Although there is a general assumption that a phenylalanine (Phe)-restricted diet promotes overweight in patients with phenylketonuria (PKU), it is unclear if this presumption is supported by scientific evidence. This systematic review aimed to determine if patients with PKU are at a higher risk of overweight compared to healthy individuals. A literature search was carried out on PubMed, Cochrane Library, and Embase databases. Risk of bias of individual studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and the quality of the evidence for each outcome was assessed using the NutriGrade scoring system. From 829 articles identified, 15 were included in the systematic review and 12 in the meta-analysis. Body mass index (BMI) was similar between patients with PKU and healthy controls, providing no evidence to support the idea that a Phe-restricted diet is a risk factor for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. Given the increasing prevalence of overweight in the general population, patients with PKU require lifelong follow-up, receiving personalised nutritional counselling, with methodical nutritional status monitoring from a multidisciplinary team in inherited metabolic disorders.

Ismael S, et al. Nutr Res Pract. 2023 Aug;17(4):616-630. https://doi.org/10.4162/nrp.2023.17.4.616

Cobalt (Co), copper (Cu), manganese (Mn), molybdenum (Mo), and zinc (Zn) are essential trace elements (ETEs) and important cofactors for intermediary metabolism or redox balance. These ETEs are crucial during pregnancy, their role on specific pregnancy outcomes is largely unknown. This prospective study (#NCT04010708) aimed to assess urinary levels of these ETEs in pregnancy and to evaluate their association with pregnancy outcomes. First trimester pregnant women of Porto and Lisbon provided a random spot urine sample, and sociodemographic and lifestyle data. Clinical data were obtained from clinical records. Urinary ETEs were quantified by inductively coupled plasma mass spectrometry (ICP-MS). A total of 635 mother:child pairs were included. Having urinary Zn levels above the 50th percentile (P50) was an independent risk factor for pre-eclampsia (PE) (aOR [95% CI]: 5.350 [1.044–27.423], p = 0.044). Urinary Zn levels above the P50 decreased the risk of small for gestational age (SGA) birth head circumference (aOR [95% CI]: 0.315 [0.113–0.883], p = 0.028), but it increased the risk SGA length (aOR [95% CI]: 2.531 [1.057–6.062], p = 0.037). This study may provide valuable information for public health policies related to prenatal nutrition, while informing future efforts to de-fine urinary reference intervals for ETEs in pregnant women.

Although elevated blood levels of trimethylamine N-oxide (TMAO) have been associated with atherosclerosis development in humans, the role of its gut microbiota-derived precursor, TMA, in this process has not been yet deciphered. Taking this into account, and the fact that increased intestinal fatty acid absorption contributes to atherosclerosis onset and progression, this study aimed to evaluate the effect of TMA on fatty acid absorption in a cell line that mimics human enterocytes. Caco-2 cells were treated with TMA 250 μM for 24 h. Fatty acid absorption was assessed by measuring the apical-to-basolateral transport and the intracellular levels of BODIPY-C₁₂, a fluorescently labelled fatty acid analogue. Gene expression of the main intestinal fatty acid transporters was evaluated by real-time quantitative reverse transcription PCR. Compared to control conditions, TMA increased, in a time-dependent manner and by 20–50 %, the apical-to-basolateral transport and intracellular levels of BODIPY-C₁₂ fatty acid in Caco-2 cells. Fatty acid transport protein 4 (FATP4) and fatty acid translocase (FAT)/CD36 gene expression were not stimulated by TMA, suggesting that TMA-induced increase in fatty acid transport may be mediated by an increase in FAT/CD36 and/or FATP4 activity and/or fatty acid passive transport. This study demonstrated that TMA increases the intestinal absorption of fatty acids. Future studies are necessary to confirm if this may constitute a novel mechanism that partially explains the existing positive association between the consumption of a diet rich in TMA sources (e.g. red meat) and the increased risk of atherosclerotic diseases.

Low phenylalanine (Phe) protein substitutes (PS), either l-amino acids (L-AAs) or casein glycomacropeptide with added amino acids (CGMP-AAs) are the mainstay of phenylketonuria (PKU) treatment. Given the central role of intestinal nutrient absorption and gut microbiota in metabolic regulation, this study investigated how different PS affect nutrient absorption and bacterial growth. It was hypothesized that l-AAs and CGMP-AAs would exert distinct effects. Caco-2 cells, an in vitro model of enterocytes, were used to assess the acute effects of PS and whey protein (WP) on glucose, amino acids, and fatty acids analogues uptake, as well as the longer-term effects on nutrient transporter gene expression. The growth and metabolite production of Escherichia coli, Lactobacillus paracasei, and Shigella flexneri were also assessed. l-AAs reduced glucose absorption and downregulated glucose transporter 2 (GLUT2). Although l-AAs did not affect amino acids or fatty acids absorption, they downregulated l-type amino acid transporter 1 (LAT1) and peptide transporter 1 (PEPT1). CGMP-AAs had no effect on glucose or fatty acid absorption but impaired amino acid absorption and upregulated LAT1. These findings demonstrate formulation-specific effects on nutrient absorption and transporter gene expression. All PS increased bacterial abundance, with l-AAs producing the most pronounced effect relative to CGMP-AAs. l-AAs and WP accelerated the growth rate of all bacterial species, whereas CGMP-AAs selectively promoted the growth of L. paracasei, indicating a potential prebiotic-like effect. In conclusion, PS distinctly modulate intestinal nutrient transport and bacterial growth, underscoring the importance of considering their specific metabolic impact in PKU and the need for further translational research.