Abstract COVID‐19 manifests as a mild disease in most people but can progress to severe disease in nearly 20% of individuals. Disease progression is likely driven by a cytokine storm, either directly stimulated by SARS‐CoV‐2 or by increased systemic inflammation in which the gut might play an integral role. SARS‐CoV‐2 replication in the gut may cause increased intestinal permeability, alterations to the fecal microbiome, and increased inflammatory cytokines. Each effect may lead to increased systemic inflammation and the transport of cytokines and inflammatory antigens from the gut to the lung. Few interventions are being studied to treat people with mild disease and prevent the cytokine storm. Serumderived bovine immunoglobulin/protein isolate (SBI) may prevent progression by (1) binding and neutralizing inflammatory antigens, (2) decreasing gut permeability, (3) interfering with ACE2 binding by viral proteins, and (4) improving the fecal microbiome. SBI is therefore a promising intervention to prevent disease progression in COVID‐19 patients.
Effective treatment to prevent hospitalization and death in people with COVID-19 exists, but people still need interventions that alleviate symptoms without drug interactions. Oral serum-derived bovine immunoglobulins (SBI) may reduce symptoms and time-to-improvement in people with mild-to-moderate COVID-19. In this randomized, open-label, single-site study, participants with mild-to-moderate COVID-19 received SBI 5.0 g bis in die (BID) + Standard of Care (SOC) or SOC alone (2:1) for 2 weeks. After 2 weeks, 78.8% of hospitalized participants on SBI + SOC improved by World Health Organization (WHO) scale of ≥3 compared to 61.1% on SOC alone (odds ratio: OR = 2.4; p = 0.0663), with older participants (>57 years) showing more significant differences between the arms (OR = 6.1; p = 0.0109). Further, more participants on SBI + SOC reported absence of COVID-19 symptoms at Week 2 (74.2%) compared to SOC alone (43.6%; OR = 3.7; p = 0.0031), most notably the absence of dyspnea on exertion (OR = 4.4; p = 0.0047), with women exhibiting the most significant eradication of all symptoms (OR = 5.8; p = 0.0080). No difference in change of IL-6 between arms was observed. Overall, participants with mild-to-moderate COVID-19 on SBI + SOC had a shorter time-to-recovery than on SOC alone, with a significantly higher rate of complete resolution of symptoms. Dyspnea on exertion was the symptom most significantly impacted. For people with mild-to-moderate COVID-19, oral SBI could be a safe and effective intervention, devoid of drug interactions.
Background Protein supplementation in addition to resistance training has been shown to increase muscle hypertrophy and lean mass. Supplemental protein sources differ in amino acid composition, size, structure, and functionality. Animal derived proteins sources such as Beef Protein Isolate (BeefISO), Serum Albumin Concentrate (SuperSerum), Serum Protein Concentrate (SerumPro), whey protein isolate (WPI), and hydrolyzed Chicken Protein Isolate (MyoCHX) each have high-quality amino acid profiles. The mammalian target of rapamycin (mTOR) signal pathway is a nutrient sensor whose activation is associated with muscle protein synthesis. In this work, mTOR pathway activation was shown by Western blot to demonstrate bioavailability of protein preparations. Protein functionality was demonstrated by lipopolysaccharide (LPS) binding to prevent antigen induced inflammatory signaling. Systemic inflammation has been shown to negatively impact athletic performance, suggesting protein preparations which can stimulate muscle protein synthesis and reduce inflammation may be advantageous following resistance training.
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.
ABSTRACT A gene encoding a glycoside hydrolase family 44 (GH44) protein from Clostridium acetobutylicum ATCC 824 was synthesized and transformed into Escherichia coli. The previously uncharacterized protein was expressed with a C-terminal His tag and purified by nickel-nitrilotriacetic acid affinity chromatography. Crystallization and X-ray diffraction to a 2.2-Å resolution revealed a triose phosphate isomerase (TIM) barrel-like structure with additional Greek key and β-sandwich folds, similar to other GH44 crystal structures. The enzyme hydrolyzes cellotetraose and larger cellooligosaccharides, yielding an unbalanced product distribution, including some glucose. It attacks carboxymethylcellulose and xylan at approximately the same rates. Its activity on carboxymethylcellulose is much higher than that of the isolated C. acetobutylicum cellulosome. It also extensively converts lichenan to oligosaccharides of intermediate size and attacks Avicel to a limited extent. The enzyme has an optimal temperature in a 10-min assay of 55°C and an optimal pH of 5.0.
Serum-derived bovine immunoglobulins (SBI) exert health benefits mediated by their ability to bind microbial components, thereby preventing translocation and subsequent inflammation. While in vivo studies have shown that a fraction of SBI also reaches the colon, little is known about the impact of SBI on the dense colonic microbiota that has great potential to impact human health. This study, therefore, investigated the impact of three bovine plasma protein fractions (SBI, bovine plasma (BP) and albumin-enriched bovine plasma (ABP)) on the gut microbiota of six human adults using the novel ex vivo SIFR® technology, recently demonstrated to generate predictive findings for clinical studies. When dosed at an equivalent of 5 g/day, all protein fractions significantly increased health-related metabolites—acetate, propionate, and butyrate. Upon simulating small intestinal absorption, SBI still markedly increased acetate and propionate, demonstrating that SBI is more resistant to small intestinal digestion and absorption compared to the other protein sources. Despite noticeable interindividual differences in microbiota composition among human adults, SBI consistently stimulated a narrow spectrum of gut microbes, which largely differed from the ones that are typically involved in carbohydrate fermentation. The SBI-fermenting consortium included B. vulgatus and L. edouardi (correlating with acetate and propionate) along with Dorea longicatena, Coprococcus comes and the butyrate-producing bacterium SS3/4 (correlating with butyrate). Overall, this study revealed that protein bovine fractions can contribute to health benefits by specifically modulating the human gut microbiota. While health benefits could follow from the production of SCFA, a broader range of protein-derived metabolites could also be produced. This study also confirms that the concept of prebiotics (substrates selectively utilized by host microorganisms conferring a health benefit) could go beyond the use of ingestible carbohydrates and extend to partially indigestible proteins.
