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In veal production, new-born calves are transported to specialized farms and fed a ration dominated by milk replacer (MR). High pathogen pressure, resulting from mixing of calves, leads to high antibiotic use, particularly for treatment of bovine respiratory disease (BRD). Even when successfully treated, reduced respiratory capacity hampers calves to perform up to their genetic potential. We propose to utilize mixtures of oligosaccharides that enforce the host defense to reduce BRD. Studies in mice have demonstrated the potential of oligosaccharides to reduce respiratory infections. In addition, faecal transplant techniques have been shown to stimulate a stable microbiota in early life, with effects stretching as far as the reduction of pulmonary damage in mice. In calves, the importance of these forms of pulmonary-intestinal cross-talk are poorly understood. Knowledge on the degradation kinetics of oligosaccharides crucial for steering their targeted release. In veal calves, this is very complex, as the influx of digesta in the small intestine is increasingly dominated by complex carbohydrates from solid feeds. In a series of ex vivo studies exposing lung and intestinal mucosal cells to BRD pathogens, optimal mixtures of oligosaccharides will be designed, and subsequently their dose dependent degradation kinetics will be studied in calves. The potential to reduce BRD by oligosaccharide enriched MR, depending on variation in microbial stability induced by antibiotics and faecal transplant techniques will be studied in a field setting with calves, focusing on their immunological responses.

The use of subtherapeutic doses of antibiotics in animal feed is now increasingly banned, mainly because of concerns about antibiotic resistance. This results in more diarrhea, is of the treated with therapeutic doses of antibiotics, while it can also be prevented and treated by lowering the protein content of feed. This is, however, economically disadvantageous, because it results in lower growth and gain in muscle mass. Young animals may be particularly susceptible, because their immune system, gut and renal function are still immature and relatively impaired compared to the adult situation. In human pathology, renal transplantation provides an interesting model, with immunosuppressive drugs impairing the immune system and gut health, while renal function is impaired because the single kidney that is transplanted usually does not achieve the function of two normal kidneys. These patients very often suffer from diarrhea, malnutrition and sarcopenia. We intend to disrupt thinking by using this patient group as an interesting human model for an important problem in animal nutrition. We will use the results of these observational studies as input for the design and performance of animal experimental studies and in vitro studies that have the prospect of making addition of antibiotics to animal feed and therapeutic use of antibiotics for treatment of diarrhea undesirable and even uneconomical for achievement of optimal growth

Pig health relies critically on well-functioning intestinal epithelium. Epithelial dysfunction causes disruption of the gut barrier resulting in inflammation, diarrhea, mal-absorption of nutrients, and, consequently, reduced growth. After weaning, gut barrier function is often compromised due to prolonged periods of low feed intake. In addition, delayed adaptation to the digestion of vegetable proteins leads to proteins escaping digestion in the proximal small intestine and an subsequent fermentation these can be fermented in the distal small intestine or colon. The end-products of fermentation contribute to the impaired barrier function and thus to the occurrence of post-weaning diarrhea. Intestinal epithelial cells require a vast amount of energetic substrates to power cellular processes that preserve its barrier function. Mitochondria not only generate most of the energy from these energetic substrates, they also form a platform that controls metabolic and immunological and metabolic function of the cell. We postulate that optimal functioning of mitochondria is crucial for maintaining pig gut barrier function. In the proposed research, we analyze the effects of protein fermentation end-products on intestinal epithelial mitochondrial metabolism and signaling in pigs using innovative metabolic and transcriptomic approaches. Furthermore, we will perform high-throughput functional screening of fermentation products on cellular metabolic health and validate whether nutritional compounds that activate mitochondria can protect barrier function from identified adverse protein fermentation products. Finally, we will analyze whether these mito-active compounds, when supplemented in milk before weaning, can support intestinal pig barrier function and protect weaned pigs from post-weaning diarrhea.