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.

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.

Subclinical ketosis (SCK) may impair white blood cell (WBC) function and thus contribute to the risk of disease postpartum. This preliminary study investigated changes occurring in the immune system before disease onset to elucidate their role in the occurrence of SCK. A group of 13 Holstein dairy cows were housed in tie-stalls and retrospectively divided into 2 groups based on their levels of β-hydroxybutyrate (BHB) measured in plasma between calving day and 35 d from calving (DFC). Levels of BHB 1.4 mmol/L were found in 6 cows at ≥1 of 6 time points considered (cows with SCK, KET group). From -48 to 35 DFC, body condition score, body weight, dry matter intake, rumination time, and milk yield were measured, and blood samples were collected regularly to assess the hematochemical profile and test the WBC function by ex vivo challenge assays. Data were submitted for ANOVA testing using a mixed model for repeated measurements that included health status and time and their interactions as fixed effects. Compared with CTR cows, KET cows had more pronounced activation of the immune system (higher plasma concentrations of proinflammatory cytokines, myeloperoxidase, and oxidant species, and greater IFN-γ responses to Mycobacterium avium), higher blood concentrations of γ-glutamyl transferase, and lower plasma concentrations of minerals before calving. Higher levels of nonesterified fatty acids, BHB, and glucose were detected in KET cows than in CTR cows during the dry period. The effect observed during the dry period was associated with a reduced dry matter intake, reduced plasma glucose, and increased fat mobilization (further increases in nonesterified fatty acids and BHB) during early lactation. A reduced milk yield was also detected in KET cows compared with CTR. The KET cows had an accentuated acute-phase response after calving (with greater concentrations of positive acute-phase proteins and lower concentrations of retinol than CTR cows) and impaired liver function (higher blood concentrations of glutamate-oxaloacetate transaminase and bilirubin). The WBC of the KET cows, compared with CTR cows, had a reduced response to an ex vivo stimulation assay, with lower production of proinflammatory cytokines and greater production of lactate. These alterations in the WBC could have been driven by the combined actions of metabolites related to the mobilization of lipids and the occurrence of a transient unresponsive state against stimulation aimed at preventing excessive inflammation. The associations identified here in a small number of cows in one herd should be investigated in larger studies.

A large body of work has been conducted to elucidate the link between the loss of viability, sensitivity to pro-inflammatory mediators and the impairment of antimicrobial functions affecting the innate immune cells, the occurrence of uncontrolled inflammations, and the sudden alteration of the metabolism during the transition from pregnancy to lactation in high-producing dairy cows. Despite this massive effort, a clear link is still missing. The intent of this review is to summarize our current knowledge on the subject and attempt to propose a link. In the first part of this review we provide an overview of the physiological adaptation during the transition from pregnancy to lactation focusing on the alterations affecting the innate immune system and the inflammation occurring during this phase. In the second part of the review, we propose a relationship between the function of the innate immune system, the inflammatory conditions, and the metabolism in dairy cows during the transition from pregnancy to lactation with the intent to elucidate the driving cause of immune alterations occurring in this phase. In the third and final part, we review some novel dietary strategies to optimize the function of the innate immunity in dairy cows describing their mode of action and their applicability as an aid for dairy cows during the peripartal phase.

Our study investigates metabolic changes occurring at dry-off and the contribution of milk yield (MY) in such alterations. Thirteen Holsteins were dried off at 55 days from expected calving day (assumed as 0 days from dry-off, DFD) and divided in two groups according to their average daily MY in the last week of lactation, assuming a cut-off of 15 kg·d⁻¹: low MY (7 cows) and high MY (6 cows). From −7 to 34 DFD dry matter intake (DMI) and rumination time were measured. Blood samples were collected at −7, 2, 7, 27 and 34 DFD to assess an haematological and metabolic profile and at −7, 7 and 34 DFD to test functions of circulating white blood cell (WBC) through ex vivo challenges. Data were included in a mixed model for repeated measures assuming MY at dry-off, time and their interaction as fixed effects. After dry-off, DMI was reduced and rumination time was increased in all the animals. High MY cows had greater DMI and rumination time than low MY cows. In blood, WBC counts decreased at 7 DFD and increased the production of pro-inflammatory cytokines at 7 and 34 DFD. Plasmatic concentrations of liver enzymes indicators, positive acute phase proteins (APPs); and nitrogen species increased after dry-off. Conversely, negative APPs and antioxidant species decreased. Those alterations were more marked in high MY animals. This study suggests that dry-off decreased liver function, triggered a systemic inflammation and depleted antioxidant systems, especially in the group of cows with high MY at dry-off.

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.