Serum-derived bovine immunoglobulin/protein isolate.
The health and performance of the gastrointestinal tract is influenced by the interaction of a variety of factors, including diet, nutritional status, genetics, environment, stress, the intestinal microbiota, immune status, and gut barrier.
Disruptions in one or more of these factors can lead to enteropathy or intestinal disorders that are known to occur in concert with certain disease states or conditions such as irritable bowel syndrome or human immunodeficiency virus (HIV) infection.
Nutritional support in the form of a medical food along with current therapies could help manage the adverse effects of enteropathy, affecting nutrient digestion, absorption, and metabolism, as well as utilization of nutrients from foodstuffs.
Oral administration of plasma- or serum-derived protein concentrates containing high levels of immunoglobulins can improve weight management, normalize gut barrier function, and reduce the severity of enteropathy in humans.
Evidence that a serum-derived bovine immunoglobulin/protein isolate is safe and improves symptoms, nutritional status, and various biomarkers associated with enteropathy in patients with HIV infection or diarrhea-predominant irritable bowel syndrome.
Enteropathy is frequently found in association with several human disease conditions, including irritable bowel syndrome (IBS) or human immunodeficiency virus (HIV) infection, and is caused by pathological changes in the lining of the intestinal tract.
Pathological changes in the lining of the intestinal tract disrupt the homeostasis of the gastrointestinal (GI) tract and lead to symptoms of abdominal pain and discomfort, bloating, and abnormal bowel function (eg, diarrhea, urgency, constipation).
Evidence suggests the involvement of genetic predispositions, diet, stress, and exposure to external antigens, toxins, or environmental insults, including infection.
Combinations of these trigger factors lead to a continuing cycle of altered gut microbiota, immune dysregulation, gut barrier dysfunction with permeability changes, and nutrient malabsorption, which serves to further amplify and prolong this cycle of events.
Oral administration of bovine immunoglobulin (Ig)-containing protein preparations improves weight gain1 and gut barrier function and permeability and to reduce the severity of enteropathy in animals.
Serum-derived bovine protein isolate (SBI) is specially formulated to increase Ig levels and contains >90% protein, over 50% of which is IgG.
SBI is safe and improves the nutritional status and GI symptoms of chronic loose and frequent stools, abdominal discomfort, bloating, urgency in patients with enteropathy associated with diarrhea-predominant IBS (IBS-D) or HIV infection.
SBI supports digestive and absorptive properties of the intestinal tract by: binding and neutralizing microbial components, helping to maintain a beneficial gut microbiota, manages gut barrier function, and maintaining GI immune balance.
A commercial form of SBI (EnteraGam) is available as a prescription medical food that is indicated for the clinical dietary management of enteropathy under physician supervision for patients who, because of therapeutic or chronic medical needs, have limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients.
It is indicated in patients with chronic loose and frequent stools based on findings from clinical studies in patients with IBS-D or HIV-associated enteropathy.
SBI provides the following nutritive benefits: improves the uptake and utilization of nutrients; increases lean body mass through increased utilization and decreased catabolism of protein; and decreases fecal fat and energy loss.
The prolonged nature of enteropathy with altered gut microbiota, immune activation, gut barrier dysfunction, nutrient malabsorption also occur in patients with IBS-D or HIV-associated enteropathy.
Pathogenesis of IBS-D is associated with a variety of factors have been implicated, including genetic susceptibility, exposure to environmental toxins or pathogens, deficiencies in tight junction proteins, intestinal abnormalities with bile acid metabolism, changes in GI motility, visceral hypersensitivity, and psychosocial factors.
The pathogenesis of IBS have also focused on alterations of small bowel and colonic microflora, inflammation, changes in tryptophan metabolism, and dysregulation of the interaction between the central and enteric nervous system, that is the brain–gut axis.
Enteropathy associated with HIV infection is likely related to direct infection of enterocytes by HIV, opportunistic infections or other intestinal dysbiosis, or host response to highly active antiretroviral therapy (HAART).
HIV enteropathy has long been associated with inflammatory damage, decreased barrier function, increased permeability, and malabsorption of nutrients.
Altered tryptophan catabolism to kynurenine and intestinal dysbiosis has also been demonstrated in HIV patients.
Inflammation or other aberrant immune responses can lead to changes in intestinal structure and function and may play a central role in enteropathy.
The homeostasis of the GI tract, and occurrence of various intestinal disorders or enteropathies, is impacted by epigenetics, diet, stress, or exposure to external antigens or other environmental insults.
There are dozens of mutated or dysregulated genes which have been implicated in IBS, a disorder that is present in 10%–20% of the population.
These mutations can affect intestinal permeability, metabolism of tryptophan, and the synthesis and metabolism of bile acids, which may result in imbalances of neurotransmitters and alterations in motility.
Modifications in tryptophan, serotonin, and bile acid metabolism, as well as alterations in the host microbiome, have been implicated in causing or exacerbating many of the symptoms endured by patients with HIV or IBS-D.
Alterations of the microbiota and gut permeability can limit or impair digestive and absorptive function, leading to changes in fluid balance, vitamin production and absorption, and maldigestion of carbohydrates and fats.
Malabsorption of key micronutrients-vitamins and minerals, and macronutrients- protein, carbohydrate, fat, during chronic diarrhea can lead to malnutrition or chronic undernutrition and play a central role in patients with enteropathy.
Colostrum and breast milk, the sole source of nutrition for the neonate, contain immunoglobulins and other proteins which, along with early exposure to external antigens and bacteria, play a critical role in establishing the intestinal microbiota, normal immune function and integrity of the gut barrier, and may provide anti-inflammatory effects.
Breast milk is considered to contain protective nutrients.
Bovine Ig preparations have provided evidence of a similar role for immunoglobulins in being a protective nutrient by helping to restore gut homeostasis in enteropathy.
Human HIV-positive adults with enteropathy:
Significant reduction in mean bowel movements/day and improvement in stool consistency scores after 8 weeks.
Significant reduction in GI questionnaire scores.
No change in gut permeability of disaccharide absorption, increase in D-xylose absorption.
Maintained stool frequency and consistency for an additional 9 months
Human Adults with IBS-D
10 g/day showed significant decrease in number of symptom days with abdominal pain, flatulence, bloating, loose stools, urgency, or any symptom over 6 weeks.
• 5 g/day showed significant improvements in loose stools, hard stools, flatulence, and incomplete evacuation.
The impact of SBI on markers of intestinal absorption, GI symptom scores, and quality of life measures have been evaluated in two clinical studies involving patients with HIV-associated enteropathy or IBS-D.
Subjects with HIV-associated enteropathy showed improvements in GI symptoms with reduced bowel movements per day and improvements in stool consistency.
Seven of the eight subjects also showed increased uptake of D-xylose, suggesting improved absorption of nutrients.
Another randomized, double-blind, placebo-controlled study was conducted in subjects with IBS-D to investigate the impact of SBI on improving GI symptom scores and quality of life.
Study subjects consuming SBI reported a significant decrease in the number of days with GI symptoms (eg, abdominal pain, flatulence, bloating, urgency, loose stools), suggesting improved GI function with implications for nutritive benefits.
The placebo, soy protein at the same daily dose, did not significantly decrease the number of days of any GI symptoms.
These results demonstrate that SBI, a specially formulated bovine-IgG preparation, provides for a distinct nutritional requirement in enteropathy patients who have a limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, and those with fluid imbalance due to chronic loose and frequent stools.
Studies also evaluated the safety, acceptability, and digestibility of specially prepared bovine Ig preparations in children.
A total of 259 children were enrolled at 6 to 7 months of age and randomized to receive one of four study products daily for up to 8 months: whey protein concentrate (control group), bovine serum concentrate, whey protein concentrate plus multiple micronutrients, or bovine serum concentrate plus multiple micronutrients.
There were no significant differences reported in the rate of dropouts between treatment groups during the study, and the rate of early dropouts did not correlate with which study product was consumed or prevalence/incidence of morbidity.
While not significant, trends were observed for improvements in weight gain and lean body mass.
In another study, spray-dried bovine plasma proteins was evaluated in young Peruvian children (9–25 months of age) recovering from severe protein-energy malnutrition.
Fractional absorption of dietary lipid and of total energy increased significantly in relation to the amount of SBI in the diet, as shown by decreased fecal fat and energy content.
Diets containing greater amounts of plasma protein mixture led to progressive reductions in wet and dry stool weights and greater fat absorption compared to the control diet, suggestIG that the plasma protein mixtures were more digestible or enhanced recovery from malnutrition.
There was a trend toward superior nitrogen and carbohydrate absorption with increasing amounts of plasma protein.
A review of 75 preclinical studies documents the nutritive benefits of the bovine Ig-containing protein preparations in terms of improving feed intake, growth, and sometimes feed conversion.
Replacement of several high-quality protein sources -meat extracts, soy, pea and potato protein isolates, skimmed milk, whey protein, fishmeal, with Ig protein mixtures similar to the composition of SBI led to superior weight gain and feed intake in animal studies (pigs) suggesting that proteins unique to SBI were involved in stimulating beneficial digestive and metabolic effects.
Results from these clinical and nonclinical studies reveal dietary requirement for Igs for the purpose of nutritional support in maintaining homeostasis to the disrupted gut environment in enteropathy.
This nutritional requirement parallels the role of Igs in neonatal nutrition for establishing the gut environment and homeostasis.
Evidence from both preclinical and clinical studies suggests that Ig-containing protein preparations, such as that found in SBI, provide for a distinct nutritional requirement in patients with enteropathy that cannot be provided by other dietary protein sources.
Bovine serum Igs in SBI plays a key role in maintaining homeostasis in areas of the GI tract, which manages enteropathy in patients with IBS-D or HIV infection.
Igs and other plasma proteins may provide nutritive benefits by supporting normal intestinal digestion, absorption, and metabolism of ordinary foodstuffs by:
binding and neutralizing endotoxins and other microbial components;
promoting a stable microbiota
managing gut barrier function to improve the uptake and utilization of nutrients)
maintaining a homeostatic immune balance in GI mucosa.
The Ig and protein content in SBI must first survive digestion in the upper GI tract to assert its effects in the management of enteropathy.
Studies have found that as much as 50% of IgG from SBI survives transit through the stomach, while 5%–10% survives during transit through the entire intestinal tract.
In a human study of SBI tolerability and digestion, intact bovine IgG was detected in the feces of volunteers but not serum.
Evidence exists that bovine Ig is not absorbed from the intestinal lumen into the circulation.
Bovine Immunoglobulin Feeding Trial found elevated plasma levels of total amino acids and leucine were observed 1–2 hours after SBI administration, suggesting at least partial digestion of the protein mixture to the amino acid level during transit through the intestine.
Survival of the bovine IgG fraction through the GI tract indicates oral SBI remains biologically active to impart benefits in conditions such as IBS-D and HIV-associated enteropathy.
SBI is prepared from plasma obtained from hundreds of animal donors.
SBI contains Igs directed against a wide array of pathogens and foreign antigens, including binding highly conserved antigens that may allow direct binding to microbial pathogens or their toxins with possible downstream benefits.
The fragment antigen-binding (FAb) regions of IgG antibody recognizes antigenic targets and provide diversity to antibodies, while the fragment crystalizable (Fc) region interacts with Fc gamma receptors on certain immune cells to enhance phagocytic activity by macrophages, monocytes, and polymorphonuclear neutrophils.
It is hypothesized that oral Igs bind microbial antigens known as pathogen-associated molecular patterns (PAMPs), such as endotoxins or peptidoglycans, which may influence the composition or metabolism of the intestinal microbiota.
Oral Igs may interfere with the ability of such microbial compounds to enter or damage epithelial cells or immune cells, thereby supporting intestinal homeostasis.
Under normal conditions PAMP binding to pattern recognition receptors (PRRs) on cells of the innate immune system initiates downstream signaling cascades that culminate in the production of proinflammatory cytokines, inflammation, and subsequent antigen elimination.
Continual PAMP binding can lead to a persistent state of inflammation associated with numerous chronic inflammatory disorders such as IBS, inflammatory bowel disease (IBD), and HIV enteropathy.
Studies have shown that the IgG, IgA, and IgM contained in SBI bind to bacterial endotoxins and a wide array of other bacterial, viral, and fungal PAMPs.
The microbial populations that reside in the human intestinal tract contribute nutrients and energy to the host via fermentation of nondigestible dietary components and influence many aspects of health, including intestinal cell proliferation and maturation, the maintenance of the immune system, and formation of metabolites with beneficial or adverse health effects.
Some aspects of the gut microbiota may have negative consequences, serving as the source of infection, inflammation, or involvement in GI or systemic disease.
Intestinal bacteria also produce a variety of molecules or substances such as cell wall endotoxins, peptidoglycan, other toxins, which are known to affect the gut barrier and junction permeability, induce inflammation in the gut, and change nutrient absorption and fluid retention.
Diet is one of the major determinants for the persistence of a given bacterium in the GI tract.
Diet may influence the composition and activity of the human gut microbiota with implications for host GI function and health.
Igs may provide nutritive benefits of SBI by impacting the growth and maintenance of the normal intestinal microbiota.
Igs in SBI are directed against a wide array of foreign antigens and microbial organisms.
SBI is prepared from plasma obtained from thousands of bovine donors, and include Igs like IgG with activity directed against highly conserved microbial antigens that allows direct binding to microbial cell wall or other microbial components to interfere with their ability to enter or damage intestinal epithelial cells.
The effect of SBI on restoring imbalances of microbiota has also been studied in patients with HIV-associated enteropathy.
In a study evaluating SBI in patients with HIV-associated enteropathy, and results suggested that some component in SBI, perhaps the IgG fraction, may be effective in normalizing gut bacteria with potential implications for improving nutrient utilization: Clostridium and Ruminococcus decreased in seven of eight patients.
The intestinal barrier separates the antigen-rich lumen from the underlying lamina propria which contains immune and other host cells.
The intestinal barrier functionality is attributed to a monolayer of epithelial cells linked with tight junctions that form an efficient polarized barrier.
With damage to the intestinal barrier its ability to prevent antigen-induced inflammation at the site of increased permeability is compromised.
An altered immune response can lead to persistent inflammation and altered intestinal barrier function due to changes in the epithelial cells and the tight junction complexes.
Studies have demonstrated that serum proteins, similar to those contained in SBI, can positively affect intestinal barrier function and nutrient absorption by changes in barrier permeability and tight junction protein expression.
The selective permeability of the intestinal barrier is required for the prevention of luminal antigen-induced inflammation.
Antigen flux across epithelial cell monolayers is limited by incubation of antigen with bovine IgG.
Together, these studies3,13–15 demonstrate that serum proteins similar to those contained in SBI, including Igs, can manage the negative effects of antigen/toxin challenge on the intestinal epithelial barrier.
The proteins contained in SBI directly alter the permeability of the intestinal barrier, prevent antigen translocation across damaged tight junctions via direct binding and steric hindrance, and have an impact on tight junction protein expression.
There is a protective effect of SBI proteins on immune cell migration, cytokine production, and the host microbiota.
Immune activation with inflammation is as an important contributor to symptoms in IBS-D
Inflammation following GI infection is a well-recognized initiating factor in IBS.
The Intestinal inflammation can alter the gut barrier and lead to increased epithelial permeability.
Patients with IBS-D were shown to have an increased number and activation of mucosal mast cells in the lamina propria compared to control subjects without IBS-D.
Some studies showed dysregulation of tight junction proteins leading to increased intestinal permeability.
Inflammatory responses are mediated by various cytokines such as IL-1β, IL-6, and tumor necrosis factor (TNF)-α, while other cytokines, such as interferon-γ, IL-12, and IL-18 affect the production and cellular response to IL-1β and TNF-α.
Specific blockade of IL-1β and/or TNF-α results in a reduction in the severity of the inflammation.
Addition of SBI to diets has been shown to reduce the expression of proinflammatory cytokines (TNF-α, IL-6) and alter the lymphocyte response of immune challenge in animal studies.
A marker for enterocyte damage,
Intestinal fatty acid protein, a marker for enterocyte initially rose in seven of eight subjects after 8 weeks, but then fell below baseline in four of five subjects who continued taking SBI for 40 additional weeks, suggesting that inflammation-based destruction of enterocytes had been ameliorated.
Monocyte chemoattractant protein-1 levels are also negatively correlated with lamina propria CD4+ density, suggesting a systemic inflammation and mucosal immunity.
Inflammation-induced tissue remodeling matrix metalloproteinases arevdecreased over time, suggesting a decrease In inflammation and tissue-specific remodeling in the intestine.
These studies support the hypothesis that oral SBI can play a role in restoring GI immune balance.
SBI consists of >90% protein, over 50% of which is IgG.
SBI surviveS digestion in the stomach and upper intestine.
SBI is a protective nutrient, supporting digestive and absorptive properties of the intestinal tract by binding and neutralizing microbial components, which helps to maintain a beneficial gut microbiota, manage gut barrier function, and maintain immune balance.
While these effects have been observed in both nonclinical (in vitro, animal) and clinical studies,
T significance of the observations from nonclinical studies to humans is not known.
SBI has been shown in preclinical studies to improve intestinal barrier function with associated decreases in epithelial permeability.
SBI has been shown to help maintain a GI immune balance in the lamina propria.
In both preclinical and clinical studies SBI demonstrateS: 1) increases in lean body mass; 2) increased utilization and decreased catabolism of protein; and 3) decreased fecal fat and energy loss.
Most therapies that are currently used in the management of patients with enteropathy, such as dietary changes, probiotics, or use of medications to modify gut motility, are aimed at lessening symptoms rather than managing the underlying causes of the disorder.
SBI is uniquely formulated and provides a distinct nutrient with a multifaceted mode of action that involves binding and neutralization of microbial components, which helps to maintain a beneficial gut microbiota, manage gut barrier function, and maintain immune balance.
These effects collectively serve to improve and maintain nutrient utilization to aid in the management of enteropathy in IBS-D and HIV-infected patients.
In the management of enteropathy, one randomized, placebo-controlled, 6-week clinical trial, subjects who received SBI at 10 g/day had statistically significant, reductions in abdominal pain, loose stools, bloating, flatulence, urgency, and any symptom reported in the daily diary.
Subjects receiving 5 g/day of SBI in the same study had statistically significant within-group reductions in days with flatulence, incomplete evacuation, and any symptom reported in the daily diary.
Subjects who were administered an equivalent level of soy protein showed no statistically significant, within-group reductions in any symptom.
Similar results were seen in HIV-associated enteropathy, with a reduction of chronic loose and frequent stools over 8 weeks to normal consistency and frequency with sustained management out to 9 months.
SBI provides for a distinct nutritional requirement in patients who, as a result of their condition, do not adequately ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or experience excessive water loss due to chronic loose and frequent stools, in such conditions as IBS-D and HIV-associated enteropathy.