A recent study from the Chaudhari Lab in the UW–Madison Department of Biochemistry explores the relationship between gut-dwelling bacteria and folate, a vitamin that is critical for health and metabolism. Their study, published this month in Nature Metabolism, reveals important information about how gut bacteria affect the amount of folate that’s retained in different organ tissues in mice.
Vitamins are essential molecules that the human body needs to survive but cannot make on its own. We rely on our diets and on the diverse community of microbes in our digestive tracts (gut microbiota), which can produce folate (vitamin B9) and other vitamins. In humans, folate deficiency is associated with conditions such as megaloblastic anemia and congenital neural tube defects during embryonic development such as spina bifida and anencephaly.
“Folate is important for essential functions in our body, like constructing the backbones of our DNA and RNA, and synthesizing amino acids needed to make proteins,” says Chaudhari. “We get folate primarily through foods like dark leafy greens, but it’s not well understood if the gut microbiome produces folate to contribute to what our body needs.”
Despite the vitamin’s importance, folate production by gut bacteria and how folate moves within and between organs, have not been well-studied. And while folic acid, a stable form of folate used in supplements and food fortification, is well understood, folates are a structurally diverse class of metabolites (molecules produced through certain biochemical reactions), many of which have not been studied. Most folate metabolites are volatile and fragile, making them challenging to isolate and quantify.
Chaudhari says that existing scientific methods haven’t been sensitive enough to accurately measure all the different folate metabolites in cells. Her lab has made significant progress by developing novel liquid chromatography and mass spectrometry methods that can be used to isolate, quantify, and catalog folate metabolites.
Applying these methods, the scientists recently discovered a previously unknown folate metabolite in mice. Chaudhari hopes to characterize this new metabolite in future research to better understand its properties and function.
The researchers also quantified each folate metabolite in mouse tissues to determine which folates accumulate in individual internal organs. As they expected, different organs had different folate levels. The liver for example, had the highest levels of folate because it’s the metabolic hub of the body.
Other findings were unexpected. “It was surprising to see that folate levels were low or not detected in digestive organs such as the stomach and intestines,” says Chaudhari. “Considering that we eat folate-rich foods, and our microbiota reside in out gut, we would expect high levels of folate within these tissues.”
Jack Williams, a graduate student in Chaudhari’s lab, wondered whether these results could indicate that gut microbes were consuming folate rather than producing it. Williams tested the hypothesis using mice without a gut microbiome. The folate levels in these “germ-free” mouse tissues looked different from those with healthy gut microbiomes. Among the differences: folate levels were higher in the gastrointestinal tracts of germ-free mice, where no microbes were consuming the vitamin.
“When we have plenty of folate in our diets, our gut microbiome is going to eat it up because it’s available to them, too. Bacteria are scavengers. They can make vitamins de novo, but it’s a very energy-consuming process,” explains Chaudhari. “These findings also beg the question: what happens to the supplements we take? How much are the supplements, protein shakes, and fortified cereals feeding us, and how much are they feeding our gut bacteria?”
Chaudhari hopes that the methods developed in her lab will pave the way for scientists to fully explore the role of folate in metabolism and disease. To expand their reach beyond the scientific community, Chaudhari partnered with a web developer to create an interactive visualization of how folate is distributed across body systems in their study.
For Chaudhari’s lab, cataloging folate metabolites is just the beginning. “The structural differences among folates may be small, but they can have a dramatic impact on the fate of a cell. For example, some cancer cells have been shown to accumulate specific forms of folate. Now that we can examine the distribution of different folates in the body, there are so many more questions to dive into about the roles of these molecules on our health.”
Written by Renata Solan.