Colostrum supply and intestinal development and maturation

Bovine colostrum provides newborn calves with high amounts of nutrient and non-nutrient biologically active substances (Blum and Baumrucker, Reference Blum and Baumrucker2008; Nissen et al., Reference Nissen, Andersen, Bendixen, Ingvartsen and Rontved2017). In addition to the great importance of colostral immunoglobulins for the passive immunity of neonatal calves (Barrington and Parish, Reference Barrington and Parish2001; Godden, Reference Godden2008), colostrum contains a large number of immunomodulatory peptides that may also affect neonatal immune response (Chase et al., Reference Chase, Hurley and Reber2008; Stelwagen et al., Reference Stelwagen, Carpenter, Haigh, Hodgkinson and Wheeler2009; Nissen et al., Reference Nissen, Andersen, Bendixen, Ingvartsen and Rontved2017). Some of these factors are provided by colostral immune cells that are involved in the establishment of local and systemic neonatal immunity (Liebler-Tenorio et al., Reference Liebler-Tenorio, Riedel-Caspari and Pohlenz2002; Stelwagen et al., Reference Stelwagen, Carpenter, Haigh, Hodgkinson and Wheeler2009; Langel et al., Reference Langel, Wark, Garst, James, McGilliard, Petersson-Wolfe and Kanevsky-Mullarky2015). In addition, potential effects of colostrum on the neonatal microbiome in the gut are likely and become more important in the research of calf nutrition (Malmuthuge and Guan, Reference Malmuthuge and Guan2017). The importance of the colostrum supply for the development and maturation of the immune system of the newborn calf is far beyond the provision of immunoglobulins. Recent studies in humans, investigating the effects of breastmilk feeding on neonatal intestinal development, illustrate the significance of colostral immune cells and the intestinal microbiome on the maturation of the neonatal immune response in the gut (Molès et al., Reference Molès, Tuaillon, Kankasa, Bedin, Nagot, Marchant, McDermid and Van de Perre2018). A comparable function of bovine colostrum in the neonatal intestine of the calf is conceivable but requires more investigations.

Bovine colostrum has an overall importance for the postnatal development of the gut (Blum, Reference Blum2006). The high concentrations of hormones, growth factors and cell-modulating factors in colostrum (Blum and Baumrucker, Reference Blum and Baumrucker2008; Nissen et al., Reference Nissen, Andersen, Bendixen, Ingvartsen and Rontved2017) stimulate villus growth of the small intestinal mucosa in calves (Blum, Reference Blum2006; Steinhoff-Wagner et al., Reference Steinhoff-Wagner, Zitnan, Schönhusen, Pfannkuche, Hudakova, Metges and Hammon2014). Colostrum feeding promotes mucosal cell growth and protein synthesis in the enterocytes of neonatal mammals (Donovan and Odle, Reference Donovan and Odle1994; Burrin et al., Reference Burrin, Davis, Ebner, Schoknecht, Fiorotto, Reeds and McAvoy1995; Xu, Reference Xu1996). The amount of overall ingested colostrum corresponds to the villus size in the intestinal mucosa, leading to a greater villus size in repeatedly colostrum-fed calves (Blum, Reference Blum2006). When feeding a colostrum extract, that is, a fraction originating from first colostrum including most of the growth-promoting peptides, together with a milk-based formula, the villus size is stimulated when compared to a milk-based formula feeding with similar protein and energy as in colostrum but no growth-stimulating peptides (Roffler et al., Reference Roffler, Fäh, Sauter, Hammon, Gallmann, Brem and Blum2003). This finding supports the general assumption that colostral peptides, such as IGF-I, or hormones, such as insulin, are involved in the growth-stimulating effect on the intestinal mucosa of neonatal calves (Blum, Reference Blum2006).

In general, the proliferation rate of intestinal crypt cells depends on feeding (Johnson Reference Johnson1988; Mathers, Reference Mathers1998). Colostrum or colostral components stimulate crypt cell proliferation in the intestinal mucosa of neonatal calves (Blum, Reference Blum2006). When comparing colostrum feeding and milk-based formula feeding (same nutrient content but no growth-promoting bioactive factors as colostrum during the first 3 days after birth), the greater stimulation of cell proliferation corresponded to the greater villus growth in colostrum than formula-fed calves on day 8 of life (Blum, Reference Blum2006). The cell turnover of the intestinal mucosa depends on cell proliferation and programmed cell death (apoptosis; mainly seen at the villus tips) (Ramachandran et al., Reference Ramachandran, Madesh and Balasubramanian2000). Colostrum intake reduces apoptosis of epithelial cells and therefore prolongs the lifespan of the epithelial cells (Blum, Reference Blum2006).

Milk-borne factors such as IGF-I are known for their stimulation of cell proliferation (Burrin et al., Reference Burrin, Wester, Davis, Amick and Heath1996; Hammon et al., Reference Hammon, Steinhoff-Wagner, Flor, Schönhusen and Metges2013; Ontsouka et al., Reference Ontsouka, Albrecht and Bruckmaier2016) as well as inhibition of cell death due to apoptosis or inflammation in the intestinal mucosa (Mylonas et al., Reference Mylonas, Matsouka, Papandoniou, Vagianos, Kalfarentzos and Alexandrides2000; Blum, Reference Blum2006). Recombinant human IGF-I, fed together with MR in neonatal calves, increases intestinal cell proliferation (Blum, Reference Blum2006). A more distinct stimulation of mucosal cell proliferation is observed when feeding a colostrum extract (see above) instead of a single growth-promoting peptide (Roffler et al., Reference Roffler, Fäh, Sauter, Hammon, Gallmann, Brem and Blum2003). This finding indicates that not a single factor but the interaction of the large amount of growth-stimulating substances in the colostrum promotes intestinal cell proliferation and growth (Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012). Receptors for IGF-I, IGF-II and insulin (IGF1R, IGF2R and InsR, respectively) are present in the intestinal mucosa throughout the total gut in neonatal calves, and their expression and/or binding capacities are modified by colostrum feeding and orally administered rhIGF-I (Blum, Reference Blum2006; Hammon et al., Reference Hammon, Steinhoff-Wagner, Flor, Schönhusen and Metges2013; Ontsouka et al., Reference Ontsouka, Albrecht and Bruckmaier2016). The density of IGF1R and InsR, but not IGF2R, in the intestinal mucosa seems to be associated with crypt cell proliferation (Georgiev et al., Reference Georgiev, Georgieva, Pfaffl, Hammon and Blum2003).

Most biologically active factors in colostrum, such as IGF-I, IGF-II and insulin, are barely absorbed and therefore likely have no systemic function (Blum, Reference Blum2006; Hammon et al., Reference Hammon, Steinhoff-Wagner, Flor, Schönhusen and Metges2013). Therefore, local effects of colostral factors on crypt cell proliferation, intestinal epithelial growth and intestinal maturation may dominate in neonatal farm animals (Donovan and Odle, Reference Donovan and Odle1994; Reference XuXu, 1996; Blum, Reference Blum2006). However, recent findings in calves indicate the absorption of colostral adiponectin in neonatal calves (Kesser et al., Reference Kesser, Hill, Heinz, Koch, Rehage, Steinhoff-Wagner, Hammon, Mielenz, Sauerwein and Sadri2015), an adipokine involved in the regulation of insulin sensitivity (Kadowaki et al., Reference Kadowaki, Yamauchi, Kubota, Hara, Ueki and Tobe2006). With respect to the lactocrine signalling theory described in pigs (Bartol et al., Reference Bartol, Wiley, Miller, Silva, Roberts, Davolt, Chen, Frankshun, Camp, Rahman, Vallet and Bagnell2013), the intestinal absorption of adiponectin may contribute to the stimulation of anabolic metabolism in neonatal calves after colostrum feeding (Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012). Colostrum feeding supports protein synthesis in the skeletal muscle of piglets (Burrin et al., Reference Burrin, Davis, Ebner, Schoknecht, Fiorotto, Reeds and McAvoy1995), and the present research suggests a similar effect in neonatal calves, indicating enhanced protein synthesis in skeletal muscle due to insulin action after colostrum feeding (Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012; Sadri et al., Reference Sadri, Steinhoff-Wagner, Hammon, Bruckmaier, Gors and Sauerwein2017). The impact of adiponectin on this finding, however, is not clear and needs further investigation.

Colostrum supply and glucose metabolism

Due to its growth-stimulating effect in the small intestine, colostrum intake promotes the absorptive capacity of the small intestine. Measurements of xylose and glucose absorption in neonatal calves clearly indicate a greater absorption after feeding with colostrum instead of formula or MR (Blum, Reference Blum2006; Steinhoff-Wagner et al., Reference Steinhoff-Wagner, Gors, Junghans, Bruckmaier, Kanitz, Metges and Hammon2011; Gruse et al., Reference Gruse, Görs, Tuchscherer, Otten, Weitzel, Metges, Wolffram and Hammon2015). Xylose absorption on day 5 of age after feeding colostrum only once was similar to that after feeding colostrum for the first 3 days after birth (Hammon et al., Reference Hammon, Steinhoff-Wagner, Flor, Schönhusen and Metges2013). Therefore, the intake of first colostrum during the first hours after birth is of great importance for glucose absorption and the postnatal glucose status in neonatal calves. In contrast, digestive enzymes and mucosal transporters with respect to carbohydrate digestion, such as lactase and SGLT1 and GLUT2, seem to be less affected by colostrum feeding. A distinct stimulation of lactase activity and the glucose transporter when feeding colostrum instead of a milk-based formula was barely observed in neonatal calves (Sauter et al., Reference Sauter, Roffler, Philipona, Morel, Rome, Guilloteau, Blum and Hammon2004; Steinhoff-Wagner et al., Reference Steinhoff-Wagner, Zitnan, Schönhusen, Pfannkuche, Hudakova, Metges and Hammon2014). For more details concerning digestive enzymes in neonatal calves, readers are referred to Guilloteau et al. (Reference Guilloteau, Zabielski and Blum2009a). Recent studies using metabolomics approaches in neonatal calves indicate that the uptake and metabolism of other nutrients (e.g. amino acids) are also influenced by colostrum feeding (Qi et al., Reference Qi, Zhao, Huang, Pan, Yang, Zhao, Hu and Cheng2018; Zhao et al., Reference Zhao, Qi, Huang, Pan, Cheng, Zhao and Yang2018).

First-pass glucose uptake in the splanchnic tissue on days 2 and 7 of life is greater in formula-fed than colostrum-fed calves, indicating a greater glucose utilisation in the splanchnic tissue (gastrointestinal tract and liver) of calves not fed with colostrum (Steinhoff-Wagner et al., Reference Steinhoff-Wagner, Gors, Junghans, Bruckmaier, Kanitz, Metges and Hammon2011; Gruse et al., Reference Gruse, Görs, Tuchscherer, Otten, Weitzel, Metges, Wolffram and Hammon2015). Possibly, nutrient absorption is generally impaired in formula-fed calves, leading to increased glucose utilisation in the splanchnic tissue, whereas colostrum-fed calves are able to use greater amounts of digested fat and protein as energy fuel in the splanchnic tissue. This hypothesis is supported by the finding that oral fat absorption is greater in colostrum- than in formula-fed or MR-fed calves, providing more fat (i.e. medium-chain fatty acids from colostrum) as energy fuel in the splanchnic tissue that partly can replace glucose utilisation (Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012). In contrast to intestinal glucose absorption, a stimulating influence of colostrum intake on endogenous glucose production, as supposed to be the case in piglets (Lepine et al., Reference Lepine, Boyd and Whitehead1991), does not occur in bovine neonates. Thus, growth-promoting substances of ingested colostrum do not affect endogenous glucose production in neonatal calves (Steinhoff-Wagner et al., Reference Steinhoff-Wagner, Gors, Junghans, Bruckmaier, Kanitz, Metges and Hammon2011). Nevertheless, the increased plasma glucose concentration and the greater hepatic glycogen content in colostrum-fed calves indicate an improved glucose status by colostrum feeding (Steinhoff-Wagner et al., Reference Steinhoff-Wagner, Gors, Junghans, Bruckmaier, Kanitz, Metges and Hammon2011; Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012 and Reference Hammon, Steinhoff-Wagner, Flor, Schönhusen and Metges2013). These findings lead to the conclusion that the improved glucose status in calves fed colostrum immediately after birth and for 3 days is a result of enhanced glucose absorption and probably of less glucose utilisation in the splanchnic tissue but is not a result of increased endogenous glucose production.

Colostrum supply and maturation in the somatotropic axis

The elevated glucose availability and the improved insulin status in colostrum-fed calves are important prerequisites for the accelerated maturation of the somatotropic axis, as indicated by several studies in neonatal calves that were previously summarised (Blum, Reference Blum2006; Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012). The stimulation of gastrointestinal hormones due to colostrum feeding may contribute to the elevated insulin secretion in the calves (Hadorn et al., Reference Hadorn, Hammon, Bruckmaier and Blum1997; Inabu et al., Reference Inabu, Pyo, Pletts, Guan, Steele and Sugino2019). The elevated insulin status due to colostrum feeding in neonatal calves is probably the trigger for stimulating endogenous IGF-I and the postnatal somatotropic axis (Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012) because glucose and insulin stimulate the hepatic gene expression of the growth hormone receptor and IGF-I as well as IGF-I secretion (Brameld et al., Reference Brameld, Gilmour and Buttery1999; Butler et al., Reference Butler, Marr, Pelton, Radcliff, Lucy and Butler2003). On the other hand and as discussed earlier, studies in neonatal calves and piglets indicate no intestinal absorption of colostral IGF-I or insulin (Donovan et al., Reference Donovan, Chao, Zijlstra and Odle1997; Blum, Reference Blum2006). Thus, the endogenously produced IGF-I determines the IGF-I status of the calf. Therefore, the nutrient supply is responsible for the maturation of the neonatal somatotropic axis, and the colostral IGF-I promotes intestinal development of the neonatal calf but does not contribute to systemic IGF-I availability (Blum, Reference Blum2006; Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012; Ontsouka et al., Reference Ontsouka, Albrecht and Bruckmaier2016).

In summary, the postnatal maturation of the neonatal intestine is enhanced due to colostrum intake, and the improved intestinal maturation results in a greater nutrient absorption and stimulation of anabolic processes that are a prerequisite for accelerated postnatal growth.

Definition of intensive milk feeding

After the colostrum period, the calf depends on the intake of liquid feed in the form of milk or high-quality MR for nutrient supply. Although it is a common feeding strategy to increase solid feed intake as soon as possible in the preweaning period by reducing milk feeding (Huber, Reference Huber1969; Gelsinger et al., Reference Gelsinger, Heinrichs and Jones2016; Kertz et al., Reference Kertz, Hill, Quigley, Heinrichs, Linn and Drackley2017), solid feed intake during the first 3 weeks of age is low, and the digestion of solid feed is impaired due to the immature forestomach in the postnatal period (Drackley, Reference Drackley2008; Khan et al., Reference Khan, Bach, Weary and von Keyserlingk2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017). Thus, sufficient milk or MR supply during the first weeks of life is a prerequisite for calf growth and development. The World Organisation for Animal Health (OIE) defines animal welfare in the Terrestrial Animal Health Code as a state where the animal is healthy, comfortable, well nourished, safe, able to express natural behaviour and not suffering from pain, fear and distress (OIE, 2017). Feeding calves limited amounts of liquid feed (i.e. 4 to 6 kg/day) during the first weeks of life results in a lack of expression in natural suckling behaviour (Schiessler et al., Reference Schiessler, Nussbaum, Hammon and Blum2002; Miller-Cushon and DeVries, Reference Miller-Cushon and DeVries2015) followed by hunger (Jensen and Holm, Reference Jensen and Holm2003; De Paula Vieira et al., Reference De Paula Vieira, Guesdon, De Passille, von Keyserlingk and Weary2008; Borderas et al., Reference Borderas, de Passille and Rushen2009; Gerbert et al., Reference Gerbert, Frieten, Koch, Dusel, Eder, Stefaniak, Bajzert, Jawor, Tuchscherer and Hammon2018) and stress for the calves. Allowing calves to drink unlimited amounts of milk or MR for several weeks during the preweaning period more than doubles liquid feed intake compared with restricted amounts of 4 to 6 kg/day of MR or milk (Hammon et al., Reference Hammon, Schiessler, Nussbaum and Blum2002; Maccari et al., Reference Maccari, Wiedemann, Kunz, Piechotta, Sanftleben and Kaske2015; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017). Therefore, an intensive milk-feeding programme contributes to the overall well-being of preweaning calves (Von Keyserlingk et al., Reference Von Keyserlingk, Rushen, de Passille and Weary2009; FAWC, 2015; OIE, 2017).

An intensive milk feeding provides milk or MR in unrestricted amounts all day long for 24 h. The calves have ad libitum access to milk (Jasper and Weary, Reference Jasper and Weary2002; Schiessler et al., Reference Schiessler, Nussbaum, Hammon and Blum2002; Maccari et al., Reference Maccari, Wiedemann, Kunz, Piechotta, Sanftleben and Kaske2015) or MR feeding (Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017; Korst et al., Reference Korst, Koch, Kesser, Müller, Romberg, Rehage, Eder and Sauerwein2017) for several weeks. Ad libitum MR feeding (125 g powder/l, 21.7% CP and 18.3 MJ metabolisable energy (ME) per kg DM) provides on average 1.6 kg DM/day, 35 MJ ME/day and 347 g protein/day to the calves during the intensive milk-feeding period. In this context, daily peaks of more than 2 kg DM intake were observed in previous studies (Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017). Such feeding schedules provide much more protein and energy than commonly used milk-feeding programmes of 4 to 6 kg milk/day. Ad libitum milk-feeding programmes are comparable to early calf rearing in beef production where calves live together with their dams and have free access to milk all day long (Egli and Blum, Reference Egli and Blum1998; Schiessler et al., Reference Schiessler, Nussbaum, Hammon and Blum2002). Main findings of an intensive milk feeding protocol compared to restricted milk feeding on calf growth, organ development, metabolic and endocrine changes, feeding behaviour and immune response have been summarised in Table 1.

Table 1 Effects of intensive milk feeding immediately after birth on growth, development, behaviour and immune response in preweaning calves¹

¹ Intensive milk feeding is defined as daily milk or milk replacer intake of 20% of BW, ad libitum milk or milk replacer feeding or feeding enhanced amounts of milk replacer with elevated CP and fat content.

² When not stated in the table, milk replacer contained 21% to 23% of CP and 17% to 20% of crude fat based on DM. Whole milk contained 320 to 350 g CP and 370 to 400 g crude fat/kg milk.

³ Data apply only for Holstein calves.

⁴ Two studies in the reference.

Stimulation of growth and endocrine growth regulation by intensive milk feeding

Ad libitum milk or MR feeding (Maccari et al., Reference Maccari, Wiedemann, Kunz, Piechotta, Sanftleben and Kaske2015; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Korst et al., Reference Korst, Koch, Kesser, Müller, Romberg, Rehage, Eder and Sauerwein2017) or enhanced milk-feeding programmes using MR with a greater protein content (up to 30% CP in DM) (Smith et al., Reference Smith, Van Amburgh, Diaz, Lucy and Bauman2002; Geiger et al., Reference Geiger, Parsons, James and Akers2016) resulted in an elevated body growth during the preweaning period when compared to restricted milk or MR feeding (4 to 6 kg milk or MR/day). In addition to stimulating muscle and fat growth (Bartlett et al., Reference Bartlett, McKeith, VandeHaar, Dahl and Drackley2006; Geiger et al., Reference Geiger, Parsons, James and Akers2016; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Koch et al., Reference Koch, Gerbert, Frieten, Dusel, Eder, Zitnan and Hammon2019), intensive milk or MR intake accelerates organ growth, for example, small intestine, mammary gland, thymus and endocrine pancreas (Prokop et al., Reference Prokop, Kaske, Maccari, Lucius, Kunz and Wiedemann2015; Geiger et al., Reference Geiger, Parsons, James and Akers2016; Soberon and Van Amburgh, Reference Soberon and Van Amburgh2017; Koch et al., Reference Koch, Gerbert, Frieten, Dusel, Eder, Zitnan and Hammon2019). As discussed later in this review, the velocity of body growth could temporarily decrease in intensive milk-fed calves during the weaning process due to the adaptation to solid feed intake. However, BW at the end of the weaning process is still greater in intensively than restrictively milk-fed calves (Maccari et al., Reference Maccari, Wiedemann, Kunz, Piechotta, Sanftleben and Kaske2015; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017).

Studies on the hepatic transcriptome and proteome in lambs and metabolome in blood plasma of calves reveal marked changes with respect to protein and energy metabolism when animals receive MR ad libitum instead of in restricted amounts (Kenéz et al., Reference Kenéz, Koch, Korst, Kesser, Eder, Sauerwein and Huber2018; Santos et al., Reference Santos, Giraldez, Frutos and Andres2019). In lambs, restricted MR feeding stimulates hepatic pathways involved in gluconeogenesis, amino acid degradation and hepatic fatty acid oxidation, which points at changes in energy utilisation to stabilise glucose homeostasis as compared to ad libitum MR-fed lambs (Santos et al., Reference Santos, Giraldez, Frutos and Andres2019). In calves, ad libitum instead of restricted MR feeding seems to increase the capacity for mitochondrial transport of fatty acids and probably affects fatty acid oxidation as well (Kenéz et al., Reference Kenéz, Koch, Korst, Kesser, Eder, Sauerwein and Huber2018). In addition, an enhanced MR-feeding programme leads to a greater metabolic activity in muscle and fat tissue as well as the ruminal epithelium (Naeem et al., Reference Naeem, Drackley, Stamey and Loor2012 and Reference Naeem, Drackley, Lanier, Everts, Rodriguez-Zas and Loor2014; Wang et al., Reference Wang, Drackley, Stamey-Lanier, Keisler and Loor2014; Leal et al., Reference Leal, Romao, Hooiveld, Soberon, Berends, Boekshoten, Van Amburgh, Martin-Tereso and Steele2018).

The improved growth development and protein accretion in calves fed intensively with milk or MR are confirmed by the stimulation of the somatotropic axis (Maccari et al., Reference Maccari, Wiedemann, Kunz, Piechotta, Sanftleben and Kaske2015; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Hoeflich, Mielenz and Hammon2018; Haisan et al., Reference Haisan, Oba, Ambrose and Steele2018). Important elements of the somatotropic axis are growth hormone (GH), IGF-I and several IGF-binding proteins (IGFBPs). The postnatal interaction of GH, IGF-I and IGFBP affects body growth and organ development in mammals (Breier et al., Reference Breier, Oliver, Gallaher and Cronjé2000), including the development of the mammary gland (Akers, Reference Akers2006) and immune function (Clark, Reference Clark1997). The stimulation of the postnatal somatotropic axis depends on the nutrient supply and reflects the glucose and insulin status of the animal (Brameld et al., Reference Brameld, Gilmour and Buttery1999; Renaville et al., Reference Renaville, Van Eenaeme, Breier, Vleurick, Bertozzi, Gengler, Hornick, Parmentier, Istasse, Haezebroeck, Massart and Portetelle2000; Smith et al., Reference Smith, Van Amburgh, Diaz, Lucy and Bauman2002). Plasma IGF-I and IGFBP-3 concentrations are elevated, and the IGFBP-2 concentration is decreased during growth in well-nourished animals as compared to animals of same age with restricted feed intake (Breier et al., Reference Breier, Oliver, Gallaher and Cronjé2000; Renaville et al., Reference Renaville, Van Eenaeme, Breier, Vleurick, Bertozzi, Gengler, Hornick, Parmentier, Istasse, Haezebroeck, Massart and Portetelle2000). A key factor in maturation of the somatotropic axis is the increased expression of the GH receptor, particularly in the liver, with age (Breier et al., Reference Breier, Oliver, Gallaher and Cronjé2000; Hammon et al., Reference Hammon, Steinhoff-Wagner, Schönhusen, Metges and Blum2012). The GH receptor mediates GH action on IGF-I synthesis and secretion and is stimulated by insulin (Breier et al., Reference Breier, Oliver, Gallaher and Cronjé2000; Butler et al., Reference Butler, Marr, Pelton, Radcliff, Lucy and Butler2003). The glucose, insulin, IGF-I and IGFBP-3 plasma concentrations are much greater, and hepatic gene expression of the GH receptor and IGF-I is higher in intensively milk-fed calves than in calves with restricted milk intake (e.g., 6 l MR/day; Maccari et al., Reference Maccari, Wiedemann, Kunz, Piechotta, Sanftleben and Kaske2015; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017 and Reference Frieten, Gerbert, Koch, Dusel, Eder, Hoeflich, Mielenz and Hammon2018). The IGFBP-2 plasma concentration and hepatic gene expression behave the other way round, as expected from the literature (Renaville et al., Reference Renaville, Van Eenaeme, Breier, Vleurick, Bertozzi, Gengler, Hornick, Parmentier, Istasse, Haezebroeck, Massart and Portetelle2000; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Hoeflich, Mielenz and Hammon2018). No signs of impaired insulin response are seen during enhanced milk feeding in calves (MacPherson et al., Reference MacPherson, Meale, Macmillan, Haisan, Bench, Oba and Steele2019).

During the first weeks of life, the elevated concentrate intake in restrictively milk-fed calves cannot compensate for impaired nutrient intake due to reduced milk feeding, and consequently, the somatotropic axis is not stimulated during early postnatal life when concentrate and forage feeding are favoured instead of milk feeding. In particular, the elevated IGFBP-2 plasma concentration in milk-restricted-fed calves indicates an impaired nutrient intake (Renaville et al., Reference Renaville, Van Eenaeme, Breier, Vleurick, Bertozzi, Gengler, Hornick, Parmentier, Istasse, Haezebroeck, Massart and Portetelle2000; Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Hoeflich, Mielenz and Hammon2018). An impaired nutrient supply with decreased IGF-I and IGFBP-3 and increased IGFBP-2 plasma concentrations also occurs during weaning when milk feeding is reduced too quickly and the solid feed intake does not meet nutrition requirements (Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Hoeflich, Mielenz and Hammon2018). These changes in the somatotropic axis are reflected by a depressed growth rate during the weaning process (Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017). To prevent a growth depression during weaning in calves with an intensified milk-feeding programme, a delayed weaning age or individual weaning based on solid feed intake is recommended (Eckert et al., Reference Eckert, Brown, Leslie, DeVries and Steele2015; de Passillé and Rushen, Reference de Passillé and Rushen2016; Welboren et al., Reference Welboren, Leal, Steele, Khan and Martin-Tereso2019). Parameters of the somatotropic axis may provide useful information on the metabolic status and may help to avoid detrimental weaning programmes in calves.

Development and maturation of the gastrointestinal tract and immune response by intensive milk feeding

An intensive milk feeding strategy affects intestinal development. The size and the absorptive capacity increase in preweaning calves with an enhanced MR-feeding programme (Geiger et al., Reference Geiger, Parsons, James and Akers2016; Koch et al., Reference Koch, Gerbert, Frieten, Dusel, Eder, Zitnan and Hammon2019). In addition, an intensive milk or MR-feeding programme seems to stimulate the expression of long non-coding RNA involved in the regulation of tight-junction protein synthesis (Weikard et al., Reference Weikard, Hadlich, Hammon, Frieten, Gerbert, Koch, Dusel and Kuehn2018). It is well established in ruminants that the diet affects tight-junction protein expression (Steele et al., Reference Steele, Penner, Chaucheyras-Durand and Guan2016). According to the upregulation of tight-junction protein-encoding genes, it is suggested that the first week of life is crucial for the development of the intestinal epithelium and the intestinal barrier of the mucosal immune system in calves (Malmuthuge and Guan, Reference Malmuthuge and Guan2017). In piglets, specific amino acids can affect intestinal permeability and integrity, protein synthesis, intestinal repair after injury and cell proliferation in the gastrointestinal tract (Jacobi and Odle, Reference Jacobi and Odle2012). Because of its composition and ingredients, milk provide the best conditions for nutrient supply in the postnatal and preweaning period to promote intestinal integrity in the bovine (Steele et al., Reference Steele, Penner, Chaucheyras-Durand and Guan2016).

There is growing evidence that an adequate nutrient supply is important for the maturation of the intestinal immune system and for successful defence against pathogens (Khan et al., Reference Khan, Weary and von Keyserlingk2011; Hammon et al., Reference Hammon, Frieten, Gerbert, Koch, Dusel, Weikard and Kühn2018). A greater nutrient supply may have beneficial effects on intestinal maturation, including the generation of a proper adaptive immune system and a stable microbiota, which may protect against diarrhoeal diseases in the neonatal and preweaning period. Common feeding schedules of not more than 6 kg of milk per day may delay the establishment of a proper immune response and microbiota in the intestine. Studies in neonatal calves have investigated the diet-dependent establishment of the intestinal microbiome, but the impact of the milk amount on the intestinal microbiome is still unclear (Malmuthuge and Guan, Reference Malmuthuge and Guan2017). A higher plane (considering the amount of MR, concentration of MR and protein and fat concentration) of nutrition seems to protect the intestine against pathogenic infections and promote overcoming of pathogenic infections. Calves with a higher plane of nutrition (intake energy: 1.3 MJ/kg metabolic BW instead of 0.5 MJ/kg metabolic BW by MR feeding) indicate a faster resolution from diarrhoea caused by infection with Cryptosporidium parvum (Ollivett et al., Reference Ollivett, Nydam, Linden, Bowman and Van Amburgh2012). Ballou et al. (Reference Ballou, Hanson, Cobb, Obeidat, Sellers, Pepper-Yowell, Carroll, Earleywine and Lawhon2015) showed that a higher plane of nutrition (610 and 735 g/day DM MR during week 1 and weeks 2 to 6, respectively, of a 28% CP and 25% fat MR instead of 409 g/day DM MR of a 20% CP and 20% fat MR) results in a higher resistance against Salmonella typhimurium in postweaning calves. Even there is first evidence that an intensive milk or MR feeding stimulates intestinal development and maturation and the intestinal immune response (Reference Hammon, Frieten, Gerbert, Koch, Dusel, Weikard and KühnHammon et al., 2018), more studies are needed to investigate the interaction between the changes of the intestinal microbiome and immune response due to an intensive milk-feeding programme.

An intensive milk feeding may delay rumen development by reducing solid feed intake during the early preweaning period (Baldwin et al., Reference Baldwin, McLeod, Klotz and Heitmann2004; Khan et al., Reference Khan, Weary and von Keyserlingk2011 and Reference Khan, Bach, Weary and von Keyserlingk2016). However, solid feed intake and rumen development accelerate during the weaning process, and rumen function is not impaired at the end of the weaning process when calves received 20% instead of 10% of BW milk per day (Khan et al., Reference Khan, Weary and von Keyserlingk2011). Rumen papilla growth and concentrations of volatile fatty acids are the same when calves are fed MR ad libitum for 5 and 8 weeks after birth, respectively, compared to 6 kg/day MR intake (Schäff et al., Reference Schäff, Gruse, Maciej, Pfuhl, Zitnan, Rajsky and Hammon2018; Koch et al., Reference Koch, Gerbert, Frieten, Dusel, Eder, Zitnan and Hammon2019). These findings are supported by the fact that ad libitum milk-fed calves immediately increase their solid feed intake and plasma β-hydroxybutyrate concentration in blood when MR intake is reduced (Schäff et al., Reference Schäff, Gruse, Maciej, Mielenz, Wirthgen, Hoeflich, Schmicke, Pfuhl, Jawor, Stefaniak and Hammon2016; Frieten et al., Reference Frieten, Gerbert, Koch, Dusel, Eder, Kanitz, Weitzel and Hammon2017; Welboren et al., Reference Welboren, Leal, Steele, Khan and Martin-Tereso2019). Plasma β-hydroxybutyrate results from ketogenesis from butyrate in the rumen epithelial cells and is an indicator for maturation of the rumen function (Baldwin et al., Reference Baldwin, McLeod, Klotz and Heitmann2004). Interestingly, the metabolic activity in ruminal epithelium is enhanced in calves fed elevated amounts of MR (Naeem et al., Reference Naeem, Drackley, Stamey and Loor2012 and Reference Naeem, Drackley, Lanier, Everts, Rodriguez-Zas and Loor2014).

In summary, an intensive milk-feeding regime is required to realise the potential for growth and development in preweaning calves. Body growth and organ maturation are improved with an intensive milk-feeding programme, and calves are less hungry and probably more resilient to infectious diseases during the preweaning period. The development of the forestomach could be delayed during the intensive milk-feeding period, but applying an adapted weaning protocol for intensive milk-fed calves avoids an impaired rumen development and body growth depression during the postweaning period.