Glycated proteins in infant formula may cause inflammation that could disturb tolerance induction and lead to autoimmune disease

The quality of the food introduced during weaning is important, since this is when the infant develops immunology and tolerance. The general recommendations from leading organisations are to breastfeed for 6 months. After that weaning patterns vary worldwide. In Sweden, for example, it is common for infants to make the transition to infant formulas and eat gruel, which is made from milk and wheat. Weaning is a physiological pro‐inflammatory state, which triggers the growth and maturation of the intestine.1 The infant's immature intestinal mucosa tends to amplify responses to pro‐inflammatory stimuli and this, in turn, increases the risk for inflammatory pathology. This is related to an increased expression of pro‐inflammatory genes and suppressed expression of feedback regulation of these genes.2 Numerous studies in laboratory animals and humans have demonstrated accelerated epithelial cell growth of the intestine during weaning and this more than doubles the intestinal surface that interferes with the nutrients. This interaction triggers the growth of the intestine. At the same time, oral tolerance is developed by an active non‐responsiveness to ingested food products that is mediated by the lymphoid tissue of the intestine. This tissue is the largest lymphoid tissue in the body, which provides a protective immune function against any harmful bacteria while, at the same time, accepting nutrients and benign bacteria. Food allergies or inflammation occur when oral tolerance fails and the incidence of allergies is between 0, 1 and 6% in Europe.3 The incidence of intestinal inflammation is not known. Various guidelines have been issued to avoid allergic symptoms. During weaning, the infant formulas that are mostly used are based on skimmed milk powders. Experimental studies carried out by our team found that infant formulas based on skimmed milk powder, which contains high levels of glycated proteins, triggered an inflammatory condition in rats that may also be relevant for humans.4 The production of infant formulas is a complex procedure, which involves mixing and drying at high temperature. This changes the structure of the three macronutrients of fat, protein and carbohydrate in a fundamental way and allows novel interactions with unknown physiological aspects.5 Fresh milk is initially homogenised at high pressure to prevent the fat separating and to produce a stable milk liquid. During homogenisation, the milk fat globules become smaller and the total surface area of the fat content is increased. As a result, the milk proteins bind to the surface membrane of the fat globules, creating a novel protein‐lipid interaction and unfolded protein structures. The pasteurisation process then ensures the microbiological safety and evaporation of the product the shortening of the final spraying time.6 Pasteurisation changes the secondary structure of the proteins, creating unfolded proteins, while spray drying leads to intensive aggregation of proteins. This affects the tertiary structure of the proteins and creates novel protein to protein interactions. Unlike homogenisation, which causes non‐covalent bonds between the macronutrients in milk, pasteurisation and spray drying causes covalent bonds between the milk proteins, fats and carbohydrates. The reaction between lactose and the milk proteins, namely caseins or whey proteins, is called glycation. In chemical terms, a Schiff's base is formed, which is a reaction between an amino group from the protein, usually from lysine residues, and the carbonyl group of lactose. The reaction starts when the milk is heated above 60°C and ends with the formation of advanced glycation end products. The reaction is pH dependent and is more pronounced during alkaline pH. Whey proteins are more reactive than caseins. The initial rate of reaction determines the overall glycation, which is more prominent in dry mixtures than in liquids. Typical glycation reactions have continuous reactivity, with novel interactions, yielding reactive aldehydes and cross‐linking between glycated proteins. We were interested to investigate if elevated amounts of glycated milk proteins could induce an inflammatory reaction.