Influence of oral administration mode on the efficacy of commercial bovine Lactoferrin against iron and inflammatory homeostasis disorders Luigi Rosa . Maria Stefania Lepanto . Antimo Cutone . Rosa Anna Siciliano . Rosalba Paesano . Roberta Costi . Giovanni Musci . Piera Valenti Received: 20 March 2020 / Accepted: 27 March 2020 Ó Springer Nature B.V. 2020 Abstract Milk derivative bovine Lactoferrin (bLf), a multifunctional glycoprotein available in large quantities and recognized as safe, possesses high homology and identical functions with human Lacto- ferrin. There are numerous food supplements contain- ing bLf which, however, can vary in its purity, integrity and, consequently, functionality. Here, we report on a clinical trial where bLf (100 mg two times/day) was orally administered before (Arm A) or during meals (Arm B) to pregnant women with hereditary thrombophilia and suffering from anemia of inflammation. A significant increase of the number of red blood cells (RBCs), hemoglobin (Hb), total serum iron (TSI) and serum ferritin (sFtn) levels, along with a significant decrease of interleukin-6 were detected after 30 days in Arm A, but not in Arm B, thus letting us to hypothesize that bLf inefficacy could be related to its degradation by digestive proteases. To verify this hypothesis, bLf was incubated in gastric juice collected before or after meals. An undigested or a digested profile was observed when bLf was incubated in gastric juice sampled before or after meals, respectively. These results can explain the beneficial effect observed when bLf is administered under fasting conditions, i.e. in the absence of active proteases. Keywords Lactoferrin Á Iron homeostasis Á Inflammation Á Quality control Á Anemia of inflammation Á Hereditary thrombophilia Introduction Lactoferrin (Lf), a multifunctional iron-binding catio- nic glycoprotein, was isolated from both human (Johansson 1960; Montreuil et al. 1960) and bovine milk (Groves 1960). Human Lf (hLf) is constitutively secreted by exocrine glands and by neutrophils following induction (Paesano et al. 2012a). Several Luigi Rosa, Maria Stefania Lepanto, and Antimo Cutone have contributed equally to this work. L. Rosa (&) Á M. S. Lepanto Á P. Valenti Department of Public Health and Infectious Diseases, University of Rome, La Sapienza, 00185 Rome, Italy e-mail: luigi.rosa@uniroma1.it A. Cutone Á G. Musci Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy R. A. Siciliano Institute of Food Sciences, National Research Council, 83100 Avellino, Italy R. Paesano Microbo S.R.L., 00153 Rome, Italy R. Costi Department of Chemistry and Technology of Drug, Institute Pasteur-Fondazione Cenci Bolognetti, University of Rome, La Sapienza, 00185 Rome, Italy 123 Biometals https://doi.org/10.1007/s10534-020-00236-2