This Real Science Exchange podcast episode was recorded during a webinar from Balchem’s Real Science Lecture Series. His webinar can be found at balchem.com/realscience.
Nutritionists are often blamed for transition cow problems like high NEFAs, clinical and subclinical ketosis, and subclinical hypocalcemia. Dr. Baumgard suggests these symptoms are a result of one of two situations: 1. These are highly productive, healthy, and profitable cows; or 2. The symptoms are the metabolic reflection of immune activation, likely stemming from metritis, mastitis, pneumonia, or GI tract inflammation. In the first scenario, the nutritionist deserves a raise; in the second, these are mostly management issues not caused by nutrition. (1:26)
If listeners are interested in more detail on this topic, Dr. Baumgard suggests reading this 2021 review in the Journal of Dairy Science: “ Invited review: The influence of immune activation on transition cow health and performance—A critical evaluation of traditional dogmas.”
Link: https://www.sciencedirect.com/science/article/pii/S0022030221006329
Dr. Baumgard highlights key concepts that underpin his thinking regarding transition cows: The best indicators of health are feed intake and milk yield, it’s too easy to overthink the immune system, Mother Nature is rarely wrong, and inconsistent or non-reproducible data should create doubt. He goes on to review the incidence of metabolic disorders in early lactation and the energy balance dynamics of the transition period. (4:29)
For decades, we’ve had the assumption that NEFAs and ketones are causing many of the health issues in transition cows. NEFAs, BHBs, and calcium have been correlated and associated with negative outcomes. However many other studies do not find these negative correlations or associations. Plasma NEFA is markedly increased following calving in almost all cows, yet only 15-20% get clinical ketosis. Dr. Baumgard suggests that it’s presumptuous and reductionist of us to assume we can use one metabolite to diagnose the disease. Little mechanistic evidence exists to explain how these symptoms cause metabolic disease issues. (10:29)
If hyperketonemia, high NEFA, and subclinical hypocalcemia are causing disease, then therapeutically treating these disorders would improve overall cow health. NAHMS data does not back that up. Dr. Baumgard dissects the dogma of ketosis. In short, mobilization of adipose tissues and partial conversion of NEFA to ketones is essential for maximum milk yield. (18:35)
High-producing cows are more hypoinsulinemic compared to low-producing cows, and transition period insulin concentrations are inversely related to whole lactation performance. Low insulin concentrations coupled with insulin resistance allow for fat mobilization. (29:02)
Post-calving inflammation occurs in all cows. Sources include the mammary gland, the uterus, and the gut. Severe inflammation precedes the clinical presentation of the disease. In one experiment, all cows exhibited some inflammation in very early lactation. However, cows that were culled or died before 100 days in milk were already severely inflamed during the first few days of lactation. Dr. Baumgard thinks inflammation is the simplest and most logical explanation for why some cows don't eat well before and after calving. (31:13)
While clinical hypocalcemia (milk fever) is pathological and requires immediate intervention, is subclinical hypocalcemia detrimental to health, productivity, and profitability? (36:33)
Dr. Baumgard’s paradigm-shifting concept suggests that increased NEFA and hyperketonemia are caused by immune activation-induced hypophagia, and hypocalcemia is a consequence of immune activation. He goes on to use a high-producing, a low-producing, and a sick cow to illustrate this concept. (43:26)
In summary, the metabolic adjustments in minerals and energy during the transition period are not dysfunctional and don’t need to be “fixed.” The real fix is to prevent immune activation in the first place to prevent the cow from going off feed. Profitable production is a consequence of wellness. (52:19)
Dr. Baumgard takes a series of engaging questions from the webinar audience. Watch the full webinar at balchem.com/realscience. (56:04)
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Moderator (00:00:00):
The following podcast is taken from a webinar presented by Dr. Lance Baumgart from Iowa State University titled, “Who Let the Dogma Out of Transition Cow Management”. To view the full webinar and access the slides referenced during this podcast. Visit balchem.com/realscience and use the search bar to jump down to this webinar presented on January 10th, 2023.
Dr. Lance Baumgard (00:00:24):
I very much appreciate the opportunity to talk about some of the way our, our, my group has been thinking about the transition period for the last 10 or so years. Who let the dogma out? Actually, I, I need a shout out to a friend of mine, Steven Leblanc. Steven and I were on a, on a another meeting together in Canada a few, a few weeks ago, and he was talking about some of our ideas and, and papers and he, he, he mentioned who let the dogma out. So I, I gotta give him credit and maybe pay him some royalties on, on that on the title. Okay, let's get into it. You know, I like to use a couple quotes, especially because I think most of us on this webinar are probably familiar with Claude Bernard and his contributions to the concepts of homeostasis.
Dr. Lance Baumgard (00:01:09):
And of course, Bauman utilized a lot of Bernard's thoughts on homeostasis when he developed the whole concept of homeorhesis. So it's what we think we know that keeps us from learning, I think is an important, and we should not forget it. So, oftentimes nutritionists are blamed for the, for transition cow problems, and in particular, cows that have high NEFA's or they're hyperemia, or if they're sub clinically hypocalcemic. And I think these are really due to one of two things. One these are high productive healthy cows. They're profitable. And in this scenario, the nutritionist deserves a raise, or they are a reflection of, of immune activation, the metabolic reflection of immune activation, likely stemming from typical ailments that transition cows experience like metritis, mastitis, pneumonia, and, and possibly GI tract inflammation. And I think these are mostly management issues, not necessarily an a nutrition issue.
Dr. Lance Baumgard (00:02:16):
Everything I'm talking about today is we go in much more detail in this, in this particular review written with two of my former PhD students, Aaron Horst and Sarah Kra. So if you are interested in learning more about exactly what I'm talking about, this is a, this is a nice, I, you know, I'm biased. I think this is a nice review that explains the way we think. Quick reminder of how important glucose is. So as the nutritionist, they're balancing rations to, to maximize efficient fermentation in a particular generation of propionic acid. This three carbon vital fatty acid is used as the primary precursor to gluconeogenesis occurring in the liver. And the reason why this monosaccharide is so important is it is because it's the primary precursor to lactose and milk lactose. This disaccharide is the primary, not the only, but the primary osmotic regulator of milk yield. So this particular pathway is very important for profitability of, of the dairy cow. And of course, this is in large part influenced by the nutritionist, but also as you'll find out later in the talk by immune activation. And it takes about 72 grams of glucose to make one kilogram of milk. Okay?
Commercial (00:03:40):
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Dr. Lance Baumgard (00:04:29):
So the foundation of our thinking and essentially everything moving forward in today's lecture, comes back to these concepts. The best indicators of health are feed and intake and milk yield. If everyone agrees that stress reduces productivity, then high productivity cannot be stressful. The idea that high milk production is stressful, then it becomes an oxymoron. Then I think we have oftentimes overt thunk, right? Made the immune system more complex and maybe what it really needs to be. I don't think we need a PhD or DVM to know when a cow is healthy, if they're milking well and eating well, they're are healthy. And another thing you'll see permeating the, the entire seminar is that mother nature is rarely wrong. Now, obviously, I'm not talking about pathological diseases, I'm talking about normal biology. The evolution of why and how an animal metabolically adapts to whatever type of stress or challenge is rarely wrong. And I don't think we should view it as being pathological. And another one is inconsistent and reproducible data should create doubts. When scientific papers do not agree and they don't agree for, for decades, on decades, then that should create a scenario where we become skeptical of whatever it is that we're we're evaluating.
Dr. Lance Baumgard (00:05:55):
Okay? you've seen slides like this. This is a, a classic slide here produced by the University of Minnesota Vet School looking at day of lactation on the x axis and, and per and the, the likelihood of leaving the herd or cuing on the left y axis. And of course, we know that about a, a very large percentage of the cows are cold prior to 60 days in milk. And Jim Drackley wrote a paper now that's over 20 years ago talking about the transition period. And in North America, only about 50% of the cows get through the transition period without experiencing one of these negative outcomes. And this is that paper I'm talking about. And if you're interested in the transition period, you've probably read this paper. And if you haven't, you need to. It is the the viable transition period metabolism.
Dr. Lance Baumgard (00:06:42):
And Jose Santos and his group wrote another review recently, or more recently, 2010, and he came down with the same thing. About 44% of that transition cows get one of these problems, right? Calving, metritis, et cetera. So it's obviously a huge issue. And the transition period of success then, in large part dictates the overall profitability of that particular lactation. So in graduate school I remember reading papers like this and right, we have some, some pioneers of dairy science and the godfathers of dairy science on this particular paper. But I remember reading it and having all these particular negative outcomes correlated with each other. And even back in the mid nineties when I was reading these papers, I'm like, okay, are all these seemingly unrelated transition periods disorders and diseases, are they actually biologically connected or are they just mathematically or is it just simply a mathematical nuance?
Dr. Lance Baumgard (00:07:47):
I'm gonna come back to this slide later. 'cause I don't think it's just mathematical nuance. I actually think it's real biology. So we're all familiar with the transition period and the negative energy balances associated with it. And this is a slide I stole from the Alberta Dairy Management website. But it is looking at here in the purple line where, where milk, the energy output in milk, coupled with maintenance cost exceeds that in the in the early stages of lactation of energy consumption, the dry intakes and the animals in negative energy balance. And this negative energy balance lasts typically between 30 and 60 days in milk. Okay? And this is a paper or this is a, a, a slide I got from one of Rick Rum's presentations just demonstrating the energy balance on the Y axis stays relative to calving.
Dr. Lance Baumgard (00:08:35):
And we're all, we're all familiar with this, right? In reality, it probably comes back into positive energy balance, maybe, like I said, two or three weeks later than day 21. And because of this lack of energy consumption, which you see here in the purple line, the animal has to compensate for that energy insufficiencies by mobilizing adipose tissue and non-certified fatty acids increase. Now, this increase in non necessary fight fatty acids is something that we have been very interested in for now, probably going on four decades. 'cause We assume that this increase in blood non-ED fatty acids is responsible or causes negative outcomes. So this is a slide that I've adapted from one of Jim Drake Lee's presentations and papers. We have apus tissue. And apus tissue is mobilized during negative energy balance. The triglycerides are hydro hydrolyzed into necessary fight fatty acids and notary fried fatty acids, and increase in circulation.
Dr. Lance Baumgard (00:09:33):
And importantly, this is accompanied by a decrease in insulin concentrations and a decrease in insulin a action or sensitivity coupled with some increase in stress hormones. Now, not a certified fatty acids then are utilized by a variety of tissues that have the capacity to do so. But in this particular example, we're talking about what happens at, at the liver, it can be reconverted back into a triglyceride and hopefully exported as VLDL or it can be stored. And that's something we probably want to minimize the storage of hepatic triglycerides. It can be oxidized brought into the mitochondria by CCPT one and two. And hopefully then if it is brought into the mitochondria, it's, it is completely oxidized the CO2 and water. And for the generation of a TP, if it's partially oxidized, well then it's kicked out of the mitochondria as as as ketones.
Dr. Lance Baumgard (00:10:29):
Okay? So now for a long time, like I said, probably four decades, we've had this fear, not fear, but this assumption that non-certified fatty acids and ketones are causing many of the transition cow problems. And the reason why we believe that is because there are hundreds of studies in Journal of Dairy Science and other, and other scientific journals that associate non-certified fatty acids, BHBs, and, and calcium with negative outcomes. And I listed here five or six different papers by people that I respect and admire, and their friends of mine. I could have listed, like I said, about a hundred of these papers. And probably every dairy scientist listening to this webinar has published data that is consistent with this, right? That the magnitude of NEFA's and BHPs and hypocalcemia, sometimes, not always, it's important, correlated with a negative outcome. But importantly like I just kind of hint the two, there are many papers that do not demonstrate a correlation or association with these and negative outcomes.
Dr. Lance Baumgard (00:11:34):
And I think that's really important. So then when you start thinking about the metabolism then of partition and early lactation amongst all females, not just cows you know, we know that mobilization of, of adipose tissue is incredibly important metabolic aspect to, to lactation. Almost all cows have a relatively high circulating concentrations of NEFA's following calving. So then with regards to, in this particular instance, ketosis, what explains why some cows, or in fact, a majority of cows can get through the transition period while having high NEFA's, but not getting ketosis, and maybe what makes more cows more susceptible ketosis or more susceptible to developing fatty liver which, which we'll talk about here in a minute. And I think it is presumptuous of us to think that we can utilize one metabolite to diagnose the disease. And I think that's you know, it's classically referred to as the reductionist approach that I think has issues and gets us in trouble, potentially gets us in trouble.
Dr. Lance Baumgard (00:12:40):
Okay? The incidence of health problems, like I showed you earlier from that University of Minnesota slide, the incidence of health problems is highest in the first month of lactation. Everyone agrees with that. No one, no one disputes that. But here's what we also know, the largest swings in energetic metabolites, insulin, glucose, NEFA's, ketones, hormones like insulin glucagon, cortisol growth hormone and minerals like calcium, magnesium, phosphorus, all of these that I've just mentioned and, and many more that I haven't, the largest swings in, in an entire dairy cow's life happens within a very short window of time, within the first 2, 3, 4 weeks of, of, of lactation. So as a consequence, you have then an enormous amount of moving parts all occurring simultaneously. So then now it's just a, it's a matter of just mathematics that you're going to all of these things that are, you know, moving quickly, and then they're gonna be, they correlated or associated with mathematically with a negative outcome.
Dr. Lance Baumgard (00:13:47):
And of course, we all know this, right? Causality and correlation are incorrectly interchanged when these two events happen at the same time. And they're claim to be inevitable rather than just simply coincidence. And this is just a, a, you know, silly example of kind of what I'm talking about. Clearly, this, this Siegel didn't bend the pipe, but maybe more important or more, more enlightening of this idea is, is this particular cartoon here we have the sun hot, sunny, sunny day, and during the hot sunny days, people are more likely to eat ice cream. So this is a cause and effect. Hot weather increases ice cream consumption. Here's what we also know, that hot weather is also increases your likelihood of getting the sunburn. So here I have a causation and a causation. Now, the ice cream is correlated with being a sunburn. So clearly eating ice cream doesn't cause you to have a sunburn, and no one would ever claim that it did.
Dr. Lance Baumgard (00:14:43):
But you can see here then how mathematically ice cream consumption would be correlated with getting a sunburn. And I think this has an enormous amount of implications. It can be transferred into our transition pre issues. So this correlation then interpretation causes suspect decision making and unnecessary farm expenses for our producers. So the traditional belief, if we assume that correlation equals causation, is that increased NEFA’s, hyper ketanemia and hypocalcemia cause. Okay, this is important. It's not just academic nuance, but increased NEFA's, hyper ket anemia and subclinical hypocalcemia cause problems, okay? And you end up getting models that are built like this, and we've all seen many types of models like this. We have negative energy balance, like I mentioned earlier, impairing reproduction right here. Over on the left, you have a variety of cause and effects on, on reproduction. Then you have increased liver or impaired liver function, RP’s, endometritis, a variety of obviously ketosis.
Dr. Lance Baumgard (00:15:56):
So here we have a cause and effect model of negative energy bonds causing problems. And this is another one I described from the internet. Here we have ketosis causing problems like metritis, cystic ovaries, RP’s, reduced milk production, increased cuing, fertility, et cetera. And you've all seen cartoons like this or models made like this. So the question is, how, and, and maybe more importantly, why would NEFA's hyper he hyper, hyper anemia and hypocalcemia cause problems? What would be the biological probability? In other words why would evolution favor a scenario where the mother mobilizes tissues or make some metabolic adjustments to help feed her young, but at the same time put herself in a compromising position where she's more likely to get sick and thus more likely to not be able to take care of her young? It doesn't I don't think that makes sense.
Dr. Lance Baumgard (00:16:55):
So I think there's very little mechanistic evidence to suggest that NEFA's ketones and calcium can directly have such a large influence on very seemingly unconnected systems and diseases. The best line is probably extrapolated from the purported role in immune suppression. An area of of research that Dr. Mark Curley at the USDA initiated is a grandfather of this immune suppression caused by NEFA's ketones, a hypocalcemia a really a pioneer in the area. And like I said, there are, there are papers that demonstrate some ex vivo most of the time, ex vivo assessment of hypocalcemia, high levels of NEFA's and hyperemia on leukocyte function oftentimes neutrophil function. But importantly, back to that early foundation of the way we think there's a lot of inconsistencies in the data. Actually, Steven Leblanc group did a nice job of highlighting this in a, in a nice review almost three years ago now.
Dr. Lance Baumgard (00:17:54):
And remember, the foundation of any dogma should be a consistent pattern of data, reproducibility of data. So this immune suppression and negative energy balance, then, so creates models like here we have a model where you got immune suppression on top and negative energy bounce in the bottom. And then these things cause problems. They cause mastitis, they cause RP’s, they cause metritis, ovarian dysfunction, ketosis, BA’s, milk fever, et cetera. See, see, they're all connected. And this, this is what I guess we're, we're, we're trying to challenging now for a long time. So if hyperemia and high NEFA's and subclinical hypocalcemia are pathological, in other words, they're causing disease, it stands to reason then that they therapeutically treating these disorders would improve overall cow health, right? That makes sense. If we, if hyper ket anemia is bad, it causes disease. If we treat the hyper anemia, it should prevent disease.
Dr. Lance Baumgard (00:18:53):
Well, here we have the NAMS report, 1996, 2002, and 2014, and have different call calling reasons on the, on the left column. And in large, in large part, other than clinical milk fever, there's very little suggestions that overall herd health is improving with time. Okay? So despite the time emphasis, money spent on high NEFA's hyperemia and subclinical hypocalcemia, arguably not even arguably pretty emphatically you can say that herd health is not improving. So maybe we're just medicating the wrong things, right? If we spent the last 40 years trying to, to prevent hypo cal, subclinical hypocalcemia and 40 years trying to prevent hyperemia, then maybe we're not medicating the right thing. So here's a traditional belief that increased NEFA’s and hyper ketone immune and hypocalcemia cause production and health problems. So the model kind of looks like this. This was put together by one of my former PhD students, Erin Horst the cow calves.
Dr. Lance Baumgard (00:20:01):
She gets subclinical hypocalcemic, she has high levels of NEFA's, which then are converted in into the ketones by the liver, and you end up getting ketosis. Importantly, the changes in these three metabolites, I thought that reduced feed intake, which then contributes to da, and again, importantly the high NEFA's, the BHPs, and the hypocalcemia cause immune suppression. Now, once immune suppression is established, well then that increases the risk of the cows getting pneumonia, mastitis, metritis, rp, et cetera. And importantly, these three have also been connected with impaired reproduction and ultimately decreased farm profitability. Okay? That's the traditional dogma of the transition period. So I want to take some time to kind of dissect through these maybe a critical evaluation of it. So ketosis, dogma, excessive adipose tissue mobilization causes fatty liver and ketosis in that this is a bigger problem in high producing dairy cows.
Dr. Lance Baumgard (00:21:09):
And because of this, we've had an academic and an industry goal now for a very long time of reducing apu. I think there's a variety of things that should have given us red flags and should have caused us to have pause a long time ago. One of is, I've already talked about the associations and correlations, the very, very few intervening experimentation, looking at how an NEFA's and ketones can do this. If you infuse ketones or NEFA's into a variety of different animals it doesn't cause these negative outcomes. Remember, animals naturally ebb and flow outta ketosis all the time and have been for the last millennia.
Dr. Lance Baumgard (00:21:47):
Interestingly, many keto cows are not, are not hypo insulin, and in fact, oftentimes they're hyperemic an endocrine profile that goes against everything we think we know about the metabolic profile, the hormonal profile of ketosis. Ketones do not reduce feed intake. You hear this a lot. If this was the case, of course, then starving animal will not have an appetite, and that would, you know, quicken their demise. If you reduce adipose tissue mobilization, which can be done pharmaceutically, we can give cows insulin injections and or we can give them A TZD, which is a, a molecule that improves insulin sensitivity. And oftentimes, type two diabetics might be on A TZD any anyway. If you give insulin or A TZD, that does markedly reduce adipose tissue mobilization. But accompanying this reduction in NEFA's and hyperemia is a, a marked reduction in milk yield.
Dr. Lance Baumgard (00:22:49):
Some female animals don't consume food after ProVation. This is some, some deer, some ocean mammals. Don't, you know, a blue whale will literally lose five metric ton of adipose tissue during lactation. And importantly, what's really sparked my interest in this whole area is the regional differences in the rate of clinical ketosis. I was at the University of Arizona from 01 to 09 and was shocked to learn that there the clinical rates of ketosis in Arizona are less than 1%. Some, some dairy producers in Arizona haven't treated a ketotic cow for decades, which always surprised me, right? Because Arizona has high milk production, they're a very progressive state, and maybe five to six months of, of heat stress. If any area of the country should have a ketosis problem, you would anticipate that Arizona would be one of them, or probably the, the primary one, but it just simply doesn't.
Dr. Lance Baumgard (00:23:46):
So just a quick reminder, hyper keto anemia and ketogenesis in general is the coordinated convergence of carbohydrate and lipid metabolism. I'll show you that in a second. Is a highly conserved amongst almost all mammals. There's some ocean mammals that might have an exception. It's such an ancient strategy that even the simplest organisms, like like, like microbes will organize and utilize store adipose tissue store excess energy as triglycerides mobilize them and convert them into ketones. I think claiming that hyper ketone anemia is a disease as a kind sign, hyperglycemia is the biologic pathological origin of diabetes. In other words, when someone has type one diabetes they are typically hyperglycemic people don't blame the hyperglycemia for the problem. They blame the lack of circulating insulin. And I think the same concepts then can apply to, to transition cow hyper, hyper keto anemia.
Dr. Lance Baumgard (00:24:47):
There are now millions of people that are on low carbohydrate ketogenic diets. And so many people that are on, on this, that dozens of papers now have been written about the health consequences of a ketogenic diet and meta analysis papers are being written about them. Here's just two examples. This is a 2000-2020 paper looking at the ketogenic diet on metabolism and obesity and over white people with without type two diabetes. And here's just another, another 2020 paper looking at the meta-analysis of the ketogenic diet on, on, on human health. Listen, we literally have hundreds of millions of people in the world that have been on ketogenic diets or low carbohydrate diets now, for, for years, some of them decades. If hyper ket anemia was going to be causing health problems, we would've identified this in the human population.
Dr. Lance Baumgard (00:25:38):
So, interestingly, probably the world's most in history's most famous biochemist, Hans Kreb was interested in bovine ketosis. And he wrote many papers on bovine ketosis. And, and, and our understanding of the, of the ketogenesis actually in large part comes from Hans grab. But so fatty acids coming from adipose tissue come into the hepatocyte, go through beta oxidation, generates a lot of acetyl-CoA. Now, normally this acetyl-CoA would enter into the TCA cycle by combining with al acetate, this for carbon molecule to, to, to generate citrate. But during early lactation the animal has is, is also hypoglycemic. So there's a huge increase in the rates of gluconeogenesis. So as a consequence of that, oxil acetate is leaving the TCA cycle for in, in the process of glucose, one of the initial steps of gluconeogenic, cysto make glucose. Consequently, there is inadequate quantities of al acetate for acetic a to combine with.
Dr. Lance Baumgard (00:26:47):
In other words, acetic. A being produced from beta oxidation of fatty acids originating from adipose tissue, can't get into the TCA cycle. Well, that's okay because what happens then is that the acetic a is converted in these three ketones and exits the liver, and that can be utilized for energy by pretty much all other tissues. Now, this I mentioned homeostasis and Belman earlier. This is a 1980 paper, if you are interested in whatever I'm talking about today. This is, this is 20 years before Jim Drake's transition period paper, but it's it's a must read if you have interest in dairy cow metabolism. And Dale and I, Bob Collier wrote a paper now, five years ago, six years ago again reviewing homeorhesis. And then Sarah and I, and, and Aaron wrote another paper, which I mentioned earlier. If you are, if you have an interest in, in this type of biology, I would encourage you to read these three papers.
Dr. Lance Baumgard (00:27:51):
Ultimately though, the, the, the end, the one of the main conclusions of these three papers is that the mobilization of adipose tissue and the partial conversion of these necessary fried fatty acids in the ketones is absolutely essential for maximum milk yield. If you prevent this from happening, it will come at the cost of milk and a common critique of our message by some of my colleagues as well. Listen, you, you, you, you mentioned that milk yield is a gauge of overall animal health, and yes, I, I firmly believe that. And so when you give propylene glycol to a cow that has subclinical hyper, that is subclinical hyperemic, SHK, well, then they produce more milk. And that is actually, that's been demonstrated three times two outta the three forms in a 2011 paper. And another two papers demonstrated the same thing. But importantly, there's been no effect of propylene glycol on milk yield and subclinical hyper, hyper keto cows in these three papers.
Dr. Lance Baumgard (00:28:50):
So right, there's about a 50-50. So the body evidence, I don't think supports the practice of giving subclinical hyper ke cows propylene glycol yet. So transition period and insulin high-producing cows are more hyperinsulinemic compared to their low producing herdmates. The transition period insulin concentrations as inversely related to whole lactation performance. In other words, you can predict an animal's overall lactation performance based upon an insulin concentration in a transition period, removal of insulin from the circulating pool, that is increased by genetic selection for milk yield. And if you give insulin or insulin sensitizing agent, it decreases milk yield. In other words, the primary endocrine profile required for high production, profitable production is hyperinsulinemia. Okay? That's important you see in a second. So the successful transition cow, she has propionate coming outta the rumen converted in the liver to glucose. Now, the successful cow becomes the hyperglycemia is unable to stimulate a lot of insulin concentration insulin secretion.
Dr. Lance Baumgard (00:29:59):
So now the animal is hyperinsulinemia. This hyperinsulinemia coupled with an increase in insulin resistance, allows adipose tissue to be mobilized, not necessarily certified fatty acids in circulation go up. They can be utilized by energy, by most cell types within the carcass. There's importantly a couple cell types that can't oxidize NEFA's. And that's okay, because then we can convert that energy in NEFA's into a ketone. Now, most of the carcass can burn one of these two fuels for the generation of a TP. And what that allows then is the sparing, or essentially the lack of having to use glucose for energy by other tissues. Now, it can be utilized by the man gland to make milk. And Allen Bell's group did a fantastic job of doing, putting some numbers to this. And it's like 95% of the amount of glucose leaving the liver in a healthy transition cow is utilized by the mammogram.
Dr. Lance Baumgard (00:30:56):
This is a super highway, right? It's the Audubon from the liver to the mammary gland for the synthesis of milk. This all occurs, this metabolic flexibility occurs because of a decrease in insulin sensitivity. Now, we'll come back to the unsuccessful transition cow and minute. We, we now know that there's inflammation, there's immune activation that occurs in the transition cow. And in large part, we know this because of the Italian group, brutoni and merino trovesese groups in Italy have done a fantastic job of characterizing and describing this inflammatory inflammation that occurs after cavi. And they've done a great job of extending that to show that there's increase in inflammation at dry off. And one of my graduate students Brady Gates has reconfirmed this in some work here at Iowa State University. But the source of this inflammation in the transition period you know, the, the two obvious ones are the mammary gland.
Dr. Lance Baumgard (00:31:57):
'Cause We know the incidence of mastitis is highest in early lactation. The uterus, of course we think the GI tract is a source of some of this inflammation, which I don't have time to talk about today. But more importantly then is, okay, what are the consequences of this immune activation that's occurring? So here's just a oversimplified cartoon of looking at the small or the intestine. We have lipopolysaccharide, which is a very potent antigen, normally doesn't get through the barrier function of of the epithelium of the gut, but in some cases it can. And what it does then is immediately attacked by acute phase protein called LPS binding protein. And this LBP then will chaperone in the LPS to a to an immune cell. In this particular example, it's a macro, it's a ma resonant macrophage in the liver called a coffer cell.
Dr. Lance Baumgard (00:32:49):
And in the process of detoxifying this LPS, you have an inflammation. And what we've been measuring a lot about is often is acute phase proteins hap to go an LBP and sheline late a this is a fantastic some work done by GERD Boase group. And what they did was they, they, they blood sampled cows for the transition period from minus 21 to 28 days. And then once the cows got to a hundred days in milk, they retro classified them as being healthy cows cows that had mild disease, severe disease, or if they sold, they, they were called or died. Again, hyper globin, which is acute phase protein, a marker of acute of immune activation is on the Y axis. So even the cows that had no problems, they had no overt health problems, have an inflammation after calving. That's important to note is that all, all animals have a mild inflammation after calving.
Dr. Lance Baumgard (00:33:44):
What was interesting to me is that if the cows didn't make it to a hundred days in milk, if they were called or died before a hundred days in milk, they were retrospectively classified as purple. So we're talking about cows that were cold or died at 50, 75, a hundred days of milk, and you could go all the way back to the first couple of days of lactation, and they were severely inflamed. On the right you have looking haptic goblin again on the Y axis and looking at metritis mildly or severe metritis, and it's the same story. Even healthy cow have an inflammatory response. But this severe immune activation occurs before the clinical presentation of the disease.
Dr. Lance Baumgard (00:34:26):
This is one of my students, MII and, and Nathan Al, they looked at ketosis. So the clinical ketosis was diagnosed between about days nine and 20 of milk by a good friend of mine, pat Gordon, a faculty member in the vet school. And so there were showing signs of clinical ketosis out here. But if you took a look at their blood L-B-L-B-P concentrations on day three, there were already two and a half times greater than their healthy controls. So the same thing inflammation far, it precedes the clinical diagnosis of a disease. And this, this immune activation, it's a subsequent inflammation, I think has a huge impact on transition cows, specifically its role in suboptimal GME intake. Everyone in on this, on this webinar is familiar with inflammation causing a reduction in feed intake. This is a highly conservative response amongst all species.
Dr. Lance Baumgard (00:35:23):
Even a cricket, if you cause it cricket to be sick, it will reduce its feed intake. So it's from the simplest organisms all the way up to humans. And we know that cows that have the highest amount of inflammation have the lowest amount of ment intake. We've known this now for 21 years, and we also know that the cows that have the highest amount of inflammation also have the largest amount of necessarily fine fatty acids in BHP because of the reduction in feed intake. I think inflammation is the simplest and most logical explanation for why some cows don't eat well before and after calving. I'm not talking about regulation of feed intake once established lactation has been obtained. I'm talking about the transition period, inflammation, reproduction. I got this slide from a former master's student of mine, McKenzie Dixon, who got her PhD with John Brumfield at the University of Florida.
Dr. Lance Baumgard (00:36:11):
And this is a, a collection of data that was generated at the University of Florida and with Martin Sheldon's lab in, in the UK, essentially showing that LPS either coming from metritis or really any, any origin has a negative consequences on a variety of metrics of reproduction from multiple angles. What about hypocalcemia? Well, of course, the dogma is that milk uptake of calcium is so extensive, so quick, so acute that it exceeds the homeostatic capacity to replenishment. And that we should have our, our industry and academic goals, we need to minimize this. And of course, we have essentially minimized or reduced, so our clinical milk fever, right? Yeah, I would say that's one of the largest contributions that nutritionists have, have contributed to overall animal health. And we owe a huge great of attitude for a scientist named Ron Horst. Ron Horst is an incredibly productive, impactful scientist as H factor is 90, that is just an amazing contribution and impact on, on the dairy in on science in general.
Dr. Lance Baumgard (00:37:16):
But Dr. Horst, Ron Horst and his students and collaborators discovered not only the biology of milk fever, but importantly, they figured out how to prevent it, right? And if you are using some type of pre-cal calcium strategy, you should thank Ron and his collaborators for that. So obviously, so clinical hypocalcemia or milk fever needs a pre calving dietary strategy. And again, I've already mentioned it, it's probably the biggest contribution of nutrition to overall animal health in the last four years. Arguably, the biggest contribution to overall animal health, regardless of whether or not it's nutrition or a pharmaceutical intervention. So clinical hypocalcemia, even if you have a pre-cal dietary calcium strategy requires immediate intervention. We all know that. I'm not saying that I've been accused of that saying that before a clinical milk fever cow needs immediate intervention. The question I am challenging is, is subclinical hypocalcemia pathological?
Dr. Lance Baumgard (00:38:14):
Is it detrimental to health, productivity and profitability? Well, this is a nice paper from Nina van Loop. Van Links group. They retrospectively classified cows within the first couple days of, of lactation as being normal or healthy, not having high subclinical hypocalcemia or animals that did. And the control animals that did not have hypo subclinical hypocalcemia are on black. And the ones that did have some critical hypocalcemia are in the gray triangles. And this is milk yield on the Y axis. Remember, I think it's incredibly important to utilize milk yield as a marker of overall health. So if hypocalcemia, subclinical hypocalcemia is pathological, then why and how would subclinical hypocalcemic cows produce more milk? It, it to me it doesn't add up. And this is a paper out of, out, out of the Cornell group looking at patterns of hypocalcemia in heifers and in in cows following calving.
Dr. Lance Baumgard (00:39:18):
And so this is calcium on the left Y axis, and here we have milk. And I wanna draw your attention to two two or three different patterns here. We have in orange, these cows that become pretty severely subclinical hypocalcemic in orange, and they bounce back within the first couple of days of lactation, and now look at their milk yield, right? These are the cows that go on to produce a substantial amount of more milk than the healthy controls supposedly do. Here we have 50 kilograms and like 43 kilograms, seven kilograms that sold about 16 pounds of milk, 16 pounds of milk between these, these cows that were transiently, subclinical hypocalcemia versus the cows that had very low levels of subclinical hypocalcemia. So clearly there are patterns and causes then for hypocalcemia, and each one of these patterns of hypocalcemia has a cause and importantly implications.
Dr. Lance Baumgard (00:40:17):
So what could contribute to this chronic and delayed subclinical hypocalcemia that I showed you just a few seconds ago? Well, we've known now for over 130 years that immune activation can be responsible for clinical milk fever. These are some papers generated by veterinarians and scientists in in England. So here's some, some facts. We, we, we know now that all transition cows experience some degree of immune activation. It's really only the magnitude of that inflammation difference between a, a healthy and a relatively sick cow. And here's another fact. We know that immune activation acutely causes hypocalcemia in the interest of time. I didn't have time to to prove that to you. You're just gonna have to take my word for it. So then I think it's reasonable to hypothesize then that some immune activation contributes to some types of clinical hypocalcemia. And we think it's these types, this immune activation induced hypocalcemia that that, that, that benefits some, an oral calcium intervention.
Dr. Lance Baumgard (00:41:22):
And that's based upon a paper we published in the Vet Science Journal three years ago now. So let's talk about the evolution of amino metabolism. There are a variety of unusual scenarios and pathologies that are characterized by an increase in insulin, heat stress. I've already talked about ketosis feed restriction, intentionally induced leaky gut. And if you cause an animal to be sick, it also has high levels of insulin. The reason why these are all strange, of course, is that all of these are associated with the reduction in feed intake. Reduction in feed intake should be associated with hypo insulinemia. But that doesn't occur in these particular scenarios. There's a reduction in feed intake, and there is an increase in circulating insulin. It's strange. So why would an animal increase the most acutely anabolic hormone during a very hypercatabolic condition? Well, it's because leukocytes immune cells are insulin responsive and need insulin to acquire large quantities of glucose.
Dr. Lance Baumgard (00:42:18):
And again, I don't have time to go through our experiments where we tried to estimate the amount of glucose in activist immune system uses. You're just gonna have to trust me that it's a large amount. So again, you, I, I showed you this slide before where propionates converted in the liver to glucose. Glucose is a precursor lactose, and this drives milk yield. So during stress you have an immune activation event, now you have insulin concentrations going up, and now it partitions glucose towards the immune system. And you notice the mam gland just simply doesn't receive the glucose that it needs. And, and so this is, this hyperinsulinemia we got done talking about during these stressful conditions. That's why I, we, we, we believe that this hyperemia. So again, I've, I've showed you this but I, importantly, this is not just an ivory tower debate.
Dr. Lance Baumgard (00:43:06):
I think it has practical, pragmatic and economic consequences. So I've showed you this already. I'm not gonna waste your time on it, but again, it's important to recognize that in this model, this traditional model, these three things cause problems. Okay? I think we need to think about it a little bit differently. We think that high increased NEFA’s and hyper and hyperketinanemia are caused by immune activation induced reduced feed intake. I've already talked about how every single critter on the planet has a reduction in feed intake when it becomes immune activated. And we know that hypocalcemia is also a consequence of immune activation. And this transcends many different types of species. We think the low feed intake, high NEFA’s hyperemia and subclinical hypocalcemia are symptoms, right? The reflection of a prior immune active stimulation. So in this model, we have I have four different immune activating events up here.
Dr. Lance Baumgard (00:44:03):
I, I wish I would've put pneumonia up here. But anyway, we have one of these causing leaky gut, for example, causing inflammation. Now, we know that immune activation causes hypocalcemia. We know that the mammary gland has TLR four receptors for the LPS. So we have a direct inhibition of milk synthesis. We know that immune activation reduces feed intake even in a cricket I didn't talk about because of time. But we know inflammation contributes to fatty to fatty liver, and we know that LPS can cause impaired reproduction. I showed you everything except for maybe the fatty liver stuff. We know it also this reduced feed intake contributes to das, and now it increases NEFA’s and con, this contributes to the fatty liver, and it causes an increase in PHP and you get ketosis. So you see here that these are no longer causing problems. They are a response to a problem.
Dr. Lance Baumgard (00:45:05):
So let's talk about inflammation. So here's, I'm gonna have three cows. The healthy producer, a healthy low producer, she's a dog, a healthy high producer, she's making you money, and we have an unhealthy cow, a sick cow. She has mastitis, leaky gut, whatever. So you have inflammation in the low producer and the high producer, right? But here's our sick cow, okay? And I'm gonna put it up here in the left. It's there for your reference. What about dry matter intake? Here's our healthy low producer, healthy high producer. She eats more, of course. And here's our sick cow, okay? I'm gonna put it up there in the second to the left. Milk yield. Here's our low producer, high producer, and our sick cow. Put that up there. Now, this is where it starts, gets confusing. Not necessarily fight fatty acids. Here are low producers, high producers, sick cow.
Dr. Lance Baumgard (00:45:58):
You see here we have a cow that two very different cows, a profitable high producing healthy cow in green, and a unhealthy cow that's not making milk, but she has high levels of NEFA's. And the similar pattern then is for BHB, here's our low producer, here's our high producer, and here's our sick cow. Same thing with hypocalcemia. Here's our low producer, here's our high producer, and here's our sick cow. So taking a blood sample, you could get tricked into thinking that a cow is unhealthy, sick immune activated, when in fact, it's just a rockstar, right? It's a profitable dairy cow. So I've already showed you this. Importantly, this is due to an decrease in insulin. Now we have the unsuccessful transition cow propionate glucose, but we have LPS coming from somewhere, whether or not it's the uterus, the mammary gland, the gut, the lung, I don't think it matters.
Dr. Lance Baumgard (00:46:53):
The immune system becomes activated. This causes directly, causes a reduction in calcium, and it directly causes a reduction in feed intake. Now the cow wants to make milk, right? It, it, it wants to make milk at the same time. This is where the early lactation cow is different than the late lactation cow. She becomes hyper hyperinsulinemic. Why? Because now all this glucose is being made, we want to drive into the immune system. LPS and inflammation also contributes to fatty liver, and it contributes to poor reproduction. This is why the two things that are, the two disorders are the two negative outcomes that are most closely related in the transition period. A ketosis and poor reproduction. Well, why? That's 'cause they're both caused by the same thing. So now we have two cases causes for ketosis. A high producing cow that spares glucose for milk synthesis or the, the, the immune activated cow. She spares glucose not for the synthesis of milk. She's sparing glucose for the immune system.
Dr. Lance Baumgard (00:47:57):
So the scenario is you have two cows in the fresh pen, which just, this is just a hypothetical. They're both hyper ketones, say 1.5, 2.0, 2.5. Well, the cow that has ketosis and she has high ketone, but she's not coming into milk. She doesn't eat very well. She's not digging a hole in front of her. Her room's not filled out. She doesn't look good. She may even have a mild fever. Well, you can treat her for propylene glycol if you want, and her knee is in ketones will go down and you'll feel as if you've, you've intervened. But somewhere she's sick. She has an immune activation going on somewhere. And, and that's clamping appetite. A cow that has high ketones, but she's eating like a champion. She's milking like a champion. She looks great, and she doesn't have a fever, and she's aggressively coming up to the bunk.
Dr. Lance Baumgard (00:48:45):
Well, she's healthy, right? She doesn't need prop glyco, she doesn't need anything. She just needs to be left alone. So a real world example is something that occurred at, at the Iowa State Dairy Farm, not even 12 months ago. Here we have two different cows. The cow in black days in milk on the x axis, pounds of milk yielded on the Y axis. So the healthy cow here is in black, and she is making 140 pounds of milk by the 14th day in milk. We have a cow that's sick, and I'll show you that in a second, but she's inflamed that she's in red. So at the 14th day in milk, she's only making 60 pounds a day. She's a dog. She's probably never gonna be profitable, okay? And our protocol is to check for ketosis between days three and five and 1113 at the farm.
Dr. Lance Baumgard (00:49:33):
And lo and behold, these, both of these two cows came up as hyper ket, anemic, and were then treated with glycol. Well, it turns out the red cow had metritis diagnosed with metritis and her activity and rumination collar are down here in the bottom right figure. So compared to the average, right? But when she got diagnosed with metritis, her activity and rumination are substantially less than average. She's sick, and she's been seen by multiple veterinarians up here. This black, the cow that is in the black line, her activity and her rumination are right on par, right where we expect them to be. She's not no deviations in really anything, but she's hyper ketone. So she gets propane glycol on the 14th day of milk, despite the fact that she's making 140 pounds of milk, right?
Dr. Lance Baumgard (00:50:32):
So we gotta ask ourselves, should we even be measuring blood ketones, calcium and rectal temperature during the transition period? It costs money. It costs time, of course, if you treat them, it costs, the treatment itself has some cost. There's potential to have improper treatment administration. I know it's low, but the risk is still there. And probably just as big for most dairy farmers at the moment, is that labor is precious. And so you have an opportunity cost for that labor. So instead, maybe we need to pay more attention to feed intake and overall milk yield. And I know rumination isn't perfect for feed intake, but if you can couple rumination and activity and general appearance and, and milk yield, you should get a good assessment of overall health. High production can only occur in the absence of stress and morbidity. If she's milking well, like a rock star eating, well, she's not sick.
Dr. Lance Baumgard (00:51:26):
Immune activation causes inflammation. We know that all the cows are inflamed. It's just the magnitude that differs. We know that inflammation or high levels of inflammation appear long before clinical disease presentation. We know that immune activation causes hypocalcemia. It is never, I've never said this's, the only cause of subclinical hypocalcemia. We know that LPS causes infertility thanks to the guys at Florida and Martin Sheldon, and we know that all animals on earth have a reduction in feed intake when they become immune activated immune system is pumping the brake on feed intake. And we wanna prevent that. And I think you would put the pedal to the metal. So remember this paper I showed you by Charlie Sniffing and those guys and I showed, I was like, how could all these things be related? Is it, is it real biology or just simply mathematical nuance? I think it's real biology because they're all created by immune activation.
Dr. Lance Baumgard (00:52:19):
So I know I'm getting to the end here. Inflammation, the metabolic adjustments in minerals and energy and energy are not dysfunctional. They shouldn't be considered dysfunctional in that we have to fix them. The real fix needs to be what's causing her to go off feed immune activation. They're not to, not to blame. Our efforts should be pre in preventing immune activation in the first place. Management minimizing stress, right? Overcrowding or the pre fesh and the fresh pens on time, feed delivery, et cetera. Hygiene, keeping the pens clean, the dry up procedure, keeping the pens dry, pen cleanliness, dietary strategies, feed hygiene, GI tract disturbance. That's like rum acidosis and hin acidosis. I think there's strategies that aim to minimize immune leaky gut.
Dr. Lance Baumgard (00:53:19):
I can't say this enough. Profitable production is a consequence of wellness. If she's producing high quantities of milk and eating like a rockstar, she is. Well, so you've seen cartoons like this probably this exact cartoon where there's, you know, the masses are following the simple but wrong answer and in the complex, but right one, you only have a few people on that path. Well, I've taken the liberty to change this a little bit. I think we've made our interpretation of the transition period too complex. Doesn't need to be, you don't need a PhD or DB M to recognize when a cow is healthy. If she's milking well, eating well and looks good, she's healthy. You know, so anyway, it's myself and Erin Hor and
Dr. Lance Baumgard (00:54:14):
I'm also very appreciative of the USDA, and there's a variety of industry partners that I'm also very appreciative too and indebted to for helping fund these students. And then these students then have a chance to go out and have an impact on the industry. And sorry I just tried to come up with, you know, here we have an, an immune activating event, right? And this causes immune activation within, causes these problems. And then these problems then are correlated with these back, with these immune activations events. And I'm, I've gone over my time and I appreciate your patience and I'd be glad to ask, answer any questions or try to answer any questions I can.
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Scott Sorrell (00:56:04):
Dr. Baard first question. You know what, I'm gonna go with Dr. Zimmerman. He says, excellent presentation Lance, additional thoughts on how to identify these problem cows if you don't have activity and rumination collars?
Dr. Lance Baumgard (00:56:20):
Yeah, yeah, that's, that's a great question. Especially some, some of these large farms don't even have daily milk meters, so that makes it even more difficult. But you know, I think it's training farm personnel to recognize healthy versus sick behavior. You know, this isn't aggressive eating, digging a hole in front of them, rooming filled out. So just some old fashioned calc side animal husbandry skills, I think.
Scott Sorrell (00:56:56):
Yeah. Very well. Dr. Knapp would like to know your thoughts on the role of feed mycotoxins on transition metabolic diseases, like effects on gut motility relationship to DA’s and effects on systematic immune system and the relationship to mastitis and metritis.
Dr. Lance Baumgard (00:57:13):
Yeah, that's a great question. I think it's probably bigger issue than what we appreciate. I'm not an expert in mycotoxins are the consequences of them, but I know 'cause we've, we've dabbled in mycotoxins to, to try to recreate some of these immune activation events at the university and have been in large part unsuccessful. But clearly we have mycotoxin issues on farm and we're probably then getting immune activating events at the gut and prob maybe even, and probably even post absorptive. So I, yeah, I, I think mycotoxin contaminations can be a, a, a contributor to overall immune activation and thus then the consequences of that immune activation would be similar to that of mastitis or metritis or et cetera. Yeah, I think, I think she's spot on.
Scott Sorrell (00:58:05):
All right. Holger wants to know your thoughts on inflammation and beef cattle?
Dr. Lance Baumgard (00:58:11):
I think that's you know, the, the, the feedlot industry has a, has an issue with receiving cattle, right? They're on the truck, they're stressed, they're fasted, they might not, they're probably not also not getting water. They arrive at the yard and seven to 10 days later they come down to the BRD. And so I, I think there's a, there's a strong connection between the gut and the lung that shouldn't been described by other people as well. So this, this immune activation and inadequate feed intake, then once they come to the yard, I think it's very similar to the transition period that we see in, in lactating dairy cows and in, and even weaning calves. The biology is very similar amongst all these stressors, and I don't think that's a coincidence.
Scott Sorrell (00:58:59):
Alright, thank you. Larry, I'd like to know, have you done any work or are aware of utilizing anti-inflammatory compounds in the transition period such as aspirin and vitamin C?
Dr. Lance Baumgard (00:59:09):
Yeah. Yep. So groups have been looking at aspirin administration. When I was at the University of Arizona, I gave banomine through the first three days of calving. And Bradford's Group has been looking at aspirin as a, as a, as a tool the NSAID or the anti-inflammatory space. I think there's an enormous amount of opportunity there. We're still identifying what type of NSAID is needed and when it needs to be provided. 'cause Right now I think there's an enormous amount of inconsistencies in that literature. But I think that is a some low hanging fruit that we'll eventually get to.
Scott Sorrell (00:59:57):
Alright, next question comes in from Mario. Thank you for a nice presentation. I have a question about the treatment of subclinical ketosis. In the literature, it is mentioned that cortisone is not indicated if there is a central role of LPS and inflammation, should that not change this indication?
Dr. Lance Baumgard (01:00:16):
Yeah, I get asked that question a lot too. I think, you know, so we know cortisol is an immune suppressor. In fact Dr. Mark Curley's group at the NADC utilized cortisol to induce immune suppression, right? To establish the model. So I, I think giving cortisol simultaneously when treating a subclinical hyper keto, hyperketoneanemia is probably a unwise decision.
Scott Sorrell (01:00:44):
Alright, next question is Ahmed. Can we say reducing inflammation will improve health and milk production, but at the same time, having less inflammation can decrease the ability of the animal to fight against disease? How do we explain this? Yeah,
Dr. Lance Baumgard (01:01:00):
That's a great question. So we, you know, so inflammation is an incredibly key component of the immune response. So what we want and I've heard Dr. Curly describe it this way, often we want a cow to have an inflammatory response to peak, to have it very robust. And then we want it to go away we want it to resolve, and it's the the lack of resolution of inflammation. That's really the problem. So he's right. Inflammation is incredibly key component to, to an effective immune response. And I'm not sure we want to prevent it. Of course, we know like for example, parturition, the act of parturition is requires inflammation. And we know that tissue remodeling requires inflammation. So for example, the uterus goes from a 50 gallon bag down to a Ziploc size bag within a week, right? That whole process requires an inflammatory response to be successful. So I think we need to not approach inflammation as, oh, we need to prevent it. We need to prevent it. We need to prevent it because we don't want to always prevent inflammation.
Scott Sorrell (01:02:08):
All right. Next question comes in from Martin. Hi Lance. Thanks for the presentation. To modulate or prevent immuno activation during the early postpartum, which of the following should be your main target? Number one, immune system the LPS or the integrity of the cells from the uterus MG or DGI tract?
Dr. Lance Baumgard (01:02:32):
Yeah, I think it's the third. I think we want to minimize immune activation to begin with. I'm not even, you know, so that, that, that goes back to management hygiene GI tract health, that's a nutrition issue, of course. Yeah, I, I think we wanna prevent immune activation from, from the get-go. That's, I think our, that's the lowest hanging fruit right there. And that is again, mostly management issues, I think.
Scott Sorrell (01:03:04):
Alright, next question comes in from Dr. Seth. Dr. Seth, glad to have you on board here. He's got a word here I don't know how to pronounce, so we'll give it a try. Lance. he says, love the challenge to transitions challenging my own paradigms. We think we like 15 milligrams of sino cabal, lamine daily. Do you know what that is? Daily for the first 12 days in milk to drive dry matter intake and metabolism, and we think we see much less health issues.
Dr. Lance Baumgard (01:03:40):
Well, I'm not sure what that compound is. He might be talking about one of the cannabinoids. Some people from Germany and Israel working on these the can can cannabis related compounds with regards to feed intake. So I think anything we can do to encourage feed intake after calving is, is obviously a good strategy. But I just keep going back to the original hypo original tenant here is that immune activation decreases feed intake. So if you remove the immune activation, you probably don't need a pharmaceutical target molecule to increase feed intake. If you remove the immune activation, she'll take off eating like a rockstar. Anyway, I'm not sure if I understood Earl's question or not, but if vitamin B12. Oh, okay. Yeah, I, I, I don't, I'm not very familiar with the vitamin B12 literature stimulate in feed intake. Really, you have to send those, send those to me, if you don't mind.
Scott Sorrell (01:04:50):
Yeah, absolutely. Vagaro is asking with screening purposes could could be an immune test be applied at transition? If so, when and which,
Dr. Lance Baumgard (01:05:03):
Yeah, I think this is a great comment Vagaro because we, we have some data, my student students have some data looking at trans, our dry period inflammation, and specifically this comes from Brady Gates' work, but dry period inflammation. And then those cows 60 days later after they calve, they are also the most inflamed. So the, the most, the cows that are most inflamed at dry period are also the most inflamed at the after calving. So maybe we could even identify a cow that's going to be problematic 60 days before she even calves. And in fact, it would be very interesting to say, okay, let's go all the way back to when there were calves. Maybe we could identify a hyper inflamed calf. So you can identify them as, okay, you need to go into the milking stream, you need to you know, you need to go to beef. But I think that's a fantastic opportunity for us then to start segregating. Hey, you're, you're going to, you know, you need to go this route on the farm and you need to go to a different route.
Scott Sorrell (01:06:16):
Alright, next question. Back to Ahmed. How does the immune activation cause hypocalcemia and how can we do future experiments to prove that immune activation is the cause of metabolic disorders, especially hypocalcemia?
Dr. Lance Baumgard (01:06:33):
Well we've pro we even others have proven that immune activation causes hypocalcemia. A a bigger question is why well, it's not really understood why we, there's a hypothesis by other people and I, and I I like it that most of the way endotoxins are removed from circulation are via lipoproteins. And this, this is a process by which endotoxins are removed that doesn't require an immune response. So lipoproteins of course, as the name applies, are mostly filled with lipids or triglycerides and of course, LPS the, the l part of lipolytic is lipid. So they can get sequestered into these triglycerides strictly in triglycerides. And from what I understand hypocalcemia allows that process to be more efficient. So then of course the, the, the, the lipoprotein will be taken up by the liver and the liver dumps out the LPS into the, into the, into the, into the intestine. So it is a, it is a way that which the animal can get rid themselves, the endotoxemia, without having a massive inflammatory response to the endo, to the endotoxin.
Scott Sorrell (01:07:51):
Alright, next question comes in from Ferl. You indicate blood insulin concentrations as a key factor to classify healthy versus sick cows. What about IGF eye situations?
Dr. Lance Baumgard (01:08:05):
So IGF one?
Scott Sorrell (01:08:07):
Yeah, IGF one.
Dr. Lance Baumgard (01:08:09):
So that, yeah, that's right. The the nice thing about insulin is it's very quickly response. It's very responsive very quickly within, you know, within, actually within minutes. So that's why it's I think more reflective, acutely reflective of immune activation rather than IGF one.
Scott Sorrell (01:08:33):
Alright, you know, we're getting pretty long here. I'm gonna go with one more question, Lance. Okay. Ken is asking if hyperinsulinemia is a state of normal physiology, but immune system is, is function is dependent on insulin and inflammatory events are normal at calving are just too late repartitioning glucose to immune cells. And what can be done to change this?
Speaker 4 (01:09:01):
Hmm, let's see.
Dr. Lance Baumgard (01:09:05):
Inflammation for events are normal, cabin are just too late. I wonder what he means by are just too late repartitioning glucose to immune cells. What coming down changes? Well to me, I I I, I hate to keep harping on a simple way of thinking, but that's the way my mind works. We just wanna prevent immune activation to begin with. Now all cows have some mild immune activation and, and thus inflammation, right? It's the exaggeration, it's the extended, it's the lack of resolution that I think stems from immune activation. So in my mind, let's go back, let's go back to the basics. Keep the keep the dry pen and close up pens, clean and dry. Have our co have our fresh pens, calving pens, clean and dry. Don't overcrowd, keep the stress level low. Don't vaccinate in the transition period. Prevent immune activation in the, in the first place. I think that's where our efforts should be placed.
Scott Sorrell (01:10:03):
All right. And I'm, I'm gonna fib and and do one more last question. Matt has one I think will work quite nicely is where should we focus on to actually prove this dogma shift?
Dr. Lance Baumgard (01:10:15):
Well, okay, I get asked that all the time and, and I, and I, and I agree with that. It'd be great to prove a dogma shift, but I think
Dr. Lance Baumgard (01:10:24):
I don't think the original dog mo has ever been proved in, in all due respect to many of my friends and, and, and colleagues. I, I just don't think that that dog Mo was ever proved with controlled and intervening experimentation. You know, proving, proving things is difficult. Here's what we know, we know immune activation causes hypocalcemia. It's not the only reason for hypocalcemia. We know that animals that have the highest amount of inflammation also have the lowest amount of dry matter intake. I, I don't, I don't know, Scott, if there is a gonna be a controlled and intervening intervening experimentation that can prove one dogma versus the other or one idea versus the other. But we've been hounding on hyperemia high, high is and hypocalcemia now for going on 35, 40 years. Maybe we're hounding on the wrong things.
Scott Sorrell (01:11:29):
Alright, very well on behalf of Alchem and Dr. Baumgart, thank you for joining us today.
Dr. Lance Baumgard (01:11:36):
Thank you.
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Scott Sorrell (01:12:37):
Yeah, thank you.