New technological processes have allowed the development of nutritionally adequate and safe infant formulas with a protein content closer to breast milk. The benefits of further decreasing the protein/energy ratio of infant formulas to <1.8g/100kcal are probably limited. However, providing the required protein and energy intake is not the only means to prevent malnutrition or disease. In addition to its nutritional qualities, human milk provides a diversity of specific bioactive proteins such as hormones, cytokines, and growth factors which have physiological relevance beyond purely nutritional properties . These factors are implicated in growth and development, protective defense mechanisms, energy metabolism and immune homeostasis in multiple tissues. Despite the improvement in infant formula development, differences in response to infection and the development of allergy and atopic disease have been reported for FF and BF infants . Although some of these bioactive proteins are also present in bovine milk , it has generally been assumed that they do not survive the technological processing used in the manufacture of infant formulas. As such, infant formulas are considered to lack some of the protective factors which human milk inherently provides.
With the advent of new methodology, the identification of milk proteins and their biological activity has received more attention. Indeed, we have recently reported that human milk contains proteins such as transforming growth factor (TGF)-p , osteoprotegerin  and soluble CD14 , which are involved in immune homeostasis, innate responses to bacterial components and bone metabolism. TGF-p is a multifunctional polypeptide. It acts upon a variety of different cells to regulate their growth, differentiation and survival, and plays a crucial immunoregulatory function in mechanisms of tolerance and the prevention of disease and autoimmunity . TGF-p is present in milk and may be activated by acidification or mild enzymatic treatment , thus it is feasible that it is activated during intestinal transit to exert a biological effect in the intestinal epithelium of the host. Furthermore, since TGF-p is present in bovine milk, we considered that it may remain biologically active after exposure to some manufacturing processes. To address this possibility, we analyzed a range of milk-based preparations and raw materials for their TGF-p content. As expected, its presence is dependent on the milk protein source and the processing conditions . Interestingly, we showed that a casein-based formulation, with acceptable preserved levels of TGF-p, prevents diarrhea in animal models of inflammation [48, 49] and induces remission and mucosal healing in children with small bowel Crohn's disease [50, 51]. It is acknowledged that the technological process used to make the TGF-p-containing casein may also have preserved some other bioactive molecules. Nevertheless, this work on TGF-p casein, although carried out for a different application, is one illustration of how further improvement in infant formula products may be possible. It remains to better characterize the bioactive molecules in human milk and more importantly to demonstrate their biological activities and their benefits for infant growth and development.
To mediate optimal biological activity some factors will require binding to specific host receptors. In this respect, supplementation with recombinant human proteins may be advantageous. Indeed, the potential benefits of using recombinant human lactoferrin expressed in plants  or transgenic cows  is currently being investigated. However, such approaches have legal and regulatory issues, which are unlikely to be resolved in the immediate future.
In the interim, new biotechnology is preferred which enables the use of naturally occurring molecules in physiological doses and in an environment which is more likely to exert optimal biological activity.
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