Gut health is a very important determinant for health and performance in production animals. The intestinal innate immune system is central in maintaining gut health. Each feed intake leads to postprandial (low-grade) inflammation response in the (small) intestines, the magnitude of which is related to the caloric value, the glycemic index and specific feed components. If not contained, postprandial inflammation could lead to undesired consequences such as muscle catabolism, inappetite, and predisposition to infections. Because of the importance of intestinal inflammation, the body has a system to control inflammation by the so-called nervous anti-inflammatory reflex. The gut of production animals is exposed to large amounts of high energy feed which is a risk factor for overwhelming the anti-inflammatory reflex, leading to production losses. In the past, this was remedied by adding anti-inflammatory compounds to feed such as the antimicrobial growth promoters (AGP). The increasing restrictions on the use of antibiotics either as AGP or as therapeutics, has led to a great need for alternative compounds and approaches. Concerning feed composition, some compounds are pro-inflammatory, and should be removed or reduced, whereas others are anti-inflammatory, and should therefore be maintained or even increased. Another possibility is to use natural non-antibiotic anti-inflammatory additives. Compounds can be easily selected in vitro for their pro- or anti-inflammatory properties, and subsequently tested in vivo for performance characteristics. In this way, several anti-inflammatory compounds with growth promoting activity have been successfully selected. The exact mechanisms behind the anti-inflammatory activity of these various compounds is still unclear, however there are indications that it may be based on the exhaustion of the energy supply of inflammatory cells by mitochondrial uncoupling. In any case, what is very clear is that these compounds are very effective, and will help reduce antibiotic use in broilers, thus contributing to sustainable and profitable practice.