 Immunoregulation via Other Pattern Recognition Receptors
There is some evidence that tolerance can also be driven via other PRR, perhaps
because the cytokine IL-1β is able to do it (Alves-Rosa et al. 2002), and many
microbial components induce its release. Under some experimental conditions
exposure to chitin, present as described above in fungal cell walls, is associated
with release of anti-inflammatory IL-10, or with suppression of anaphylaxis and
reduced allergen-specific IgE (Elieh Ali Komi et al. 2018). The latter effect might be
attributable to a broad anti-inflammatory mechanism, but it could be due to induction
of a Th1 bias, with reduced Th2-mediated allergic pathways. For example, signals
from TLR7 can reduce airway inflammation, by promoting a Th1-bias that reverses
airway hyperresponsiveness and reduces airway remodelling (Dong et al. 2016).
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acting via TLR2, was shown to correct age-related gut leakiness and inflammation,
and increase mucin production and increase the abundance of a mucin-degrading
bacterium Akkermansia muciniphila, an organism associated with protection from
obesity and diabetes (Wang et al. 2019). Similarly, a TLR2 agonist administered to
mice induced both TLR2 tolerance and attenuation of the autoimmune disorder
Experimental Autoimmune Encephalomyelitis (EAE). This tolerance was accompanied by reduced Th17 cells and an increase in splenic type 1 regulatory T cells
(Anstadt et al. 2016). Moreover, the same authors find that patients suffering from
Multiple Sclerosis have abnormally low circulating levels of a bacterium-derived
TLR2 agonist, when compared to healthy donors (Anstadt et al. 2016).
18.4.5.3 Immunoregulation via TLR9
There is evidence that signals via TLR9 might sometimes exert anti-inflammatory
effects. This intracellular TLR detects unmethylated CpG motifs. These are relatively common in microbial genomes, and they drive an inflammatory response.
However, several workers have identified variants of the CpG motif and other
microbial DNA sequences, that have lost their pro-inflammatory effects, or become
anti-inflammatory (Krieg et al. 1998; Hiramatsu et al. 2014). A recent study found
that the genomes of a large range of Lactobacillus species are rich in these immunosuppressive motifs, when compared to several pathogens (Mazhary et al. 2020).
Lactobacilli are ubiquitous, associated with food and people, but also notably with
flowers, animals, insects, and soil containing fermentable matter such as grass
(silage). We know that at least part of the probiotic effects of lactobacilli require
the presence of TLR9, which is well expressed in the gut and airways (Rachmilewitz
et al. 2004). This raises the possibility that organisms such as lactobacilli breathed in
from the natural environment can exert immunoregulatory effects in this way.
18.4.5.4 Immunoregulation via Other Pattern Recognition Receptors
There is some evidence that tolerance can also be driven via other PRR, perhaps
because the cytokine IL-1β is able to do it (Alves-Rosa et al. 2002), and many
microbial components induce its release. Under some experimental conditions
exposure to chitin, present as described above in fungal cell walls, is associated
with release of anti-inflammatory IL-10, or with suppression of anaphylaxis and
reduced allergen-specific IgE (Elieh Ali Komi et al. 2018). The latter effect might be
attributable to a broad anti-inflammatory mechanism, but it could be due to induction
of a Th1 bias, with reduced Th2-mediated allergic pathways. For example, signals
from TLR7 can reduce airway inflammation, by promoting a Th1-bias that reverses
airway hyperresponsiveness and reduces airway remodelling (Dong et al. 2016).
18 Darwinian Medicine: We Evolved to Require Continuing Contact with the. . .
343