30 March 2016

29 minute read

Summary

• Nutritional strategies to reducing the negative energy balance post-partum and increasing glucose supply will improve metabolic health and immune response; it should be part of the type of additive used during the transition period. Energy supply of the cow and the immune system should take an integrated approach.
• Propylene Glycol (PG) or glycerol should be a routine component of transition diets.
• Direct Feed Microbial (DFM) that stimulate rumen fermentation and improve energy supply are recommended as part of a transition diet.
• Rumen Protected Choline (RPC) is effective in avoiding fatty livers but needs to be evaluated in the presence of other methyl donors.
• Anti-oxidants notably Selenium and Vitamin E are basic components of the transition cow diet.
• Complementarities and synergies among additives are important and need to be considered.

Introduction

Over the last decade productivity and management of the dairy cow has changed dramatically.

In the US and many other countries, production has increased with an average of more than 100 kg/year over a period of 50 years (Oltenacu and Broom, 2010).

The current level of production has been paralleled by a significant increase in metabolic, locomotion (laminitis) and fertility problems. The dry period and the ensuing period around parturition have been recognised as being at the origin of many these problems.

This has resulted in an increased attention to the dairy cow at the end of the dry period and the beginning of lactation now commonly referred to as the transition period.

It is this period that has become, over the last 20 – 30 years, the focus of much research, resulting in a significant increase in our understanding of the biochemical and molecular processes associated with the transition period.

This in turn has led to important changes in the recommendations regarding management and nutrition of the periparturient cow focusing primarily on the supply and metabolism of energy.

Nevertheless, our understanding of the underlying processes remains incomplete underlining in part the multi-faceted aspect of the transition cow problem and the many interactions between e.g. energy metabolism and other physiological processes.

This is especially true for the immune system whose importance during the transition period is now well accepted. The role of the immune system and the interactions between metabolism and immunity has more recently received increased attention (e.g. Sordillo, 2014; Waldron, 2007).

The depressed immune system of the cow around calving, associated with the dramatic changes in circulating metabolites, is thought to be at the basis of the high disease incidence postpartum and the subsequent low performance.

In an effort to better regulate or attenuate the abrupt changes in nutrient supply and immune responses, there is an interest to look beyond the relatively short 6 weeks period that classically represents the transition period.

Changing to a shorter dry period, reducing post-partum energy demands and fluxes in circulating metabolites may be a first step in offering practical solutions (Santchi and Lefebre, 2014; Grummer and Rastani, 2004; Shoshani et al. 2014).

Coupled with the feeding of a ration formulated for a more favourable ratio between glucogenic and lipogenic precursors, may improve metabolism and overall health status (van Knegsel et al., 2014).

Confronted with the need for practical solutions and, as a logical consequence of the large number of studies, a number of additives have been developed (and are being developed).

Many of these additives have proven to be effective aids in avoiding metabolic problems or reducing their impact and have now become routine components of transition cow rations. This despite the fact that they often only address one particular aspect of the metabolic and/or immune challenges of the periparturient cow.

Since the value of these additives is well recognised and management of the underlying causes remains complex, “stacked solutions” (based on combinations of these additives) are offered and often included in the transition diet.

These solutions aim at combining beneficial effects on energy metabolism with stimulatory action on the liver and immune system. A better understanding of these additives and the conditions under which they need to be applied, will allow for a more judicial selection and application.

Energy supply during the transition-period; metabolism and immune status

At the end of the lactation period and much of the dry period cows are in a positive energy balance. At this stage the greatest risk in terms of energy supply is a relative excess resulting in over-conditioned cows.

While the ideal body condition score for these cows is 3.25, even at moderate levels of dietary energy dry cows tend to consume more net energy (NE) than needed (Drakley and Janovick-Guretzky, 2007). This occurs despite the use of low energy diets generally rich in roughages and fibre.

The first objective of these diets in the far-off dry cow is to control changes in body weight and BCS which generally equates to maintaining dry matter intake while limiting energy supply with the intention to correct the normal decrease in dry matter intake (DMI) of the dry cow.

DMI in the weeks before calving is known to decrease (Bertics et al. 1992) and is thought to be a major factor in the post-calving changes in blood metabolites resulting from excessive tissue (esp. fat and Ca) mobilisation. The pre-calving decline in DMI appears to be inversely correlated to BCS which predisposes over-conditioned cows to greater metabolic health problems.

Postpartum performance and well-being of the cow is improved by limiting the extent of negative energy balance.

Strictly from an energy point of view, the objective of a successful transition cow feeding program is therefore to reduce fat mobilisation and lower blood levels of non-esterified fatty acids (NEFAs) and ketone bodies, while increasing glucose and insulin. As part of this strategy feeding programs seek to maximise DM and energy intake after calving.

Imposing a restricted energy supply during the dry period (below NRC 2001 recommendations) has shown to improve post calving intakes and reduce body fat mobilisation as indicated by lower plasma NEFA levels (Douglas et al., 2006; Roche et al., 2005).

Cows allowed to over-consume energy in the dry period have a lower energy balance, higher BHBA), liver triglycerides (TG) and NEFA levels at the onset of lactation (Dann et al., 2006). However, the literature is not unanimous; other studies have shown that in general, energy density of dry diets (from 28d pre-calving to calving) only have a minor effect on post-partum metabolic status but that there are significant differences between primi- and multi-pari cows (Rabelo et al., 2005; Law et al 2011).

Lower energy intake during the dry period is often associated with lower plasma NEFAs and BHBA while insulin and glucose is not affected or only shows a small increase relative to cows fed higher energy diets (Dann et al., 2006; Douglas et al., 2006; Law et al 2011).

This however, is often associated with lower milk production contributing to the reduction in negative energy balance. Restricted-fed animals appear to have an increased capacity for hepatic gluconeogenesis, beta-oxidation and TAG accumulation in the liver (Roche et al., 2013), thus reducing the risk of metabolic problems, which underlines the importance of controlling energy intake.

Similar metabolic profiles post-partum are obtained by reducing the dry period (Rastani et al., 2005; Remond et al., 1997; Shoshani et al. 2014) suggesting that a reduction in energy supply during the dry period will have a beneficial effect on disease incidence and herd health.

It has been also been suggested (van Knegsel et al., 2014) that this can be further improved by feeding a more glucogenic diet (i.e. a diet that provides a larger proportion of glucogenic relative to lipogenic precursors, notably in the form of non-structural carbohydrates – at similar NE concentrations).

Combined with the increased capacity for hepatic gluconeogenesis this type of diet improved liver health and the metabolic profile of the periparturient cow, notably glucose levels and increase insulin production (Chen et al., 2014).

Indirectly, these results seem to be supported by the results obtained with feeding supplemental fat to increase energy supply and reduce NEFAs although the effects of specific, metabolically active fatty acids remains inconclusive (Overton and Waldron, 2004).

All cows experience some form of immune suppression around calving and it is now well accepted that the cow’s immune status at this period plays a major role in managing metabolic problems.

The period of reduced immunological capacity or immune dysfunction is not limited to isolated immune parameters but is rather broad in scope and affects various immune cell types (Waldron 2007).

The differential effect of dry matter or energy intake on immune status during the dry period is difficult to discern. However, it is well recognised that nutrition and nutritional status (along with management factors) play a pivotal role in the immune response and that specific nutrients influence various aspects of the immune response. These aspects have recently been reviewed in a number of publications.

Glucose and ketones play a critical role in the effectiveness of the immune cells which is accentuated by the changes in metabolism during the transition phase. This is especially the case for glucose – already in short supply – whose requirement has been demonstrated for phagocytic cells.

Glucose is preferred over other energy sources such as ketones or fatty acids by PMN, macrophages and lymphocytes. Consequently, it is to be expected that a reduction in circulating glucose – as is observed in periparturient cows – reduces their functionality (Ingvartsen and Moyes, 2013).

Other energy substrates used by the immune cells are, at least in part, a direct result of the cow’s metabolic status. The exact nature of the energetic demands and – how these are met – differs among immune cells and the type or level of response required.

It is reasonable to assume that in the immune challenged periparturient cow, with reduced blood glucose levels; these energy substrates play an important role. This especially in light of the fact that specific fatty acids have direct regulatory actions on immune cells (i.e. leukocytes) (Wolowczuk et al 2008) and that these immune cells appear to be selective in which fatty acids to incorporate from the NEFA or blood phospholipid fraction (Contreras et al., 2010).

On the other hand, a number of studies exist that suggest a direct inhibitory effect of NEFAs and BHBA on specific immune cell populations (Ingvartsen and Moyes, 2013; Sordillo and Mavangira, 2014). From a strict immunological point of view, maximising blood glucose supply and reducing NEFA and ketone levels should be beneficial.

Transition cow additives to enhance energy metabolism and immunity

Improving Energy and Glucose supply

The use of energy supplements as glucogenic precursors in the form of oral drenches to prevent or treat ketosis is more than half a century old.

Originally this concerned mainly PG and calcium propylene but more recently glycerol (also called glycerin) has been added to the list. Because of its effectiveness, PG and glycerol are now commonly used in transition cow diet as part of a TMR mix or as top feeding.

Due to the price differential the most widely used compound is feed grade glycerol. Results of in vitro and in vivo fermentation studies indicate that glycerol is rapidly fermented and will increase rumen propionate and butyrate (Remond, 1993). This also appears to be the case when PG is fed but PG’s effect on propionate is larger than that of glycerol.

Consequently, supplying PG or glycerol affects microbial fermentation with a significant increase of not only the glucose precursor propionate but also butyrate (Hippen et al., 2008; Linke et al., 2004).

In a number of studies supplying PG or glycerol increased postpartum blood glucose levels and lowered plasma NEFA and BHBA. This effect was more readily observed in drenched cows than in cows receiving a diet that had incorporated PG or glycerol.

The immediate effects on milk production or composition appear to be limited especially when glycerol or PG is used to replace another non-starch carbohydrate (NSC) source. Application of these products under practical conditions depends thus greatly on the risk of ketosis; clinical or subclinical.

It is of interest to note that glycerol supplementation increased butyrate production without a concomitant increase in BHBA. Feeding of butyrogenic carbohydrate sources (e.g. molasses, beet pulp and lactose) or direct butyrate supplementation to dairy cows have been tested as a possible alternative strategy to improve energy status and reduce ketonuria (Defrain et al., 2004; Herrick, 2012 ;).

However, neither the feeding of butyrogenic feeds nor direct butyrate infusion (at the rumen or abomasal level) have shown to increase blood glucose or insulin levels; rather the contrary (Krehbiel et al., 1992; Herrick, 2012).

Direct glucogenic effects of butyrate are thus highly unlikely. Indirect positive effects may be possible through a glucose sparing effect of butyrate by shifting glucose metabolism from the liver to peripheral tissues (Kristensen et al., 2005).

The possible role of butyrate in the etiology of periparturient health problems or the potential use as an additive remains inconclusive and deserves greater consideration; especially given the high blood levels of BHBA associated with dietary or rumen-generated butyrate and the importance of BHBA as an indicator of ketotic status.

Propionate supplementation in the form of Ca or other mineral salts has been suggested as a strategy to enhance supply of glucogenic precursors. However, results have been variable and often disappointing, possibly due to the relatively low levels of supplementation – especially relative to normal rumen propionate production (Overton and Waldron, 2004).

Although not a strict “additive solution”, dietary changes that modify rumen fermentation and stimulating glucose supply and gluconeogenesis should be mentioned; notably since they will affect additive use.

Most of these modifications are long term and look to stimulate production of propionate, quantitatively the most important glucogenic precursor.

Propionate, lactate, and amino acids are considered to be important substrates for glucose synthesis however, recent work by Larsen and Kristensen (2013) question the importance of amino acids as glucogenic precursors in periparturient cows.

This would leave lactate and propionate as the main glucose precursors. In order to increase their supply higher levels of concentrate should be fed raising the risk of rumen acidosis.

Rations moderately rich in non-fibre carbohydrates (NFC) limit this risk and these types of diets have been suggested as an effective means to achieve improved metabolic profiles and health as well as post-partum DMI and milk production. However, more recent analyses would suggest that since most of the trials evaluating this approach confounded NFC with energy supply the data do not support this concept in favor of rations higher in structural carbohydrates (Overton and Waldron, 2004; Roche et al., 2013). On such diets the use of glucogenic additives (above) may be less frequent but are likely to be more effective.

Dutch workers have suggested that ration formulations that reduce the lipogenic-to-glucogenic nutrient ratio would improve the negative energy balance (NEB) and decrease plasma ketone concentration in early lactation.

Such formulations would result in lower concentration of acetate and butyrate and higher propionate levels; with fat of dietary or body origin also being included as a lipogenic component (van Knegsel et al., 2007). These diet formulations – especially in short dry period situations – appear promising in improving energy balance and reducing plasma levels of NEFAs and BHBA while improving blood glucose and liver TAG levels. (Chen et al., 2014; van Knegsel et al., 2007; 2014).

Modifying Rumen Function - Direct-fed Microbials

Utilisation of additives that modify rumen function is of course not limited to the transition cow but their application seeks to meet specific objectives in support of the transition cow. The DFM most widely used in lactation diets of all ruminant spp. are fungal cultures notably various yeast varieties, primarily Saccharomyces cerevisiae and Aspergillus oryzae (AO) extracts (Amaferm).

The exact mode of action of these additives remains unknown but they have been shown to work primarily at the rumen level by enhancing microbial fermentation and thus increasing substrate utilisation.

Among ruminal bacteria, two specific functional groups are stimulated, the fibre digesting and lactate utilising bacteria. In addition, it has been demonstrated that AO extracts stimulate the growth of ruminal fungi that have been shown to play an important role in fibre digestion (Nagaraja, 2012).

These additives increase rumen function by enhancing fibre digestion and reducing the transient post-prandial drop in pH. The combined effect of these DFM will assist cows to transition from high roughage diets to higher concentrate diets.

Feeding of transition cows’ diets supplemented with DFM has shown an increase in milk production and dry matter intake (e.g. Nocek and Kautz, 2012; Baumgard et al., 2004). The increase in rumen fermentation and total VFA concentration or production should improve overall energy supply and metabolic profiles especially if propionic acid production is enhanced (Miller-Webster et al., 2002).

An increase in relative proportion of propionic acid will stimulate gluconeogenesis. Improvements in levels in blood glucose, NEFA- and BHBA have been observed (Nocek and Kautz, 2012) confirming the potential positive effect on energy balance – especially postpartum. However, the response to DFM supplementation is variable in terms of production as well as blood parameters since some studies report no or limited effects.

The absence of a response underlines the need to control the conditions under which these additives are applied, most importantly, diet composition, rumen pH and possibly overall stress (Chiquette et al., 2012; AlZahal et al., 2014).

DFM – or their cell wall components – have a well-recognised effect on the immune function in monogastric animals. Mannan oligosaccharide (MOS) have been shown to act as a ligand offering competitive binding sites for gram-negative bacteria allowing removal from the digestive system. Beta-glucans have been shown to exhibit immune-modulatory effects.

The effect of DFM on the immune status of cattle is much less studied. Recent results of feeding yeast fermentation extracts to transition cows would suggest that DFM can effectively induce the nonspecific immune system postpartum but do not seem to affect immunoglobulin concentrations (Zaworski et al., 2014).

Nocek et al., (2011) demonstrated that enzymatically hydrolysed yeast had a beneficial effect on SCC numbers in early lactation cows although the greatest effect was associated with a more advanced stage of lactation (8 – 14 weeks) rather than the period immediately post-partum.

A number of commercial products based on DFM or their products are on the market and they are indeed being used as immune-stimulants in dairy cow rations. Practical experience and proprietary reports are encouraging and would suggest that these are effective in stimulating – directly or indirectly – the immune system. Further, additional and impartial evaluation is needed.

Monensin

Modification of rumen function needs to include consideration of monensin (although its utilisation is limited to a few countries). Monensin – an ionophore – selectively inhibits gram-positive bacteria which results in a shift in rumen bacterial populations with a concomitant increase in propionate production.

The increased production of propionate should stimulate gluconeogenesis and thus glucose supply. A meta-analysis of 59 studies on Monensin confirmed the increase in glucose (3 per cent) and a concomitant decrease in NEFAs, ketone bodies (BHBA, acetoacetate) especially in the transition period thus demonstrating an improvement in the energy metabolism (Duffield et al., 2008).

A direct effect of monensin on the immune response has not been shown, consequently its effect in this area is probably mediated through its effect on circulating metabolites.

Improving Liver Function

The NEB that cows experience during the transition period is associated with the extensive mobilisation of lipids from adipose tissue, causing marked elevations in circulating blood NEFAs and subsequently TG accumulation in the liver.

In coping with the energy metabolism and the associated challenges this poses for the periparturient cow, the liver plays a key role. Liver function is impaired by TG accumulation and fatty liver is considered to be a determining factor in the reduction of normal liver function including gluconeogenesis and the metabolism of NEFAs as well as the elimination of endotoxins.

Directly or indirectly it is also considered to play a major impact in the immune response. Reducing the extent and duration of fat accumulation in the liver is thus an essential part of dealing with the challenges associated with the transition cow.

The first step in dealing with the fatty liver syndrome remains the feeding program that maximises postpartum energy supply, limits the NEB and reduces lipid mobilisation. Subsequently, additives can be used to help the liver deal with the increased supply of NEFAs resulting from the obligatory fat mobilisation through complete oxidation or the evacuation of esterified fatty acids as a constituent of VLDL.

Export of VLDL from the liver is a slow process that can be stimulated though the feeding of choline. As a constituent of VLDL, choline supplementation will stimulate the production of the latter and therefore the transport of TG from the liver (Grummer, 2011).

The use of choline in a RPC has been tested and reviewed on a number of occasions (Grummer, 2011; Overton and Waldron, 2004). Overall, RPC has been shown to be effective in improving milk production (Sales et al. 2010) and reducing the impact of some of the parameters associated with the periparturient health challenges, most importantly liver TG levels (Piepenbrink and Overton, 2003; Zom et al., 2011).

RPC has also been found to enhance specific gene expression that confirm the reduction in liver TG through improved FA processing and VLDL synthesis (Goselink et al., 2013). However, under practical conditions the effects remain variable.

Some of this variability in response may be related to the quality of the rumen protection or supply of other dietary components notably the methyl donors contributing to the generation of choline (or its use).

Unprotected choline in the stearate or chloride form has been shown to be degraded upwards of 98.0 per cent (Sharma and Erdman, 1989) and most publications assume a 100 per cent effectiveness of the fat coating which is highly unlikely.

Beside choline, ruminants have two main sources of dietary methyl donors: methionine and betaine. Studies concerning the effect of betaine are limited but methionine has been the subject of a consequential number of studies.

In most modern dairy rations methionine is the first limiting amino acid for milk – but especially milk protein – production. Under those conditions methionine should play a minor role as a critical methyl donor.

Nevertheless, considerable variations exist in rations concerning methionine supply and it is not clear as to what extent methionine has a sparing effect on choline’s function as a methyl donor or vice versa. Methionine requirements are normally based on the established official tables (NRC 2001 or any other feeding system) based primarily on milk protein production. Its function as methyl donor is only indirectly considered, if considered at all.

Methionine deficiencies however, may interfere with the process required to produce choline from phosphatidylethanolamine or other reactions such as DNA methylation and histone modifcations (thus affecting transcription of genetic information), an effect that may become more acute when choline is limiting.

The work by Ardalan et al. (2009) demonstrated a degree of additivity when rumen protected methionine was supplemented to a control diet or a diet containing 15 g of protected choline. Reproductive performance, health status and milk production of dairy cows was improved by a combined supply relative to a single components or a negative control.

Also the meta-analyses of Sales et al., (2010) concluded that on the basis of the estimated values for the metabolisable methionine, supplementary RPC functions primarily as a methyl donor to spare methionine for milk protein synthesis thus explaining the primary positive effect of RPC on milk protein.

The work by Osorio et al., (2014b) seems to confirm this as they demonstrated that methionine supplementation increased gene activation for the enzymes associated with methyl generation in periparturient cows. However, it is difficult to conclude on the exact relative role and effectiveness of the three methyl donors as the work by Davidson et al. (2008) demonstrated.

These workers found no effect of rumen protected methionine or betaine on milk production or composition in early lactation cows fed a methionine deficient ration while RPC was effective in increasing milk production and milk fat or protein in multi-parous cows.

Improving anti-oxidant status

It is now well accepted that the relatively large number and frequency of metabolic disorders associated with the transition period reflect in part a low antioxidant status resulting from the significant and fairly sudden increase in nutrient demands.

Indeed, the final stages of pregnancy and onset of lactation result in an increased production and accumulation of reactive oxygen species (ROS) and consequently higher requirements for antioxidant (Spears and Weiss, 2008).

The general relationship between oxidative stress and metabolic disorders during the periparturient period has been demonstrated by a lowered antioxidant status during metritis, retained placenta, acidosis, ketosis, milk fever and mastitis, (Celi, 2011).

Also, it has been suggested that the impaired immune status, often associated with reduced liver function and increased inflammation associated with the periparturient cow results, in part, from an increase in the production of ROS. Consequently, it stands to reason that the supply of anti-oxidants and micro-nutrients to control the effects of oxidative damage should be considered as a routine component of the transition cow.

From a direct supplementation point of view, the (preventive) anti-oxidative system that can be affected through the diet seems limited to the supply of Vitamin E, beta-carotene and selenium.

In general, supplementation with these anti-oxidants improves immune function and health status in transition cows and an inadequate dietary vitamin E or Se decreases neutrophil function (Spears and Weiss, 2008). However, the productive and reproductive improvements following the supplementation with vitamin E and selenium vary with an important number of variables notably prior antioxidant status (enzymatic as well as non-enzymatic i.e. vitamins and Se), alternative dietary sources and – not in the least – the pro-oxidative stressors resulting from a sudden accelerated energy metabolism.

Improvements in liver function and how the cow deals with the inflammatory response can be improved through improvements in nutritional status i.e. the supply of nutrients that are not directly characterised as anti-oxidants but may stimulate parallel systems.

This was explored by Osorio et al. (2014a) who measured a large set of variables that were directly or indirectly related to oxidative stress, liver function and inflammation in periparturient cows. These workers were able to demonstrate a change in oxidative stress associated with the supplementation with a methyl donor.

Increasing methionine on a methyl-deficient diet improved de novo glutathione and carnitine synthesis in liver and, thus, increased antioxidant and beta-oxidation capacity. This offers the possibility to reduce oxidative stress through other means than anti-oxidant supplementation.

Conclusion

The transition cow is confronted with a large array of physiological and nutritional challenges. Each of these can be addressed by a solution in the form of a specific additive. However, these additives must primarily be considered as support tools to a solid nutrition or feeding program that provides the basis for improvements in the cow’s energy status through an enhanced dry matter and nutrient intake leading to better health, production, and reproduction post-partum.

The selection of a specific additive needs to be based on a thorough analyses of the existing feeding program and the identification of the weakest link within the program.

Many of the additives that meet this objective need to be incorporated in the transition cow diet over the entire period in order to stimulate rumen fermentation and or energy metabolism. Since the liver plays a critical role in how the cow copes with the periparturient challenges improvements in liver function should be an important objective of the choice of additive. Direct or indirect effects on the immune system are equally important but direct effects of the available additives remain relatively poorly defined.

The additives available for incorporation in the transition cow diet affect a limited range of identified and quantified metabolic actions. Thus the use of a single additive is unlikely to cover all situations.

The use of a combination of several additives in a supplement will provide broader support and greater protection. Critical selection of these in one product or solution will offer the additional advantage of potential synergistic effects. Reports from practical experience seem to corroborate this multi-factorial approach.

Authors: J.E. van Eys (Nutriad Inc.) and S. Moreland.

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