Positive function? | Researchers say inflammation may be a biological response to help quickly boost milk production
LINDELL BEACH, B.C. — Inflammation in livestock comes and goes and is almost always treated as a result of some form of pathogen infection.
But what if the inflammation was actually a necessary and positive biological function?
Dairy cows go through profound changes in the transition from giving birth to producing milk for the nursing calf.
It increases the requirements for energy, glucose, amino acids and other nutrients while also depressing feed intake.
This negative energy balance can suppress the immune system and lead to inflammation, which results in metabolic disorders such as fatty liver or ketosis.
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Barry Bradford, an associate professor in Kansas State University’s animal sciences and industry department, was reading biomedical literature on signals that could change metabolism while in grad school 10 years ago.
When he started working at KSU, he began turning conventional thinking on its head, wondering if it was the inflammation that was triggering metabolic disorders in postpartum dairy cows rather than the other way around. If so, why?
Bradford and his team, which included researchers at Iowa State University and Michigan State University, studied 75 Holstein cows maintained in individual tie stalls at KSU’s research barn. The cows were fed twice a day and milked three times a day.
They initially tried reducing the inflammation in postpartum cows with the anti-inflammatory drug sodium salicylate (SS) during the first seven days of lactation. They expected to see the drug curb the increase in liver fat and maintain glucose supply, but the results surprised them.
“I’ve been involved in enough science to know sometimes things come out the opposite,” Bradford said in an emailed response to questions.
“So we watched milk production responses and what really blew me away was that those animals that had all those negative responses in early lactation then turned around at the end of lactation and gave up to 5,000 pounds more milk. It looked like (at first) it was problematic, but the milk production was astronomical in the oldest group of cows.”
When analyzing the results of using SS, Bradford found that liver fat increased and plasma glucose concentration dropped. These counter-productive responses became the markers for the metabolic diseases sometimes seen in early lactating cows.
Bradford and his team began to realize that rather than treating a nursing cow with an anti-inflammatory drug, it actually benefits from the inflammation in the transition from carrying a calf to providing it with milk. He said the mammary gland is turned on immediately following birth, and the demand for milk soars overnight.
“Her demand for glucose and nutrients goes up two-fold,” he said.
“She can’t possibly crank up production that fast. She has to do other things to not run out. One of those things is for adipose tissue and muscle to use less glucose. I think this is a quick signal to get that (milk production) done. It’s quicker than other signals that would turn off glucose use in those tissues.”
The biological responses at the onset of lactation are triggering a temporary state of insulin resistance akin to diabetes. It is an adaptive condition rather than a pathological one.
Bradford said the big difference with diabetes is that in most animals it will resolve itself as their metabolism adapts to lactation. However, the issue with fatty liver is a more transitory byproduct.
“In fatty liver we’re measuring triglyceride buildup in the liver, so then people make the assumption that it’s the triglycerides that cause the problem leading to fatty liver,” he said.
“Well, someone with a mouse model about 10 years ago said if that’s true and we get rid of the gene necessary to make triglycerides, then the disease should not be a problem. They did that and the mice were horribly sick. So to my way of thinking, it’s the least bad option the cow has to deal with in the excessively high amount of fat coming into the liver. (However), in three percent or four percent of animals, it (can) go too far and she can’t cope with it. A problem with fatty liver is that we still don’t have any diagnostic other than to do a biopsy, which is invasive and time consuming to do properly.”
A calf is exclusively dependent on its mother’s milk in the first two to three weeks of life. As a result, the mammary gland is selfish in its demand for nutrients and glucose to feed the baby.
From an evolutionary point of view, there is huge pressure to make sure the young calf survives with enough milk to carry it before it starts eating grass. Therefore, other physiological functions must compromise or cope with annoying side effects while the cow’s body makes the full adjustment to lactation.
However, whether this is an evolved bovine trait is still a mystery.
“I can’t even say now that it’s a bovine characteristic,” said Bradford.
“It could possibly be a byproduct of heavy selection for really high milk production. We have a proposal to look at this in different species to see whether there is evidence that it is a conserved trait or not. I couldn’t find any study in other species quite like this one where they measure the same things that we did. We really have no idea.”
The research will likely prompt questions about diabetes in humans during pregnancy, but Bradford said there is a difference in humans based on the studies that have already been done. Insulin resistance in pregnant women tends to occur during pregnancy rather than during milk production, which is why there is greater reference to gestational diabetes rather than lactation diabetes.
“I think, and it needs to be asked, that there is plenty of data showing that extreme gestational diabetes is a serious problem that needs to be addressed,” said Bradford.
“However, this research might lead us to more carefully think about mild gestational diabetes and maybe acknowledge that there is some potential benefit to that.”
The results of Bradford’s research have triggered more hypotheses to be examined.
As a result of the unique metabolic response they saw in the high milk volume response, the researchers plan to study whether different organ systems respond independently to the onset of lactation.
They have proposed researching multiple species to look at muscle and adipose tissue insulin resistance at the beginning of lactation to see if the inflammation condition is more widespread. The goal is to better understand the immune system and the role of inflammation in metabolic function.
They also plan more studies on the mammary gland, the influence of inflammation and the high volume of milk production during the entire lactation process.
The research team’s findings were published in the American Journal of Physiology.