Loss of Gut Barrier Integrity In Lupus

Abstract

Systemic Lupus Erythematosus is a complex autoimmune disease and its etiology remains unknown. Increased gut permeability has been reported in lupus patients, yet whether it promotes or results from lupus progression is unclear. Recent studies indicate that an impaired intestinal barrier allows the translocation of bacteria and bacterial components into systemic organs, increasing immune cell activation and autoantibody generation. Indeed, induced gut leakage in a mouse model of lupus enhanced disease characteristics, including the production of anti-dsDNA antibody, serum IL-6 as well as cell apoptosis. Gut microbiota dysbiosis has been suggested to be one of the factors that decreases gut barrier integrity by outgrowing harmful bacteria and their products, or by perturbation of gut immune homeostasis, which in turn affects gut barrier integrity. The restoration of microbial balance eliminates gut leakage in mice, further confirming the role of microbiota in maintaining gut barrier integrity. In this review, we discuss recent advances on the association between microbiota dysbiosis and leaky gut, as well as their influences on the progression of lupus. The modifications on host microbiota and gut integrity may offer insights into the development of new lupus treatment.

GWAS of depression in 4,520 individuals from the Russian population highlights the role of MAGI2 (S-SCAM) in the gut-brain axis

“…MAGUKs are synaptic scaffolding proteins, which play crucial role in spatial organization of presynaptic and postsynaptic compartments, mediate functioning of multiple G protein-coupled receptors (GPCRs), interacting with them through their PDZ domains ( Hammad et al, 2016 ). MAGI2 itself is considered as an essential gene associated with intestinal barrier function, being involved in tight junction assembly ( González-Mariscal et al, 2003 ; Ma and Morel, 2022 ). Its impairment has been associated with ulcerative colitis, Crohn’s disease, and levels of antibodies involved in IBD ( McGovern et al, 2009 ).…”

Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets

“…Growing interest in the role of the microbiome in the pathogenesis of autoimmune diseases is reflected in studies relevant to SLE, with murine lupus models supporting a contribution of microbial products to increased gut permeability and studies in patients with SLE, suggesting that microbial antigens can drive production of autoantibodies through a molecular mimicry mechanism 102–104. Translocation of a gut microbe, Enterococcus gallinarum , to liver induced autoimmunity in mice with susceptible genetic backgrounds, such as those with a TLR7 duplication, was associated with autoantibodies specific for dsDNA and Sm, and that microbe was also found in human liver biopsy tissue from patients with SLE 105 106.…”

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

“…When thinking about this problem, studying the microbiome may allow us to reconceptualize some autoimmune disorders as conventional immunity against translocating microbes or their antigens, a model that has already been proposed in the etiopathogenesis of systemic lupus erythematosus (SLE) [160,161]. This is significant as methotrexate, a drug often prescribed to patients with autoimmune disorders, can increase intestinal permeability, further facilitating microbial translocation, while at the same time, lowering host immune defenses that oppose these agents [162][163][164].…”

“…Moreover, Mycoplasma infections are associated with increased susceptibility to SLE, a condition also associated with excessive fatigue, linking this microorganism to other illnesses marked by exhaustion [224][225][226]. This could be important, because SLE has been associated with microbial translocation from various niches, possibly linking this autoimmune disease to Mycoplasma colonization [160,175]. Furthermore, lipid-associated membrane proteins (LAMPs) of Mycoplasma fermentans and Mycoplasma hominis have been shown to increase cortisol secretion, further connecting this bacterium to biological barrier dysfunction and chronic fatigue [227].…”