Single nucleotide polymorphisms (SNPs) in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women (n = 75) consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9) for 10–12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N-methyltransferase (PEMT) denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term.

Although single nucleotide polymorphisms (SNPs) in folate-mediated pathways predict susceptibility to choline deficiency during severe choline deprivation, it is unknown if effects persist at recommended intakes. Thus, we used stable isotope liquid chromatography-mass spectrometry (LC-MS) methodology to examine the impact of candidate SNPs on choline metabolism in a long-term, randomized, controlled feeding trial among pregnant, lactating, and nonpregnant (NP) women consuming 480 or 930 mg/d choline (22% as choline-d, with d indicating a deuterated trimethyl amine group) and meeting folate-intake recommendations. Variants impairing folate metabolism, methylenetetrahydrofolate reductase (MTHFR) rs1801133, methionine synthase (MTR) rs1805087 [wild-type (WT)], MTR reductase (MTRR) rs1801394, and methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) rs2236225, influenced choline dynamics, frequently through interactions with reproductive state and choline intake, with fewer genotypic alterations observed among pregnant women. Women with these variants partitioned more dietary choline toward phosphatidylcholine (PC) biosynthesis via the cytidine diphosphate (CDP)-choline pathway at the expense of betaine synthesis even when use of betaine as a methyl donor was increased. Choline intakes of 930 mg/d restored partitioning of dietary choline between betaine and CDP-PC among NP (MTHFR rs1801133 and MTR rs1805087 WT) and lactating (MTHFD1 rs2236225) women with risk genotypes. Overall, our findings indicate that loss-of-function variants in folate-metabolizing enzymes strain cellular PC production, possibly via impaired folate-dependent phosphatidylethanolamine-N-methyltransferase (PEMT)-PC synthesis, and suggest that women with these risk genotypes may benefit from choline intakes exceeding current recommendations.-Ganz, A. B., Shields, K., Fomin, V. G., Lopez, Y. S., Mohan, S., Lovesky, J., Chuang, J. C., Ganti, A., Carrier, B., Yan, J., Taeswuan, S., Cohen, V. V., Swersky, C. C., Stover, J. A., Vitiello, G. A., Malysheva, O. V., Mudrak, E., Caudill, M. A. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis.

A central goal of neuroscience is to advance knowledge of the molecular basis of human brain function. Most molecular studies of the human brain have been performed using tissue from postmortem brain donors rather than living people. The assumption underlying this practice - which had never been rigorously tested prior to this report - is that the postmortem human brain is an appropriate proxy for the living human brain at the molecular level. Here, this assumption is thoroughly challenged for the first time by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Vast differences in gene expression were found between the living and postmortem human brain. Expression levels differed significantly for nearly 80% of genes, and this finding was not a consequence of any potential technical or biological confounders of the gene expression data. Postmortem brain gene expression signatures of Alzheimer's disease, schizophrenia, Parkinson's disease, bipolar disorder, and autism spectrum disorder were shown to be inaccurate representations of disease processes occurring in the living brain. In light of these findings, the use of postmortem tissue as a proxy for living tissue in human brain research should be reconsidered. To advance knowledge of the molecular basis of human brain function, the study of tissue from living people should be prioritized.

Context Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing’s disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients. Purpose To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission. Methods 30 CD patients, mean age 40.0 yr. (range 17–70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed. Results Remission decreased prospective consumption, sweet and savory craving (p<0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p<0.05). Conclusions Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission.

Objectives Current irritable bowel syndrome (IBS) treatments have limited efficacy and probiotics like Bacillus clausii ( B. clausii ) were found to be effective in the management of several gastrointestinal disorders. This phase III trial assessed the efficacy and safety of adding B. clausii (four strains: O/C, N/R, SIN, T), versus placebo, to conventional treatment of pediatric IBS in Mexico. Methods Patients aged 6–17 years 11 months with IBS (Rome IV) for at least 2 months were randomized to receive either B. clausii (oral suspension, total dose 4 billion spores/day) or placebo once daily for 8 weeks. All patients also received conventional treatment. The primary endpoint was the difference in the proportion of patients with clinical improvements at Week 8 (Global Assessment Questions [GAQ]). Secondary endpoints included responders by Subject’s Global Assessment of Relief for Children with IBS (SGARC); number/consistency of stools; abdominal distention/bloating; abdominal pain/intensity; and IBS behavior. Results 73.6% (95% confidence interval [CI] 67.3–80.0; B. clausii n = 129) and 78.5% (95% CI 72.5–84.4; placebo n = 130) of patients had symptom improvement ( p = 0.8182). For Week 8 SGARC, 19.2% ( B. clausii ) and 20.9% (placebo) reported complete symptom relief. Stool evaluations, bloating, abdominal pain/intensity, and IBS behavior were similar between groups. Both treatments were well tolerated. Conclusion No significant differences in efficacy between B. clausii and placebo were demonstrated in addition to conventional treatment. The sample size calculation was based on an expected placebo/conventional treatment response of 30–40%. However, the actual treatment response observed was 80% and, thus, a study with larger population would be warranted. In addition, this study was conducted during the COVID-19 pandemic, when such controlled social conditions may have resulted in better diet, greater family stability, less psychological stress, and lower risk of infections exacerbating IBS, thereby improving symptoms in both groups. EudraCT number 2018-004519-31. Supplementary Information The online version contains supplementary material available at 10.1007/s40272-022-00536-9.