There has been a drastic increase in the incidence of autoimmune diseases (ADs) in industrialized nations versus non-industrialized nations over the past several decades (1). Industrialization is often associated with several consequences: improved medical care, better hygiene, and higher standards of living. These factors work together to lower the infection rate, and therefore the microbial exposure, within the country’s population. This would seem to be a positive outcome of industrialization, but the hygiene hypothesis posits that it may actually have a negative effect on immune system development and could be responsible for the higher incidence of ADs in these developed nations.
The importance of the dialectic relationship between the human immune system and our microbiota has come to the forefront in recent years (2). Early in life, the composition of the gut microbiome has been shown to play a key role in the development of a healthy immune system (3). The hygiene hypothesis speculates that the public health measures taken by industrialized nations to limit microbial exposure can significantly alter the gut microbiome composition and therefore affect the development of the immune system (1). Due to the plethora of genetic and environmental factors responsible for the pathogenesis of ADs, this theory is difficult to evaluate in a laboratory setting. However, the varying rates of industrialization in Europe and the close proximity of nations lends a unique opportunity to study this phenomenon.
In the paper “Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans,” Vatanen et al. sought to elucidate the underlying mechanism for the discrepancy in ADs between Finland (industrialized), Estonia (industrializing), and Russian Karelia (rural). As expected by the hygiene hypothesis, Finland exhibits the highest rates of type 1 diabetes and allergies while the rates in Russian Karelia are the lowest. Interestingly, as Estonia has become more developed, the incidence of type 1 diabetes and allergies has transitioned from rates similar to Russian Karelia to rates closer to Finland. Vatanen et al. hypothesized that this increase in the incidence of ADs is due to decreasing microbial exposure in Estonia, which is significantly altering the composition of Estonian infants’ gut microbiome and, therefore, affecting their immune system development.
A longitudinal metagenomics study, using monthly stool samples, was conducted to characterize and compare the gut microbiome composition (down to strain-level identification) of infants from the three countries of interest from birth to three years old. Once the gut microbiome was characterized for each country, Vatanen et al. sought to compare the difference in microbial functions between the populations. Most notably, they studied the source of lipopolysaccharides (LPS) in each country and compared the functional abilities of the LPS subtypes found within each population. LPS was the endotoxin of choice because it is known to elicit a strong immune response in mammalian cells and plays a critical role in immune system education early in life (4). It is important to note that LPS subtypes can differ in the acylation of their lipid A domain, affecting their ability to stimulate the immune system and induce endotoxin tolerance (a crucial aspect for the development of a healthy immune system). To read the paper and get a more in depth look at the methodology: click here.
As predicted by the hygiene hypothesis, there was a significant difference in the infant gut microbiomes. This difference was the largest in the first year of life, but then diminished in the second and third years of the study. In the first year, Russian infant’s microbiome was dominated by phylum Actinobacteria (genus Bifidobacterium) and was overall less diverse than the Finnish and Estonian infant’s gut microbiome that was dominated by Bacteroides species (these populations remained stable in Finns and Estonians throughout the experiment). Despite this, Russian infants actually exhibited a more diverse microbiota over the length of the study. The species with the largest population difference between Finns and Russians was Bacteroides dorei (higher in Finns), which has previously been linked with type 1 diabetes pathogenesis (5).
When it came to the source of LPS within each population, E. coli proved to be the major contributor to lipid A biosynthesis in all countries studied. However, in both Finnish and Estonian infants the genus Bacteroides was also a significant contributor (most notably B. dorei). The subtypes of LPS produced by E. coli and B. dorei were found to differ in the acylation of the lipid A domain, and therefore had a significant difference in their abilities to evoke an immune response (and induce endotoxin tolerance). B. dorei LPS failed to stimulate inflammatory cytokine production in primary human peripheral blood mononuclear cells and while E. coli LPS was a potent stimulator of inflammatory cytokine production. Interestingly, B. dorei LPS was also shown to act as an inhibitor of E. coli LPS immune stimulation in a dose dependent manner. To further their understanding of the role these LPS subtypes play in AD pathogenesis, Vatanen et al. studied the development of type 1 diabetes in the non-obese diabetic mouse model. They found that injection of E. coli LPS delayed the onset and reduced the incidence of type 1 diabetes while B. dorei LPS did not affect the onset of type 1 diabetes.
The results of this study clearly highlight the importance our gut microbiome has on our overall health. Early in life, the immune system is heavily stimulated by the gut microbiome, laying the foundation for how the immune system will respond to all future pathogens and exogenous substances. For instance, E. coli LPS stimulation of the immune system induces a controlled inflammatory response responsible for development of immunosuppressive activity via endotoxin tolerance. The slightest change in this immune system education, such as varying contributors to LPS biosynthesis, can have a drastic long term effect on immune system health. Even if the immune system undergoes a “proper education” the gut microbiome can still exhibit a substantial effect on our health later in life.
Studies indicate that the GI mucosa permeability can be influenced by a variety of factors such as immunosenescence, GI disorders, and physical/psychological stress (6). An increase in GI mucosa permeability allows for the translocation of exogenous substances (LPS, SEB, bacteria, "mimic antigens") from the gut to surrounding tissues and into the circulatory system, thus stimulating the production of anti-bacterial antibodies. These exogenous substances normally cause controlled inflammation, but an increase in GI mucosa permeability allows the controlled inflammation to turn into pathological inflammation associated with certain ADs (such as inflammatory bowel disease and RA). In fact, byproducts of bacterial cell wall and nucleic acid degradation have been found in the joints of rheumatoid arthritis (RA) patients, indicating that this translocation plays a role in RA pathogenesis (6). Whether the effect is exerted early or late in life, it is apparent that gut microbiome composition is a key aspect of an individual’s immune system health and plays a role in AD pathogenesis. Future models of ADs must consider the effect that intestinal bacteria and the various substances they produce have on the immune system and the development of pathological inflammation.