The transition period of dairy cattle is characterized by a number of metabolic, endocrine, physiologic, and immune adaptations, including the occurrence of negative energy balance, hypocalcemia, liver dysfunction, overt systemic inflammatory response, and oxidative stress status. The degree and length of time during which these systems remain out of balance could render cows more susceptible to disease, poor reproductive outcomes, and less efficient for milk production and quality. Studies on both monogastrics and ruminants have reported the health benefits of nutraceuticals (e.g. probiotics, prebiotics, dietary lipids, functional peptides, phytoextracts) beyond nutritional value, interacting at different levels of the animal’s physiology. From a physiological standpoint, it seems unrealistic to disregard any systemic inflammatory processes. However, an alternate approach is to modulate the inflammatory process per se and to resolve the systemic response as quickly as possible.To this aim, a growing body of literature underscores the efficacy of nutraceuticals (active compounds) during the critical phase of the transition period. Supplementation of essential fatty acids throughout a 2-month period (i.e. a month before and a month after calving) successfully attenuates the inflammatory status with a quicker resolution of phenomenon. In this context, the inflammatory and immune response scenario has been recognized to be targeted by the beneficial effect of methyl donors, such as methionine and choline, directly and indirectly modulating such response with the increase of antioxidants GSH and taurine. Indirectly by the establishment of a healthy gastrointestinal tract, yeast and yeast-based products showed to modulate the immune response, mitigating negative effects associated with parturition stress and consequent disorders.The use of phytoproducts has garnered high interest because of their wide range of actions on multiple tissue targets encompassing a series of antimicrobial, antiviral, antioxidant, immune-stimulating, rumen fermentation, and microbial modulation effects. In this review, we provide perspectives on investigations of regulating the immune responses and metabolism using several nutraceuticals in the periparturient cow.

The dry-off of dairy cows represents an important phase of the lactation cycle, influencing the outcome of the next lactation. Among the physiological changes, the severity of the inflammatory response can vary after the dry-off, and this response might have consequences on cow adaptation in the transition period. The plasma protein profile is a diagnostic tool widely used in humans and animals to assess the inflammatory status and predict the outcome of severe diseases. The albumin-to-globulin ratio (AG) can represent a simple and useful proxy for the inflammatory condition. In this study, we investigated the relationship between AG before dry-off and inflammation, metabolic profile, and performance of 75 Holstein dairy cows. Blood samples were collected from -62 (7 d before dry-off) to 28 d relative to calving (DFC) to measure metabolic profile biomarkers, inflammatory variables, and liver function. Daily milk yield in the first month of lactation was recorded. Milk composition, body condition score, fertility, and health status were also assessed. The AG calculated 1 wk before dry-off (-62 DFC) was used to retrospectively group cows into tertiles (1.06 ± 0.09 for HI, 0.88 ± 0.04 for IN, and 0.72 ± 0.08 for LO). Data were subjected to ANOVA using the PROC MIXED program in SAS software. Differences among groups observed at -62 DFC were almost maintained throughout the period of interest, but AG peaked before calving. According to the level of acute-phase proteins (haptoglobin, ceruloplasmin, albumin, cholesterol, retinol-binding protein), bilirubin, and paraoxonase, a generally overall lower inflammatory condition was found in HI and IN than in the LO group immediately after the dry-off but also after calving. The HI cows had greater milk yield than LO cows, but no differences were observed in milk composition. The somatic cell count reflected the AG ratio trend, with higher values in LO than IN and HI either before dry-off or after calving. Fertility was better in HI cows, with fewer days open and services per pregnancy than IN and LO cows. Overall, cows with high AG before dry-off showed an improved adaptation to the new lactation, as demonstrated by a reduced systemic inflammatory response and increased milk yield than cows with low AG. In conclusion, the AG ratio before dry-off might represent a rapid and useful proxy to evaluate the innate immune status and likely the ability to adapt while switching from the late lactation to the nonlactating phase and during the transition period with emphasis on early lactation.

Recent research on the transition period (TP) of dairy cows has highlighted the pivotal role of immune function in affecting the severity of metabolic challenges the animals face when approaching calving. This suggests that the immune system may play a role in the etiology of metabolic diseases occurring in early lactation. Several studies have indicated that the roots of immune dysfunctions could sink way before the “classical” TP (e.g., 3 weeks before and 3 weeks after calving), extending the time frame deemed as “risky” for the development of early lactation disorders at the period around the dry-off. Several distressing events occurring during the TP (i.e., dietary changes, heat stress) can boost the severity of pre-existing immune dysfunctions and metabolic changes that physiologically affect this phase of the lactation cycle, further increasing the likelihood of developing diseases. Based on this background, several operational and nutritional strategies could be adopted to minimize the detrimental effects of immune dysfunctions on the adaptation of dairy cows to the new lactation. A suitable environment (i.e., optimal welfare) and a balanced diet (which guarantees optimal nutrient partitioning to improve immune functions in cow and calf) are key aspects to consider when aiming to minimize TP challenges at the herd level. Furthermore, several prognostic behavioral and physiological indicators could help in identifying subjects that are more likely to undergo a “bad transition”, allowing prompt intervention through specific modulatory treatments. Recent genomic advances in understanding the linkage between metabolic disorders and the genotype of dairy cows suggest that genetic breeding programs aimed at improving dairy cows’ adaptation to the new lactation challenges (i.e., through increasing immune system efficiency or resilience against metabolic disorders) could be expected in the future. Despite these encouraging steps forward in understanding the physiological mechanisms driving metabolic responses of dairy cows during their transition to calving, it is evident that these processes still require further investigation, and that the TP—likely extended from dry-off—continues to be “the final frontier” for research in dairy sciences.

The mismatch between the nutrient intake from the diet and the output by the mammary gland causes a negative energy balance in transition dairy cows that, if excessive, can promote several metabolic disorders. Other relevant phenomena occur during transition, such as inflammation at calving and changes in immunocompetence, redox balance, and mineral metabolism. Despite previous efforts, some aspects of the adaptive mechanisms observed in the transition period still need to be clarified. For instance, alterations of physiological responses even before the dry-off or during the dry period can affect the success of the whole transition period in certain cows. In this context, the mechanism regulating the inflammatory response around calving may play a pivotal role, as suggested by the variety of factors influencing it and its consequences, particularly feed intake depression, that can amplify and anticipate the negative energy balance. When this mechanism derails is still unclear, but detecting the triggers of diverted or abnormal physiological responses and their origins (e.g., liver, rumen and gut epithelia, uterus, or mammary gland) will help to discover the weak points in the immune system and the possible ways of restoring it. Furthermore, the postpartum healthy cow appears to have an acute phase response at the liver level, despite a decrease in circulating proinflammatory cytokines. What is physiological and what is pathological in this context? To understand the latter, finding markers of an unsuccessful transition period that go beyond the energy deficit would be advisable. Future efforts should be dedicated to clarifying the causes of the acute phase response at calving, exploiting the potential of the system biology. Moreover, it would be helpful, for both basic and applied research, to define biomarkers associated with pathological responses (i.e., cytokines and acute phase proteins) and to introduce in the genetic selection phenotypes related to the ability of cows to adapt to the immunometabolic stress typical of the transition period.

Huge differences exist between cow yields and body sizes during their first and second lactations. The transition period is the most critical and investigated phase of the lactation cycle. We compared metabolic and endocrine responses between cows at different parities during the transition period and early lactation. Eight Holstein dairy cows were monitored at their first and second calving during which they were reared under the same conditions. Milk yield, dry matter intake (DMI), and body weight (BW) were regularly measured, and energy balance, efficiency, and lactation curves were calculated. Blood samples were collected on scheduled days from -21 d relative to calving (DRC) to 120 DRC for the assessment of metabolic and hormonal profiles (biomarkers of metabolism, mineral status, inflammation, and liver function). Large variations in the period in question for almost all variables investigated were observed. Compared with their first lactation, cows during their second lactation had higher DMI (+15%) and BW (+13%), their milk yield was greater (+26%), lactation peak was higher and earlier (36.6 kg/d at 48.8 DRC vs. 45.0 kg/d at 62.9 DRC), but persistency was reduced. Milk fat, protein, and lactose contents were higher during the first lactation and coagulation properties were better (higher titratable acidity, faster and firmer curd formation). Postpartum negative energy balance was more severe the during the second lactation (1.4-fold at 7 DRC) and plasma glucose was lower. Circulating insulin and insulin-like growth factor-1 were lower in second-calving cows during the transition period. At the same time, markers of body reserve mobilization (β-hydroxybutyrate and urea) increased. Moreover, albumin, cholesterol, and γ-glutamyl transferase were higher during second lactation, whereas bilirubin and alkaline phosphatase were lower. The inflammatory response after calving was not different, as suggested by the similar haptoglobin concentrations and only transient differences in ceruloplasmin. Blood growth hormone did not differ during the transition period but was lower during the second lactation at 90 DRC, whereas circulating glucagon was higher. These results agree with the differences in milk yield and confirmed the hypothesis of a different metabolic and hormonal status between the first and second lactation partly related to different degrees of maturity.

Dairy cows have to face several nutritional challenges during the transition period, and live yeast supplemen-tation appears to be beneficial in modulating rumen activity. In this study, we evaluated the effects of live yeast supplementation on rumen function, milk produc-tion, and metabolic and inflammatory conditions. Ten Holstein multiparous cows received either live Saccha-romyces cerevisiae (strain Sc47; SCY) supplementation from -21 to 21 d from calving (DFC) or a control diet without yeast supplementation. Feed intake, milk yield, and rumination time were monitored until 35 DFC, and rumen fluid, feces, milk, and blood samples were collected at different time points. Compared with the control diet, SCY had increased dry matter intake (16.7 vs. 19.1 +/- 0.8 kg/d in wk 2 and 3) and rumination time postpartum (449 vs. 504 +/- 19.9 min/d in wk 5). Milk yield tended to be greater in SCY (40.1 vs. 45.2 +/- 1.7 kg/d in wk 5), protein content tended to be higher, and somatic cell count was lower. In rumen fluid, acetate mo-lar proportion was higher and that of propionate lower at 21 DFC, resulting in increased acetate: propionate and (acetate + butyrate):propionate ratios. Cows in the SCY group had lower fecal dry matter but higher acetate and lower propionate proportions on total vola-tile fatty acids at 3 DFC. Plasma analysis revealed a lower degree of inflammation after calving in SCY (i.e., lower haptoglobin concentration at 1 and 3 DFC) and a likely better liver function, as suggested by the lower gamma-glutamyl transferase, even though paraoxonase was lower at 28 DFC. Plasma IL-1 beta concentration tended to be higher in SCY, as well as Mg and P. Overall, SCY supplementation improved rumen and hindgut fermentation profiles, also resulting in higher dry mat -ter intake and rumination time postpartum. Moreover, the postcalving inflammatory response was milder and liver function appeared to be better. Altogether, these effects also led to greater milk yield and reduced the risk of metabolic diseases.