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Research scientists have also demonstrated that HDL has at least three distinct subclasses based on particle size. Different subclasses include nascent HDL, HDL2, and HDL3 with nascent HDL being the smaller and more dense followed by HDL3 and HDL2. One study found gender differences were most pronounced for large HDL, with women having a twofold higher (8 vs. 4 micromole/L) concentration of large HDL particles than men. Additionally, the observed differences in males and females large HDL particle size also decreased with age (Freedman et al., 2004). The authors of a similar study found that the antioxidative activity of large HDL was significantly higher than that of small HDL (Kontush, Chantepie, & Chapman, 2003). Numerous small studies suggest greater predictive power for each of the HDL components including the observation that large HDL particles are more cardioprotective. All subclasses of HDL have been demonstrated to have a role in reverse cholesterol transport, but HDL2 seems to have the most protective effect, with recent evidence suggesting that HDL3 may play a role in LDL oxidation that is just as vital (Yoshikawa, Sakuma, Hibino, Sato, & Fujinami, 1997). Finally HDL seems to have an antioxidant, anti-inflammatory, anti-adhesive, anti-aggregatory, and profibinolytic effect that aids in the control of CAD beyond reverse cholesterol transport mechanisms (Tulenko & Sumner, 2002).

The ATP-III recommended ranges for HDL are low (<40 mg/dL) and high (>60 mg/dL). This is a significant change as previous reports also set recommended levels for HDL, but the low designation was set at less than 35 mg/dL (NIH, 2002). Additionally, the third report has removed specific HDL levels for men and women, and made one recommendation of greater than 50 mg/dL.

Another subclass of lipoprotein is VLDL which can be divided into VLDL1 (large and less dense), VLDL2 (smaller and more dense), and VLDL3 (smallest and most dense). Hypertriglyceridemia is associated with an excess of VLDL1 while hypercholesterolemia is associated with excess VLDL2. VLDL is triglyceride rich and contains C-II, ApoE, and ApoB-100. Lipoprotein lipase reduces the size of VLDL through the release of triglyceride creating a smaller, dense and more cholesterol rich lipoprotein. About two-thirds of VLDL passes down the lipoprotein metabolism cascade terminating as LDL (Tulenka & Sumner, 2002). VLDL1 is a key component is what has been called the atherogenic lipoprotein profile, which when combined with small dense LDL, and low HDL, it is theorized to be a significant lipid risk factor for CAD (Austin et al., 1988). Most triglycerides are consumed from food, but during times of decreased caloric intake, the liver produces triglyceride endogenously (Kwiterovich, 1989). The ATP-III reports that VLDL levels should be less than 31 mg/dL.

Previous studies have identified a LDL cholesterol “disconnect” between LDL concentration and the number or size of LDL particles among patients with low levels of LDL cholesterol (Otvos, Jeyarajah, & Cromwell, 2002). The term disconnect suggests a differing risk profile depending on the type of LDL cholesterol measure that is used. Typically many individuals who are considered to have normal levels of LDL cholesterol will screen abnormal using phenotype designation. This difference, or disconnect, may help to explain why myocardial infarction can occur in some people who have normal cholesterol and/or LDL levels. Furthermore, since cholesterol is carried via lipoproteins within the blood in spherical particles, between any two individuals there can be tremendous differences in both the number, size and composition of these particles (Garvey 2003; Tulenko & Sumner, 2002). The implication of this disconnect is that CAD risk between two patients with identical LDL particle number and particle size would be the same, despite differing LDL concentration values (Garvey, 2003; Otvos et al., 2002; Tulenko & Sumner, 2002).

The ATP-III (NCEP) report establishes the following ranges for LDL cholesterol levels: optimal (<100mg/dL), near optimal/above optimal (100-129 mg/dL), borderline high (130-159 mg/dL), high (160-189 mg/dL), and very high (≥190 mg/dL) (NIH, 2002). When risk is very high (two or more additional risk factors of existing heart disease), an LDL goal of <70 mg/dL is a therapeutic option, but lifestyle changes should still be pursued. This therapeutic option extends also to patients at very high risk who have a baseline LDL <100 mg/dL (Grundy et al., 2004). The metabolic balance of lipoproteins which is both vital and dangerous also uses reverse cholesterol transport to lower cholesterol in the periphery (Trigatti, 2005). HDL is synthesized by intestinal mucosal cells and the liver. It contains a small amount of phospholipids and ApoA1 (Tulenko & Sumner, 2002). Research has consistently identified an inverse relationship between HDL levels and CAD incidence. The mechanism for this relationship is still unclear, leading some researchers to suggest that low HDL levels are simply a marker for other lipid abnormalities. While the role of decreased HDL levels in atherosclerosis is still vague, it is considered an independent risk factor for CAD (NIH, 2002). It also has been identified as the greatest predictor, along with ApoA1 as the most important risk factor in patients with existing CAD (Bolibar, von Eckardstein, Assman, &Thompson, 2000; Devroey, 2004). HDL absorbs cholesterol in peripheral cells which enter the core of the cell through the action of lecithin-cholesterol acyltransferase. Inclusion of HDL in risk assessment can greatly enhance risk stratification (Kannel & Wilson, 1992).

LDL ranges in size from the largest and least dense (LDL1), intermediate density and size (LDL2) to the smallest and most dense (LDL3). The ATP-III report states that small LDL particles are formed in large part, although not exclusively, as a response to elevation of triglycerides via the production of very-low density lipoproteins (VLDL) and specifically VLDL1 (Malloy & Kane, 2001; NIH, 2002).

The presence of small, dense LDL particles is associated with more than a three-fold increase in the risk of CAD and is independent of LDL levels (Austin, Breslow, Hennekens, Buring, Willett, & Kraus, 1988). Tulenka & Sumner (2002) further suggest that not all LDL particles are the same and that variations in disease outcomes may by attributable to differences in particle size and number even when LDL levels are the same between patients. The authors of the Physicians Health Study demonstrated that each decrease of eight angstroms in LDL peak particle size was associated with a significant 38% increase in the seven-year risk of myocardial infarction after adjustment for age and smoking status (Lemarche, Lemieux, & Depres, 1999).

The correlation between particle size and CAD may exist because of the physiological properties of smaller particles. Researchers suggests smaller and denser LDL particles are more susceptible to in vitro oxidation and have been shown to be degraded less rapidly (Hsueh & Law, 1998). In addition, smaller particles diffuse more easily into the sub-endothelial space in the periphery. A stronger diffusion gradient would push more particles into the arterial wall, attract more macrophages, and develop more foam cells.

Using gel electrophoresis, previous studies have computed and investigated both LDL peak particle size and the mean LDL particle size (Hsueh & Law, 1998). Mean LDL particle size is determined by computing the relative abundance of each of the LDL subclasses within one individual through a densitometric scan (Hsueh & Law, 1998; Lemarche et al., 1999). The results of these studies have led to the development of two different categories of LDL classification that rely on both peak particle size and LDL subclass distribution (Tulenko & Sumner, 2002). These two designations are Phenotype A and Phenotype B. Phenotype A consists of a predominance of LDL particles of >25.5 nanometers and Phenotype B is defined as the predominance of small LDL particles with diameters However, Cromwell and Otvos (2004) believe it is not clear that small LDL particles are more atherogenic than large ones simply because individuals with small LDL particles also have a higher LDL particle number. The authors further state that LDL particle number measured by nuclear magnetic resonance has consistently been shown to be a strong, independent predictor of CAD. In other words, small dense particles may have been found to be more atherogenic due to a higher number of particles that are typically associated with small dense particles. Also, the combination of the two (high particle number, and small dense particles) may place individuals at more risk than either risk factor alone.

Historically, total cholesterol concentration was used to assess an individual’s risk of CAD (Bowden & Kingery, 2004). Because cholesterol contributes to the buildup of atherosclerotic plaques, an individual’s blood cholesterol concentration could be a way to measure risk for heart disease. Clinical studies are consistent in supporting the projection that for serum cholesterol levels in the 250-300 mg/dl range, each 1% reduction in serum cholesterol level reduces CAD rates by approximately 2% (NIH, 1989a). However, the degree of stenosis and CAD varies between individuals with the same total cholesterol and other lipid levels (Bowden, Kingery, Rust, 2004, Kmietowicz, 1998; Telenko & Sumner, 2002).

Total cholesterol tends to reflect average dietary habits that affect LDL, and can reasonably provide an assessment of CVD risk between participants. Yet, the differences in risk between individuals can be strongly influenced by many additional factors. Therefore the measurement of total cholesterol alone cannot adequately reflect individual risk of CAD (NIH, 2002) and should rarely be used as the sole lipid measure in cholesterol screenings. Other studies have also demonstrated the process of heart disease to consist of many factors that are independent of total cholesterol (Katerndahl & Lawler, 1999). These other risk factors fall into two three broad categories, consisting of blood markers, behavior, and biology. New blood tests that identify increased cardiovascular risk include various subfractions of cholesterol. Many of these new markers relate to the physiological functions of cholesterol and the interaction between these markers and the cholesterol in the periphery.

The generally accepted ranges for total cholesterol levels (NIH, 2002) consist of desirable (<200mg/dL), borderline high (200-239mg/dL), and high (≥240mg/dL). If a patient’s cholesterol level is in the high category, a LDL cholesterol measure should be performed. If the patient is in the borderline high range, another total cholesterol measurement should be taken within eight weeks and the average of the two readings used to guide future decisions (NIH, 2002).

Cholesterol Subfractions
LDL cholesterol accounts for 60-75% of the total serum cholesterol and is the terminal end of in the pathway of lipoprotein metabolism called cholesterol transport. Numerous epidemio-logical, physiological, and animal models have linked high LDL levels to CAD (American Heart Association, 2004; Assman, Cullen & Schulte, 1998; NIH, 1989a; Smith et al., 2004; Stone, 2005). High levels of LDL cholesterol are able to penetrate the porous endothelium of arteries and begin to accumulate if plasma concentrations are abnormal. This natural plaque is eventually converted to unstable plaque increasing the likelihood of rupture and possible thrombosis (NIH, 2002). Accordingly, the greatest absolute diminution of risk can be achieved by the reduction of LDL which may directly lower platelet aggregation, vascular reactivity, and lower cytokine release leading to a further reduction in risk for myocardial infarction (Sullivan, 2002). In fact, when elevated LDL levels are combined with comorbidity factors of smoking and hypertension, this complex explains over 90% of myocardial infarction cases occurring in middle age (Wilhelmsen, 1997). The landmark INTERHEART data suggests that 90% of risk comes from combination of abnormal levels of apolipoproteins found in LDL and smoking. LDL contains ApoB-100 which has been linked to atherogenesis (Yusef, Hawken, Ounpuu, Dans, Avesum, Lanas et al., 2004).

Finally, it should be noted that although LDL lowering therapy is believe to offer the greatest benefit for CAD risk reduction, LDL alone is insufficient to predict CAD incidence and risk stratification. The best risk prediction strategy requires measurement of other cholesterol components and particle size and concentration (Wald, Law, Watt, Wu et al., 1994).

According to the American Heart Association [AHA] (2002), more Americans die from CAD every year than the next five leading causes of death combined. One in every 2.5 deaths in the year 2000 was from heart disease (Kohlman-Trigoboff, 2005). Though there has been a decrease in mortality rate in the US, CAD has become a leading cause of global mortality, accounting for almost 17 million deaths annually with nearly 80% of mortality and disease burden occurring in developing countries (Smith, Jackson, Pearson, Fuster, Yusuf, & Faergeman, et al., 2004).

The etiology of CAD is multi-factorial, involving numerous factors including genetics, diet, and environment with several risk factors significantly increasing an individual’s susceptibility to the disease. These risk factors include cigarette smoking, obesity, sedentary lifestyle, dietary habits, homocysteine, high blood pressure, high blood cholesterol and others. However, much of the research into CAD, which has being quite extensive and spanning a number of decades, has focused on the general relationship between plasma lipids and CAD (Gotto, 1997; Kannel, Castelli, Gordon, & McNamara, 1971; McGee, Reed, Stemmerman, Rhoads, Yano, & Feinlab, 1985; NCEP, 2002; NIH, 1989a;). Researchers have suggested that approximately twenty-five percent of the adult population ages twenty and older has blood cholesterol levels that are considered high (National Institutes of Health [NIH], 1989b). In addition, researchers have demonstrated that a total cholesterol level in the “high” category (>200 mg/dL) accompanied with high blood pressure (>130/85) increases an individual’s risk of coronary heart disease by a factor of six (NIH, 1989b). Therefore, establishing specific guidelines for cholesterol levels is both important and necessary to enhance the health of individuals.

Lipoprotein metabolism is a process that is not completely understood with fragmentary findings (Tulenka & Sumner, 2002). Attempting to have a clearer understanding of the relationship between cholesterol levels and CAD, individuals who have abnormal lipid levels can make the lifestyle changes necessary to reduce the risk of CAD and its associated complications. Similarly, adequately informed health professionals are better able to educate the public about cholesterol and heart disease and more equipped to implement effective health intervention programs.

Understanding the pathophysiology of CAD in population studies underlie the vital role of cholesterol metabolism. Protective mechanisms of the endothelium are evident in reverse cholesterol transport performed by high-density lipoprotein (HDL) and conversely low-density lipoprotein (LDL), specifically small, dense LDL, may penetrate the subendothelial space if concentrations are high in the plasma. Penetration of the endothelial space can cause acute and chronic endothelial damage, leading to CAD. Because movement into the arterial wall is likely driven by diffusion, hyper-cholesterolemia increases the infiltration of cholesterol into the endothelial space (Bowden, 2001; Wada & Karino, 1999). In response to this accumulation of cholesterol, macrophages respond to inflammatory markers from inflammatory cells, cytokines, growth factors and cellular responses (Sullivan, 2002) and absorb the cholesterol resulting in the formation of foam cells. Formations of foam cells are critical in the development of plaque in the endothelium (Ockene & Ockene, 1992). As the CAD progresses, lesions may begin to cause chronic injury to the endothelium. This process results in a positive-feedback cycle due to cytokine release that sends even more macrophages to the area, resulting in more foam cells, and eventually results in stenosis and occlusion of blood flow. Fatty streaks are first evident in this disease process followed by fibrous plaques that can develop necrotic cores which develop fissures leading to plague rupture. Hyperlipidemic concentrations also increase platelet aggregability, which attenuate the severity of the thrombotic process (Sullivan, 2002). Therefore, cholesterol metabolism plays a significant role in the development of plaque, stenosis, and eventually, myocardial infarction.

As research continues in the field of coronary artery disease, more information is revealed about various etiological factors. Emerging lipoprotein risk factors have been identified and are now starting to surface as instrumental in the cause and prevention of coronary artery disease. In order to conduct comprehensive cholesterol screening programs and counseling sessions a health professional must have a thorough understanding of lipid metabolism. Recent changes in cholesterol guidelines make it necessary to have a review that addresses the specifics of lipid management. A health professional needs an appropriate knowledge base to be able to understand a major coronary artery disease risk factor and thereby more effectively educate the public about lipid management and coronary artery disease risk reduction. Therefore, the purpose of this article is to review the role of cholesterol in both normal physiological functioning and disease causation and to examine the research concerning new emerging cholesterol risk factors.
Cholesterol Screening and the Health Professional
Recommendations by the National Cholesterol Education Program (NCEP) suggest that all Americans over the age of twenty should have their cholesterol concentrations measured (National Heart, Lung, and Blood Institute [NHLBI], 2003). An estimated 70.8% of the US population twenty years and older had participated in cholesterol screening at least once by the year 2000. This is a substantial increase from the mid-1980s when 35% had been screened at least once (Brown, Giles, Greenlund, & Croft, 2001). A number of health education programs have an emphasis on cholesterol screening followed by counseling with a health professional. Through these screenings health professionals can have a significant impact on cardiovascular disease outcomes by being involved in primary and secondary prevention, raising awareness, and successfully referring participants to physicians for further testing (Bowden, Kingery, & Brizzolara, 1999; Muratova, Islam, Demerath, Minor, & Neal 2001). In order to conduct comprehensive cholesterol screening programs and counseling sessions, health professionals must have a thorough understanding of coronary artery disease (CAD) risk factors which includes lipid metabolism (Ostwald, Weiss-Farnan, & Monson, 1990). Since the most important aspect of cholesterol screening is the action the participants take after receiving their screening results (Garber & Browner, 1997), having accurate and up-to-date information on the role of cholesterol in CAD enables health professionals to effectively develop and implement prevention programs, educate the public, and make referrals (Sullivan, 2002). Recent changes in cholesterol guidelines make it necessary to have a review that addresses the specifics of lipid management and CAD prevention. Therefore, the purpose of this paper is to review the role of cholesterol in both normal physiological functioning and disease causation and to examine the latest research concerning the new emerging cholesterol risk factors of CAD.

Immune system development in infants is closely tied to gastrointestinal maturation. The immunological factors found in breast milk are key instigators in the maturation of the gastrointestinal tract, as well as the gut-associated and systemic immune systems. Microflora such as Bifidobacterium have been identified in studies of infant fecal composition in association with maternal breast milk composition. Maternal breast milk Bifidobacterial counts dramatically impacted the infants’ fecal Bifidobacterium levels, demonstrating that breast milk is a powerful modifier of infantile gastrointestinal microflora and thus immune status. Breast milk–fed infants showed high levels of fecal calprotectin, indicating a low level of gastrointestinal inflammation. The excessive inflammation seen in NEC is less severe with a lower incidence when infants are given their mothers breast milk, in part due to the influence breast milk has on the intestinal flora. Recent research shows that the mucosal microflora acquired in early infancy determines the production of mucosal inflammation and the consequent development of mucosal disease, autoimmunity, and allergic disorders later in life. The non-absorbed milk oligosaccharides found in breast milk block attachment of microbes to the infant’s gastrointestinal mucosal membranes, thus preventing infections.Although oligosaccharides are major components of breast milk, the milk is also rich in other glycans, including glycoproteins, mucins, glycosaminoglycans, and glycolipids. Glycans protect the infant primarily by inhibiting pathogens’ binding to their host cell’s target ligands. At the same time, human milk oligosaccharides strongly attenuate inflammatory processes in the intestinal mucosa. Undigested glycans stimulate colonization by probiotic organisms through a prebiotic effect, modulating mucosal immunity and protecting against pathogens. Interactions between breast milk glycans, intestinal microflora, and intestinal mucosal surface glycans assist in the development of the innate mucosal immunity, protecting infants from infection and autoimmune inflammatory bowel diseases.

Conclusion
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There is a need for more extensive research into the development of the immune system in infants so that we have a more complete understanding of how to target and prevent immune disorders. Our current understanding points to 4 main areas in the ontogeny of the infant’s immune system as potential early intervention points for the prevention of immune disorders. First, nutritional support that aids in the prevention of immune disorders must be provided for infants. Second, the infant requires Th1 support so that he has protection from infections and the inflammatory damage they can incite. Third, immune tolerance and anti-inflammatory measures must be encouraged so inflammatory reactions and the corresponding immune disorders can be prevented. Fourth, the gastrointestinal health of the infant plays such a foundational role in immune status that it must be supported as well. The research demonstrates how breast milk targets all 4 of these areas and has the potential to be a powerful tool in the prevention of immune disorders. More research is necessary to confirm breast milk as a preventative treatment for asthma, allergies, and autoimmune disorders, but the current evidence is promising.

Breast milk provides optimal nutrition to the developing infant, and that has prompted both the American Academy of Pediatrics and the World Health Organization to increase the recommendation for exclusive breastfeeding to age 6 months. As a part of the diet, the AAP recommends breast milk for at least 1 year, while the WHO advises continuing for 2 years or more. Breast milk provides nutrition with polyunsaturated fatty acids that have also been shown to help prevent allergies. In susceptible infants, the development of allergic symptoms was modified by the intake of n-3 long-chain polyunsaturated fatty acids through breast milk. Another study demonstrated the substantial reduction in risk of childhood asthma as assessed at age 6 years, if exclusive breastfeeding is continued for at least the first 4 months of life. Breast milk protects against the infant’s susceptibility to infections as well as against future development of allergic diseases, in part due to its fatty acid content. Breast milk not only provides nutrition that helps to balance immunity in infants, it also directly impacts the development of the Th1 response.
Evidence points toward the importance of breast milk in the maturation of the infant’s immune system, helping with immature Th1 function. During the education of the immune system in infancy, maternal milk provides signals to the immune system that generate appropriate response and memory. Although infants’ Th1 response is somewhat inefficient, breast milk compensates for this relative inefficiency by providing considerable amounts of secretory IgA antibodies and lactoferrin. These secretory IgA antibodies bind the microbes at the infant’s mucosal membranes, preventing activation of the pro-inflammatory defenses while lactoferrin both destroys microbes and reduces inflammatory responses. Breast milk also contains various cytokines, including IL-1, IL-6, IL-12, TNF-alpha, IFN-gamma, and IL-8, that help defend against gastrointestinal and respiratory infections. A recent study found high levels of immune-related miRNAs that were stable under acidic environments in breast milk for the first 6 months of lactation. The dietary intake of miRNAs by infants can have a profound impact on the development of the infant’s immune system. Breast milk clearly imparts important factors for the proper maturation of the infant’s immune system.
Breast milk also provides a significant amount of Th3 tolerance factors and anti-inflammatory compounds that help regulate immune responses and inflammation. Breast milk is rich in TGF-beta, IL-10, erythropoietin, and lactoferrin, which can help reduce the excessive inflammatory response to stimuli in the infant’s intestine. In research conducted with mice, the presence of TGF-beta and an allergen conveyed protection from allergic asthma. Some studies suggest that breast milk may even protect against type 1 diabetes, multiple sclerosis, and rheumatoid arthritis.

We must first look at the immune system of an infant and the necessity of its proper development in the prevention of immune disorders. The infant’s immune system differs from that of an adult. During gestation, the immune system of the fetus is actively down-regulated to avoid immunological reactions that would end in termination of the pregnancy. This adaptation is demonstrated by high levels of Treg cells, by the down-regulation of antigen-specific T-cell proliferation, and by removal of activated T cells via FasL-induced apoptosis. The immune system remains in this state through birth and doesn’t fully develop until several years after birth.17,18 Th1 cytokines, such as interleukin-2 (IL-2), interferon-g (IFN-gamma) and Th2 cytokines, mainly interleukin-4 (IL-4), are seen at different levels in infants versus adults. Infants have more IL-2 and IL-4, with less IFN-gamma than seen in adults, giving them a predominately Th2-driven immune system.19 Infants have less Th1 memory effector function compared to adults.20 Even though infants produce ample amounts of IL-2, it does not induce the increase in IFN-gamma necessary to incite a Th1 response.21 When looking at the immunological cytokine response in infants, we see the production of Th1 cytokines tumor necrosis factoralpha (TNF-alpha), IFN-gamma, IL-12, and IL-1 are downregulated, whereas the cytokines IL-6, IL-8, IL-10, and IL-23 that are associated with inflammation and autoimmunity are up-regulated.
All of these contribute to a down-regulation of the Th1 immune response in infants. The immune response of tolerance, which modulates rampant Th1 or Th2 reactions, is vital to the immune development and health of the infant. A study that examined children with no clinical or pathological diagnosis, children with multiple food allergies, children with celiac disease, and children with inflammatory enteropathies showed that the deciding factor in the allergic group was the reduction of a Th3 response with a corresponding reduction in TGF-beta.23 The celiac and inflammatory enteropathies groups showed a dominance of the Th1 response, typical of inflammatory autoimmune diseases in which the control of the Th3 Treg cells is a necessity.
The production of IL-10, a cytokine released by Treg cells, was lower in infants of atopic mothers compared with non-atopic mothers. Oral TGF-beta has demonstrated a preventive role for allergic diseases in infants, again highlighting the importance of immune tolerance in the prevention of immune disorders. Research into the etiology of necrotizing enterocolitis (NEC) has found another difference in the immunological state of adults and infants. The immature enterocytes that line the infant’s intestine react with an excessive pro-inflammatory cytokine production after inflammatory stimulation. This reaction leaves infants vulnerable to the influence of excessive inflammation. Another difference in the infants’ mucosa is the variety of glycoproteins as compared to adults. Lining the gastrointestinal and respiratory tracts are glycoproteins, such as mucins, which cover the entire epithelial layer with protective mucus. These glycoproteins play an important role in inflammatory and antigen control in these mucosal tracts. The composition and glycosylation of the mucus layer differs significantly between infants and adults. An infant’s gastrointestinal tract not only has low levels of mucus, but it also has increased permeability and low levels of secretory immunoglobulin A.Although much is known, more studies are needed to complete our understanding of the immunological workings of infants. Research highlights the infant’s need for Th1 support to protect against infection and the damage that can ensue, a refined and effective Th3 response that can control rampant immune responses, and a healthy mucosal lining to ensure proper immune development and potentially prevent allergy, asthma, and autoimmune disorders.