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Serum-derived bovine immunoglobulin/protein isolate (SBI) may have a prebiotic mechanism of action, resulting in an increase in short-chain fatty acid production (SCFA), as published in Microorganisms. SBI is a concentrated form of immunoglobulins that has several clinical trials demonstrating benefits for IBS, IBD, and enteropathy, but its mechanisms of action may only be partially understood, and this recent study suggests that it may stimulate the growth of specific microbes that produce SCFAs, including acetate, propionate, and butyrate.
Conducted with 3 plasma protein fractions, including SBI, this study utilized ex vivo SIFR (Systemic Intestinal Fermentation Research) technology. This microbiome testing platform has previously been shown to preserve in vivo-derived microbiota (this sample had fecal samples from 6 separate donors to provide for a small degree of interpersonal differences) and to create artificial conditions that mimic small intestinal digestion and colonic fermentation. It also allows for more rapid results than a clinical trial, and while there are limitations to this methodology, it at least suggests the potential impact of SBI on the microbiome. Of the protein fractions, SBI was associated with the largest increase in SCFA production.
Specific bacterial changes with SBI included an increase in B. vulgatus and L. edouardi (associated with acetate and propionate production), as well as Coprococcus comes, Dorea longicatena, and the butyrate-producing bacterium SS3/4 (not yet named, but a major butyrate producer in the human gut). Depletion of C. comes has previously been associated with fibromyalgia-related pain as well as major depressive disorder.
Results of a small trial published in Physiological Reports suggested a number of plausible mechanisms to explain the clinical benefits observed with SBI. This included support for the GI mucosal barrier function and/or mucosal immune function, as well as binding to and neutralizing microbial components. However, this small open-label trial with SBI, which was associated with clinical improvements among patients with IBS, did not clearly identify a mechanism, as no significant changes were observed in GI permeability, bile acid synthesis, gene expression, or tryptophan metabolism. Duodenal brushings (but not stool samples) did find significant changes to the microbiome, again suggesting that alterations in the microbiota, perhaps the microbiota of the small intestine, may underlie the clinical improvements observed.
The possibility that SBI may bind to and eliminate microbial components is supported by results from a co-culture model of the intestinal barrier. This model demonstrated that SBI was able to bind to Pam3CSK4, a synthetic TLR2 (toll-like receptor 2) stimulator. Binding to this inflammatory mediator both prevented it from interacting with immune cells, and also prevented it from crossing a damaged intestinal barrier. Up to 25% of intact antibodies in SBI may be recovered in the stool, suggesting that it resists digestion, and may be able to bind and neutralize antigens throughout the digestive tract.
An experimental model of inflammatory bowel disease (IBD) also found that SBI reduced the expression of several inflammatory markers (TNF-α, IFN-γ, and inducible nitric oxide synthase), partially blocking damage to the colonic barrier. Additionally, in a randomized and double-blinded study, participants with HIV receiving antiretroviral therapy that also had chronic diarrhea received either SBI or placebo for 24 weeks. At the end of this trial, those receiving SBI had significant reductions in I-FABP and zonulin, indicative of improvements in gut barrier integrity, as well as reductions in interleukin-6 (IL-6), suggesting an anti-inflammatory mechanism. Thus, protection of the intestinal barrier remains a plausible mechanism of SBI, possibly through an anti-inflammatory mechanism.
A retrospective chart analysis of patients (12) with refractory IBD given SBI found mean reductions in nausea and diarrhea when taken over a period of at least 6 weeks, though given this was not a clinical trial, a causal effect cannot be established. Similarly, significant reductions in abdominal pain and improved stool form (but not a reduction in stool frequency) were observed among children with diarrhea-predominant IBS when receiving SBI compared to placebo over a 3-week period, as well as significant improvements in the overall Pediatric Quality of Life Inventory™ for Gastrointestinal Symptoms (PedsQOL) and the Pediatric Functional Disability Index (FDI) scores, including subscale scores for pain, discomfort when eating, diarrhea, worry about stomach aches, and communication. Although clinical benefit was observed in both trials, the mechanism of action was not established.
A comprehensive review of the effects of bovine immunoglobulins on immune function was published in Frontiers in Nutrition (not restricted to SBI). This review suggests that bovine immunoglobulins may also interact with swallowed respiratory pathogens and inhaled allergens, and includes citations for a number of studies indicating that immunoglobulins may have a role in preventing or ameliorating viral respiratory tract infections. Immunoglobulins may directly bind to pathogens, preventing their entry into the body (immune exclusion), and in the GI tract, this entails keeping the pathogen restricted to the GI lumen, preventing adhesion to the intestinal epithelium. This review also suggests that bovine immunoglobulins may modify innate as well as adaptive immunity. Hopefully, future trials will clarify the mechanisms that appear to promote gastrointestinal integrity and a healthy inflammatory response.
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