Understanding biological mechanisms underlying absorption of immunoglobulins in newborn ruminants

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In calves, pre-weaning morbidity and mortality remain high, at 24% and 6%, respectively. A strong predictive factor of morbidity and mortality risk is a failure to absorb immunoglobulins in colostrum. At birth, calves have no immunoglobulins, which are needed to fight off disease; until they produce their own immunoglobulins, the calf's entire adaptive immune response rests on the ability to absorb immunoglobulins fed in colostrum. Efficiency of immunoglobulin absorption is low, ranging from 25 - 50%, owing to the short time window for immunoglobulin absorption in neonatal calves. Classical research demonstrated immunoglobulin absorption to decrease rapidly in the first six hours of life. Both feeding of colostrum as well as a high bacterial load in colostrum further decrease immunoglobulin absorption, until cessation of immunoglobulin absorption at 24h of life. The cessation of immunoglobulin absorption is known as "gut closure" and was, until recently, thought to be relatively immutable at 24h of life. Recent research from our team indicates that the immunoglobulin absorption window can actually be manipulated by supplementing colostrum with butyrate. Despite the negative impact of butyrate on immunoglobulin absorption, the mere fact that the immunoglobulin absorption window can be nutritionally manipulated holds great potential to improve efficacy of immunoglobulin absorption. The objective of the proposed research is to improve our understanding of how immunoglobulin absorption is regulated in newborn calves. My hypothesis is that immunoglobulin absorption is predominantly FcRn-dependent and is regulated by cellular proliferation and establishment of epithelial barrier integrity. To test this hypothesis, the proposed research has several specific objectives: 1) Determine the role of epithelial maturation on immunoglobulin transport; 2) Investigate the role of FcRn-dependent and paracellular transport in immunoglobulin absorption; and 3)Investigate the impact of luminal bacterial load on immune response and tight junction formation. To test this hypothesis and meet the specific objectives, a series of experiments will be conducted that include in vivo and in vitro methods, and use a variety of analytical techniques from transport kinetics to microscopy to transcriptomics for a holistic approach to improving our understanding of immunoglobulin absorption in young calves. The proposed work will support one PhD, two MSc, and two undergraduate students. In all, the proposed research will improve our understanding of the regulation of immunoglobulin transport in young calves, thereby bolstering our understanding of the biological systems influencing absorption physiology of macromolecules.