91 The consequences of leaky gut and opportunities for intervention.

Abstract In recent years, leaky gut has emerged as a common denominator for seemingly unrelated challenges experienced by farm animals. Conditions such as heat stress, infectious diseases, feed restriction, and psychological stress have all been linked to deficiencies in the gastrointestinal barrier function. However, the relative contribution of leaky gut to the negative consequences of such challenges is poorly understood. When the gastrointestinal barrier is impaired, components of the digestive content can permeate through the epithelium. The intestinal content is highly immunogenic and its translocation across the epithelium results in the activation of a local inflammatory response, which may progress to the liver via portal circulation and become systemic if left unresolved. While the implications of the infiltration of lipopolysaccharide (LPS) derived from the gastrointestinal tract into systemic circulation have received much attention, a plethora of other immunogenic molecules have also been shown to trespass the intestinal barrier during episodes of hyperpermeability. These include other bacterial components such as flagellin from motile bacteria or lipoteichoic acid from Gram-positive bacteria, and even whole bacteria. In ruminants, a well-established consequence of leaky gut are liver abscesses, a prevalent disease in feedlot cattle, where the causing pathogens (e.g., Fusobacterium necrophorum) breach the damaged rumen epithelium. Whether defects in the gastrointestinal barrier function contribute to other hepatic diseases in cattle (e.g., fatty liver in dairy cows), as described in other species, remains to be elucidated. In the last two decades, the role of the digestive tract as a source of systemic inflammation has been extensively researched. Apart from its implications on animal welfare, excessive inflammation represents a burden for animal productivity, as immune activation is a costly process from an energetic and nutrient point of view, associated with metabolic adaptations intended to support the immune response at the expense of productive purposes. Further, inflammation has been associated with an increased incidence of metabolic diseases in dairy cows. Understanding the contribution of leaky gut to systemic inflammation holds important practical implications for animal health and performance. The fact that leaky gut is a common finding among different challenges makes it an attractive target for intervention. Different nutritional strategies aimed at improving gastrointestinal health have been shown to alleviate some of the consequences of leaky-gut inducing conditions. However, determining if such benefits are specifically due to an enhanced barrier function is technically difficult. Ultimately, the consequences of a leaky gut are likely dependent on the nature of the causal insult, its magnitude and duration, as well as the occurrence of simultaneous stressors. Further insight into how the interplay among these and other factors affects the barrier function and the ultimate consequences on animal health and productivity will facilitate the development of targeted solutions.