Abstract
Intestinal barrier dysfunction is associated with chronic gastrointestinal tract inflammation and diseases such as IBD and IBS. Serum-derived bovine immunoglobulin/protein isolate (SBI) is a specially formulated protein preparation (>90%) for oral administration. The composition of SBI is greater than 60% immunoglobulin including contributions from IgG, IgA, and IgM. Immunoglobulin within the lumen of the gut has been recognized to have anti-inflammatory properties and is involved in maintaining gut homeostasis. The binding of common intestinal antigens (LPS and Lipid A) and the ligand Pam3CSK4, by IgG, IgA, and IgM in SBI was shown using a modified ELISA technique. Each of these antigens stimulated IL-8 and TNF-α cytokine production by THP-1 monocytes. Immune exclusion occurred as SBI (≤50 mg/mL) bound free antigen in a dose dependent manner that inhibited cytokine production by THP-1 monocytes in response to 10 ng/mL LPS or 200 ng/mL Lipid A. Conversely, Pam3CSK4 stimulation of THP-1 monocytes was unaffected by SBI/antigen binding. A co-culture model of the intestinal epithelium consisted of a C2BBe1 monolayer separating an apical compartment from a basal compartment containing THP-1 monocytes. The C2BBe1 monolayer was permeabilized with dimethyl palmitoyl ammonio propanesulfonate (PPS) to simulate a damaged epithelial barrier. Results indicate that Pam3CSK4 was able to translocate across the PPS-damaged C2BBe1 monolayer. However, binding of Pam3CSK4 by immunoglobulins in SBI prevented Pam3CSK4 translocation across the damaged C2BBe1 barrier. These results demonstrated steric exclusion of antigen by SBI which prevented apical to basal translocation of antigen due to changes in the physical properties of Pam3CSK4, most likely as a result of immunoglobulin binding. This study demonstrates that immunoglobulins in SBI can reduce antigen-associated inflammation through immune and steric exclusion mechanisms and furthers the mechanistic understanding of how SBI might improve immune status and reduce inflammation in various intestinal disease states.
Highlights
The intestinal epithelial barrier is critical in maintaining homeostasis of the gastrointestinal (GI) tract
It can be assumed that intestinal inflammation can be attenuated by retaining antigens in the intestinal lumen as well as limiting the ability of antigens to interact with immune cells, reducing inflammatory cytokine production which serves to limit enteropathy and support gut homeostasis
We demonstrate the role of the immunoglobulins in Serum-derived bovine immunoglobulin/protein isolate (SBI) in immune exclusion and steric exclusion of antigen-induced inflammatory cytokine production
Summary
The intestinal epithelial barrier is critical in maintaining homeostasis of the gastrointestinal (GI) tract. The persistent nature of the enteropathy associated with these conditions can be attributed to the cyclical cause and effect relationship of an altered gut microbiota, gut barrier dysfunction, and immune activation with each contributing factor cascading into the resulting in a progressive loss of gut homeostasis and chronic enteropathy Enteropathy associated with these GI diseases is most likely not attributable to a single factor, but is rather the result of the combined effects of genetic susceptibility, exposure to environmental pathogens or toxins, abnormal bile acid metabolism, diet or other physiological factors. Any combination of such factors can contribute to dysregulated immunity and aberrant cytokine production, which have been shown to compromise the structural integrity of the intestinal epithelium [4]. It can be assumed that intestinal inflammation can be attenuated by retaining antigens in the intestinal lumen as well as limiting the ability of antigens to interact with immune cells, reducing inflammatory cytokine production which serves to limit enteropathy and support gut homeostasis
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