Microbiota influences on systemic lupus erythematosus and Sjögren’s syndrome

Microbiota effects on the host immune system

A reciprocal relationship exists between a microbial community and its host. Commensal microbes modify and metabolize host substances (e.g., food and drugs), synthesize vitamins, stimulate immune responses, and may become pathogenic under certain conditions. In turn, microbial communities are influenced by host genetics, environment, food, drugs, cosmetics, hormones, disease states, and the immune system. Our immune system directly shapes the microbiota by secreting mediators of the innate immune system such as antimicrobial peptides, lectins, and complement. Furthermore, evolution of the adaptive immune system allowed for specific “pruning” of the microbiota through secretion of IgA. However, adaptive immune memory also puts the host at risk of immune-mediated diseases linked to the microbiota—once a colonizing species is targeted as an inflammatory trigger, its temporal stability may lead to chronic inflammation.

Development of a mature, healthy immune system requires the microbiota. Neonatal intestinal epithelial cells have an assortment of microbe-sensing receptors, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors, that detect microbe-associated molecular patterns. Without microbial stimulation, germ-free (GF) mice develop reduced size and cellularity of secondary lymphoid tissues, reduced circulating CD4 ⁺ T cells, enhanced Th2 skewing of CD4 ⁺ T cells, and a deficiency in secretory IgA-producing plasma cells, with the expected resulting impairment in responses to injury and infection. Similar interactions are important at other barrier sites; for example, the cutaneous microbiota is required for the recruitment of T regulatory cells (Tregs) into neonatal skin and antigen-specific tolerance of normal commensals.

At the same time, mucosal surfaces require both tolerance of commensal microbes and resistance to infection, necessitating a careful homeostatic balance between pro- and anti-inflammatory responses. Too much tolerance can lead to increased risk of infection with pathogens and invasion of commensal bacteria beyond the barriers; too much inflammation can lead to inflammatory, autoimmune, and other chronic diseases. The immunologic influence can be broad if mediated by shared patterns of microbes across taxa or focused if triggered by a particular bacterium that confers species- or even strain-specificity. When GF mice were monocolonized with 62 individual common human gut commensal species and strains across five phyla, most organisms induced or suppressed multiple components of the innate and adaptive immune system, further illustrating the complex interplay between our microbiota and our immune health.

Host effects on the microbiota

The importance of microbial biodiversity has emerged as a common thread for resilience and immune health, as it is the case in global ecosystems. Human and animal models of autoimmune and inflammatory diseases consistently exhibit a reduced number of bacterial species frequently termed “dysbiosis.” The rising incidence of lupus within only decades (also refer to chapter in this book) strongly suggests that genetic factors alone do not explain disease risks, and thus raise the question of which environmental factors may be at play. The hygiene hypothesis, initially posited in 1989 relating birth order to atopy, has been expanded to include other allergic diseases and further to autoimmunity. Epidemiologic data shows that high-income countries have a lower incidence of infection that parallels a higher incidence in allergic and autoimmune diseases. The lowered infection rate is due to both public health measures as well as other hygienic measures including frequent antibiotic use. Antibiotics target not only pathogens but also innocuous commensals, thereby profoundly altering the gut microbiota composition.

While antibiotics clearly influence the survival and growth of microbes colonizing a host, new evidence shows that many common pharmaceuticals also have inhibitory effects on the human gut microbiota. A comprehensive screen of over 1000 drugs against 40 representative gut bacteria found that 24% of all drugs inhibited the growth of at least one strain in vitro when used at plasma concentrations. 203 of these drugs were not classified as antibiotics and included medications commonly used for autoimmune diseases, including methotrexate, azathioprine, and cyclosporine, not to mention other commonly used drugs for hypertension, diabetes, and depression. These therapies may be concurrently treating and exacerbating autoimmune disease as they alter the gut microbial community structure.

Diet unsurprisingly has also a profound influence on the composition of the gut microbiota and likely affects autoimmunity via this mechanism. Vice versa, the nutritional value of food is partly derived from activity of the microbiota, demonstrated by the microbiota from obese or lean humans transplanted to mice similarly influencing the mouse body habitus independently of genetics. For example, the microbiota processes indigestible plant fiber into short-chain fatty acids (SCFA) that affect the host immune response. Production of SCFAs such as butyrate promote intestinal barrier integrity and regulatory T cells (Tregs) among various other biologic effects. Production of the SCFA acetate reduces intestinal inflammation and protects against pathogenic Escherichia coli infection.

There are many mechanisms by which the microbiota influences autoimmunity. Some bacterial species are pathobionts— microbes that normally have a symbiotic relationship with the host but cause disease under the right conditions. Other species appear to have no direct potential for host tissue damage but trigger cross-reactive autoantibodies that lead to immune-mediated disease. This chapter outlines the role of commensal bacteria in triggering or sustaining SLE and pSS. SLE and pSS have overlapping autoantibodies and disease manifestations and as a result may have overlapping microbial triggers as detailed later.