Maternal Dietary Deficiencies in Folic Acid and Choline Result in Larger Damage Volume, Reduced Neuro-Degeneration and -Inflammation and Changes in Choline Metabolites after Ischemic Stroke in Middle-Aged Offspring

Abstract

Maternal dietary levels of one-carbon (1C) metabolites (folic acid and choline) during pregnancy play a vital role in neurodevelopment. However, the impact of maternal dietary deficiencies on offspring stroke outcomes later in life remains undefined. The aim of this study was to investigate the role of maternal dietary deficiencies in folic acid and choline on ischemic stroke outcomes in middle-aged offspring. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. At 10 months of age ischemic stroke was induced in male and female offspring. Stroke outcome was assessed by measuring motor function and brain tissue. There was no difference in offspring motor function; however, sex differences were present. In brain tissue, maternal dietary deficiency increased ischemic damage volume and offspring from deficient mothers had reduced neurodegeneration and neuroinflammation within the ischemic region. Furthermore, there were changes in plasma 1C metabolites as a result of maternal diet and sex. Our data indicate that maternal dietary deficiencies do not impact offspring behavior after ischemic stroke but do play a role in brain histology and one-carbon metabolite levels in plasma. Additionally, this study demonstrates that the sex of mice plays an important role in stroke outcomes.

Maternal dietary deficiencies in folic acid and choline change metabolites levels in offspring after ischemic stroke

“…Ischemic stroke is a major health concern, with nutrition being a modifiable risk factor. We have previously demonstrated offspring from female mice deficient in either folic acid or choline have worse outcome after stroke (Clementson et al, 2022; Hurley et al, 2023; Pull et al, 2023) . Metabolites are important marker to measure the changes in the gut microbiota, which can be significant markers for different pathophysiological diseases in the body.…”

“…Ischemic stroke is a major health concern, with nutrition being a modifiable risk factor. We have previously demonstrated offspring from female mice deficient in either folic acid or choline have worse outcome after stroke (Clementson et al, 2022;Hurley et al, 2023;Pull et al, 2023) .…”

“…Experimental manipulations are summarized in Figure 2. Two-month-old female mice were habituated for seven days before they were placed on either control (CD), folic acid (FADD, folic acid: 0.3 mg/kg), or choline deficient diets (ChDD, choline bitrate: 300 mg/kg) (Clementson et al, 2023; Dam et al, 2017; Hurley et al, 2023; Jadavji, Deng, et al, 2015; Jadavji, Farr, et al, 2015) (Envigo, Indianapolis, IN). The control diet contains the minimum amount of folic acid (2 mg/kg) and choline bitrate (1150 mg/kg).…”

“…can modulate cerebrovascular structure and function, leading to endothelial dysfunction, reduced smooth muscle contractility, and decreased myogenic tone, all of which significantly influence peripheral and cerebral vascular health in mouse and rat adult offspring (Campbell et al, 2005; Durrant et al, 2014; Lin et al, 2018). Our group has demonstrated that maternal dietary deficiencies in folic acid or choline impact offspring ischemic stroke outcome (Clementson et al, 2023; Hurley et al, 2023; Pull et al, 2023). However, the mechanisms are not yet clear, our hypothesis is that maternal diet deficient in either folic acid or choline combined with ischemic stroke will result in changes to metabolites within the gut.…”

Maternal dietary deficiencies in folic acid or choline reduce primary neuron viability after exposure to hypoxia through increased levels of apoptosis

“…One-carbon (1C) metabolism is a critical biosynthetic process that is involved in the closure of the neural tube, neuronal plasticity, and cellular proliferation in the developing embryo. We have previously demonstrated that maternal dietary deficiencies in folic acid or choline worsen stroke outcomes in offspring [34], [35]. However, there is insufficient data to understand the mechanisms involved.…”