Gut Barrier Damage and Gut Translocation of Pathogen Molecules in Lupus, an Impact of Innate Immunity (Macrophages and Neutrophils) in Autoimmune Disease

Abstract

The gut barrier is a single cell layer that separates gut micro-organisms from the host, and gut permeability defects result in the translocation of microbial molecules from the gut into the blood. Despite the silent clinical manifestation, gut translocation of microbial molecules can induce systemic inflammation that might be an endogenous exacerbating factor of systemic lupus erythematosus. In contrast, circulatory immune-complex deposition and the effect of medications on the gut, an organ with an extremely large surface area, of patients with active lupus might cause gut translocation of microbial molecules, which worsens lupus severity. Likewise, the imbalance of gut microbiota may initiate lupus and/or interfere with gut integrity which results in microbial translocation and lupus exacerbation. Moreover, immune hyper-responsiveness of innate immune cells (macrophages and neutrophils) is demonstrated in a lupus model from the loss of inhibitory Fc gamma receptor IIb (FcgRIIb), which induces prominent responses through the cross-link between activating-FcgRs and innate immune receptors. The immune hyper-responsiveness can cause cell death, especially apoptosis and neutrophil extracellular traps (NETosis), which possibly exacerbates lupus, partly through the enhanced exposure of the self-antigens. Leaky gut monitoring and treatments (such as probiotics) might be beneficial in lupus. Here, we discuss the current information on leaky gut in lupus.

Keywords: innate immunity; leaky gut; systemic lupus erythematosus.

Figure 1

The representative picture of zona occludens-1 (ZO-1, green fluorescent color), a tight junction protein, in enterocyte of the colon from 8-week-old mice of wild-type control and FcgRIIb-/- lupus mice are demonstrated (original magnification 630×) [26]. The blue color is the staining of the nucleus using DAPI (4′,6-diamidino-2-phenylindole), a blue-fluorescent DNA stain (Alexa Fluor 488, Abcam, Cambridge, MA, USA). The samples were prepared in Cryogel (Leica Biosystems, Richmond, IL, USA) and photographed by a ZEISS LSM 800 (Carl Zeiss, Germany). Notably, there is a well-defined green color border in wild type versus the unclear borders of ZO-1-stained colon in FcgRIIb-/- lupus mice at 8 weeks old (full-blown lupus).

Figure 2

The working hypothesis diagram demonstrates the possible mechanism of leaky gut-exacerbated lupus through the elevated circulating immune complexes, from (i) increased exposure to the self-antigens from overwhelming apoptosis (such as splenocytes and hepatocytes) and (ii) enhanced autoantibody production from inflammatory mediators, due to the activation by PAMPs from leaky gut.

Figure 3

The hypothesis diagram demonstrates gut permeability defects in lupus through several mechanisms (microbiome alteration, drugs, and lupus-induced inflammation) facilitate the translocation of microbial molecules that induce the death of immune cells (apoptosis, NETosis, and pyroptosis), the release of cytokines (type I IFN and IL-6), and molecular mimicry, results in extracellular DNA exposure, autoantibody production, and cross-reactive antibodies. Hence, leaky gut might enhance pathogen molecules in the blood, such as lipopolysaccharides (LPS) from Gram-negative bacteria and (1→3)-β-d-glucan (BG) from gut fungi, autoantibody production, and the circulating immune complex.