Do Orally Administered Immunoglobulin-Based Agents Represent the Future of IBD Therapeutics?

Inflammatory bowel disease (IBD), commonly divided into Crohn’s disease and ulcerative colitis, is a chronic, debilitating condition characterized by relapsing and remitting episodes of gastrointestinal inflammation. While the exact etiology of IBD is unknown, its pathogenesis has been attributed to numerous factors, including genetic predisposition, alterations in the gut microbiome, defects in the innate and adaptive immune system, and putative environmental exposures [1]. The majority of currently available therapies mostly alter immune responses rather than target-specific factors that may elicit an aberrant, gutspecific inflammatory cascade. Of these, the intestinal microbiome is an attractive candidate for such IBD-specific therapeutics, particularly since it is altered in patients with IBD. One such example of an IBD-specific dysbiosis is the observation that certain strains of pathogenic adherentinvasive Escherichia coli (LF82) are associated with persistent ileal inflammation in patients with Crohn’s disease [2]. Combined with the observation that animal models of colitis require gut bacterial colonization in order to induce an inflammatory phenotype, the importance of the microbiome in IBD pathogenesis is emphasized. In this issue of Digestive Diseases and Sciences, Henderson et al. assessed the effect of oral serum-derived bovine protein isolate (SBI) administration on downstream mucosal inflammation in a microbiota-defined LF82/dextran sulfate sodium (DSS) mouse model of colitis [3]. SBI is a specifically formulated protein preparation that contains [50 % bovine immunoglobulin G (IgG), its use based on the observation that the immunoglobulins in SBI reduce bacterial antigen-associated intestinal inflammation via immune and steric exclusion mechanisms [4]. In the accompanying manuscript, the investigators reported reduced mucosal and systemic inflammation in the LF82/ DSS mouse model when administered SBI compared with controls treated with the unrelated protein, hydrolyzed collagen. Based on these results, the authors conclude that SBI–immunoglobulin binding of bacterial antigens in the intestinal lumen may inhibit the downstream activation of gut-specific inflammatory cascades that have been implicated in IBD pathogenesis. The potential therapeutic effects of SBI are likely multifactorial. While early work focused on SBI’s potential value as a protective nutrient that supports the physiologic digestive and absorptive properties of the intestinal tract, recent data support its ability to bind specific bacterial antigens that promote and sustain inflammation, reduce pro-inflammatory cytokine production, and improve intestinal barrier function. SBI is used clinically to treat conditions such as irritable bowel syndrome—diarrhea predominant (IBS-D), antibiotic-associated diarrhea, small intestinal bacterial overgrowth, and human immunodeficiency virus (HIV)-associated enteropathy [5]. A mechanism similar to that proposed for SBI was reported by Greenberg et al. [6], who demonstrated the successful use of colostrum-derived bovine immunoglobulin for the treatment of diarrhea caused by Cryptosporidium parvum infection in immunosuppressed patients with acquired immunodeficiency syndrome (AIDS). & Jason M. Shapiro jshapiro@lifespan.org