Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha-/- mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a 9-fold elevation of brain 2-ketoisocaproate accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase 2 flux and destabilization of glutamate-2-ketoglutarate mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.

Background/Objectives: Liver fat represents an early metabolic lesion in the development of diabetes and its cardiometabolic complications. Diets high in free sugars, particularly from sugar-sweetened beverages (SSBs), are associated with abdominal obesity and increased cardiometabolic risk, prompting global guidelines to limit SSBs as a major public health strategy. Low-fat cow's milk is promoted as the preferred caloric replacement strategy for SSBs due to its high nutritional value and cardiometabolic advantages. Fortified soymilk is a plant-based alternative with approved health claims for cholesterol and coronary heart disease risk reduction that offers an equivalent nutritional value to cow's milk. However, given concerns about its classification as an ultra-processed food (UPF), it is unclear whether soymilk offers comparable metabolic health benefits to milk as part of clinical and public health strategies to reduce SSB intake. The Soy Treatment Evaluation for Metabolic (STEM) health trial seeks to evaluate the impact of replacing SSBs with either 2% soymilk or 2% cow's milk on liver fat and other cardiometabolic risk factors in habitual adult consumers of SSBs with obesity. Methods: The STEM trial is a 24-week, pragmatic, 3-arm, parallel, randomized trial. We recruited adults with obesity (high BMI plus high waist circumference based on ethnic specific cut-offs) consuming ≥1 SSB/day. Participants were randomized to one of three groups based on their usual SSB intake at baseline (servings/day): continued SSB (355 mL can) intake; replacement with fortified, sweetened 2% soymilk (250 mL); or replacement with 2% cow's milk (250 mL). The primary outcome is the change in intrahepatocellular lipid (IHCL) measured by 1H-MRS at 24 weeks. Hierarchical testing will be done to reduce the familywise error rate. The superiority of cow's milk to SSBs will be assessed first to establish assay sensitivity. If superiority is established, then the non-inferiority of soymilk to cow's milk will be assessed using a pre-specified non-inferiority margin of 1.5% IHCL units (assessed by difference of means using a 90% confidence interval [CI]). Analyses will be conducted according to the intention-to-treat (ITT) principle using inverse probability weighting (IPW) for superiority testing and per-protocol analyses for non-inferiority testing, using ANCOVA adjusted for age, sex, metabolic dysfunction-associated steatotic liver disease (MASLD) status, medication use, intervention dose, and baseline levels. We hypothesize that soymilk will be non-inferior to cow's milk (Clinicaltrials.gov NCT05191160). Results: Recruitment began in November 2021. A total of 3050 individuals were screened. We randomized 186 participants (62 per group) between 19 April 2022 and 16 April 2024. Participants are 57% male; with a mean [SD] age of 39.9 [11.8] years; BMI of 34.6 [6.1] kg/m2, waist circumference of 112.6 [13.8] cm; IHCL of 10.0 [8.2] % with 64.1% meeting the criteria for MASLD; and SSBs intake of 2.3 [1.3] servings/day. Conclusions: Baseline characteristics were balanced across the study arms, with participants representing adults with a high-risk metabolic phenotype, and 64.1% meeting the criteria for MASLD. Findings will contribute to evidence on the cardiometabolic benefits of soymilk, informing clinical practice guidelines and public health policy.

Stunting, or impaired child growth due to poor nutrition and infections, is characterized by a low height-for-age and affects 48%-56% of school-aged children worldwide. It is associated with later weight gain and chronic diseases. The gut microbiome in undernourished children may increase obesity risk if they are exposed to high-calorie environments. To investigate this, we assessed whether the intestinal microbiome of stunted children elevates obesity risk upon exposure to an obesogenic environment. Fecal microbiota transplantation (FMT) was performed using pooled stools from healthy (n = 6) or stunted (n = 6) school-aged children from a low-income cohort in Mexico. Eight-week-old male C57BL/6 mice underwent bowel cleansing with polyethylene glycol (PEG), followed by weekly intragastric FMT for 4 weeks. The mice were subsequently fed either a control diet (CT) or a high-fat, high-fructose corn syrup diet (HFFr, including 15% HFCS-55) for 15 weeks. Metabolic outcomes were assessed through body composition, indirect calorimetry, oral glucose tolerance test, insulin tolerance test, and histological analysis of visceral adipose tissue. The microbiota composition was evaluated by 16S rRNA V3-V4 hypervariable region sequencing, and the predicted functional capacity was analyzed using PICRUSt2. FMT from stunted children increased susceptibility to diet-induced obesity, visceral adipose tissue hypertrophy, and insulin resistance. In contrast, FMT from healthy children promoted energy expenditure and visceral adipose tissue hyperplasia, conferring a protective effect against diet-induced obesity and insulin resistance in the mice. Healthy-FMT led to sustained enrichment of Akkermansia and Parabacteroides, whereas stunting-FMT increased Proteobacteria, Veillonella, Desulfovibrionaceae, and Bifidobacterium. Microbial‒phenotypic correlations showed that Akkermansia and Parabacteroides were negatively correlated with fasting glucose, body weight, and fat mass, and positively correlated with postprandial RER, VO2, and lean mass. In conclusion, stunting-FMT recipient mice showed a higher risk of obesity and metabolic issues in an obesogenic environment. Healthy-FMT confers metabolic resilience, characterized by increased abundance of taxa such as Akkermansia and Parabacteroides, which are linked to enhanced energy expenditure, improved glucose metabolism, and favorable adipose tissue structure.

The health-promoting effects of functional oligosaccharides have garnered significant attention. However, the physiological effects of gentiooligosaccharide, a novel functional oligosaccharide, remain largely unexplored. In this study, a gentiooligosaccharide-based syrup was synthesized using the crystalline glucose mother liquor as the substrate, and its potential to regulate glycolipid metabolism was evaluated through in vitro fermentation. Then, a high-fat-diet-induced obese mouse was employed to verify the effects. The results demonstrated that the syrup intervention significantly attenuated weight gain in the mice. Further analysis revealed that the syrup could regulate lipid metabolism, decrease ectopic fat deposition, and improve the morphology of liver and adipose tissues. Additionally, the syrup modulated obesity by affecting key metabolic pathways, including bile secretion and fatty acid decomposition, with these effects mediated by alterations in the intestinal microbiota composition. This research lays a solid groundwork for assessing the efficacy of gentiooligosaccharide and creating new syrup products based on functional oligosaccharides.

Premature infants suffer from conditions such as necrotising enterocolitis and sepsis, whose risk is reduced by breastmilk. Rates of breastfeeding are lower in premature infants compared to term infants. Insufficient breastmilk is the most commonly cited reason for breastfeeding termination. Herbal medicines are commonly used for promoting breastmilk production, but their safety and efficacy are unclear. We wanted to assess whether specific herbal galactagogues can safely and effectively increase lactation in mothers who delivered prematurely. Six databases were searched (Medline, Embase, CINAHL, AMED, COCHRANE library, ProQuest Dissertations and Theses Global) with no language or date restrictions. We included randomised controlled trials (RCTs) of herbal galactagogue use in preterm infant mothers. Ten RCTs were included, each investigating a different galactagogue or mixture. Two scored 'high' for risk of bias, the remainder scored 'some concerns'. There was low certainty evidence of an increase in milk volumes by day 7 of the intervention period with barley malt and lemon balm (mean difference 149 ml, 95% CI: 38-260); silymarin in combination with phosphatidylserine and Galega (mean difference 105 ml, 95% CI: 27-183); Pimpinella anisum seed tea (mean difference 98 ml, 95% CI: 63-133); and Latuca sativa (lettuce) syrup (mean difference 82 ml, 95% CI: 60-105). There is a lack of high-quality RCTs on herbal galactagogues within the preterm population. There is low certainty evidence that Barley malt with lemon balm, silymarin phytosomes with Galega, Pimpinella anisum seed tea, Moringa oleifera leaf capsules and Latuca sativa (lettuce) syrup increase breastmilk production. Higher-quality trials are needed to confirm this effect.

Inborn errors of metabolism (IEM) are inherited disorders affecting metabolism which can result in intellectual disability, cognitive impairment or death if left untreated. Nutritional management plays a major role in ensuring adequate growth, nutritional status and development, reducing levels of toxic metabolites, preventing deficiencies and avoiding catabolism in infants with IEM. The aim of this consensus is to provide recommendations for nutritional management of metabolic diseases in neonates and infants in Saudi Arabia, where a high frequency of IEM has been reported.Consensus generation was performed using the Delphi method. Six metabolic dietitians from five hospitals across KSA formed the expert panel. Two face-to face meetings and one virtual meeting were conducted to generate consensus statements. Voting was conducted anonymously on SurveyMonkey to determine the level of agreement with each recommendation.The expert panel reached consensus on 105 recommendations relating to the nutritional management of metabolic disorders, focusing on PA, MMA, GA1, PKU, MSUD, VLCAD, and HCU.These recommendations will facilitate more consistent management of metabolic patients across Saudi Arabia and strive to highlight ongoing challenges faced by dietitians, patients, and caregivers. Future work should focus on outcomes associated with dietary management strategies in Saudi Arabia.