Search Results (551)

Isolated REM sleep behavior disorder (iRBD) is among the most reliable prodromal markers of α-synucleinopathies. Under the body-first (gut-first) model of α-synuclein pathology, in which pathology may originate in the enteric nervous system and ascend to the brain, the gut is a biologically plausible compartment in which early and accessible molecular alterations might be detectable; however, the fecal metabolome remains poorly investigated in this population. In this exploratory, cross-sectional study of 21 iRBD patients and 15 healthy controls, we characterized fecal samples through an integrated multi-omics framework. The fecal metabolome was profiled on two complementary mass spectrometry platforms: HS-SPME GC-EI-high-resolution MS, used for both untargeted volatilomics and targeted quantification of linear and branched short-chain fatty acids, and untargeted LC-MS/MS for the non-volatile fraction. Gut microbial community composition was characterized on the same material by 16S rRNA gene sequencing, and the metabolomic and microbial layers were combined by DIABLO multi-omics integration. Linear short-chain fatty acids were preserved, whereas branched-chain fatty acids were selectively increased in iRBD, indicating a shift toward proteolytic fermentation. Volatile indole was reduced, while p-cresol and 2-octanone were increased, paralleled at the LC-MS/MS level by attenuation of the tryptophan–indole axis, class-level bile acid depletion, and increased acylcarnitines. The microbiome was depleted of Blautia and Faecalibacterium and enriched in Oscillospirales. Integration resolved a coherent host-microbe signature that discriminated iRBD patients from controls within this discovery cohort (84.8% cross-validated accuracy). These cross-sectional findings characterize candidate fecal signatures associated with iRBD; given the exploratory design and the limited sample size, they are hypothesis-generating, and their value for predicting phenoconversion remains to be established in prospective studies. Full article

The conceptualization of Parkinson’s disease (PD) has shifted from a strictly central neurodegenerative disorder to a systemic synucleinopathy that may, in some patients, originate in the enteric nervous system. This review synthesizes recent evidence highlighting the potential role of sulfate-reducing Desulfovibrio (DSV) bacteria as candidate pathobionts in the proposed “gut-first” pathogenic cascade. By colonizing anaerobic niches within the colon and metabolizing dietary sulfur compounds, DSV generate hydrogen sulfide (H₂S), a gaseous metabolite that may compromise intestinal barrier integrity and impair mitochondrial function through the inhibition of cytochrome c oxidase. These processes have been associated with ATP depletion, cytochrome c release, and iron-dependent oxidative stress, creating conditions that may favor α-synuclein misfolding and aggregation within enteroendocrine cells. We further examine evidence supporting the retrograde propagation of α-synuclein pathology from the gut to the brain via the vagus nerve—a hypothesis strengthened by experimental findings and epidemiological observations, including studies reporting reduced PD risk following truncal vagotomy. Although the increased prevalence of DSV in PD patients suggests potential applications in prodromal diagnostics and microbiome-based risk stratification, a definitive causal relationship has yet to be established. We therefore discuss key methodological limitations, including biases associated with 16S rRNA sequencing and the current lack of robust in vivo metabolomic evidence. Finally, we consider whether targeted modulation of the intestinal environment, including DSV-specific bacteriophages and [FeFe]-hydrogenase inhibitors, could emerge as a future strategy for influencing early disease processes. Full article

Background/Objectives: The enteric nervous system (ENS) is essential for gastrointestinal homeostasis and is vulnerable to oxidative imbalance associated with inflammatory, metabolic, and neurodegenerative disorders. However, research linking the ENS and oxidative stress has not been comprehensively mapped. This study characterized the temporal evolution, productivity patterns, collaboration networks, geographical distribution, and thematic structure of this field. Methods: Original research articles were retrieved from the Web of Science Core Collection, Scopus, and PubMed from database inception to 12 September 2026. Records were merged, deduplicated, screened, and harmonized before analysis. Bibliometrix/Biblioshiny and VOSviewer were used to assess annual production, Lotka’s and Bradford’s laws, author and journal productivity, collaboration networks, keyword co-occurrence, trend topics, thematic evolution, and thematic mapping. Results: A total of 251 original articles published between 1989 and 2026 were included. Scientific production showed an annual growth rate of 6.95%, with peaks in 2016 and 2021. Author productivity followed a Lotka-type distribution, and journal dispersion was compatible with Bradford’s law. Brazil had the largest number of corresponding-author publications, followed by the United States and China. Keyword analyses identified recurrent themes involving diabetes mellitus, inflammation, enteric glial cells, Parkinson’s disease, antioxidant mechanisms, neuroprotection, and aging. Temporal analyses indicated increasing integration of neurodegenerative, glial, and gut–brain-related topics. Conclusions: Research linking the ENS and oxidative stress has expanded and diversified over time. The field combines established metabolic and redox-oriented research with increasing attention to inflammatory, neurodegenerative, glial, and gut–brain perspectives within heterogeneous international collaboration networks. Full article

Micro- and nanoplastics (MNPs) have emerged as ubiquitous environmental contaminants, with dietary ingestion serving as the primary route of human exposure. While their capacity to induce localized epithelial damage is well recognized, recent evidence suggests that MNPs can alter the complex regulatory networks governing gastrointestinal (GI) transit. The objective of this narrative review is to evaluate the role of MNP exposure as a possible pathogenic factor in GI dysmotility, assessing the intersection of neuromuscular toxicity, microbial dysbiosis, and barrier failure. A comprehensive literature search was conducted across major biomedical databases to synthesize emerging biomonitoring studies, preclinical models, and clinical correlations from the past five years characterizing MNP-mediated intestinal dysfunction. Ingestion of MNPs triggers a distinct, size-dependent, multifaceted, interconnected pathological triad characterized by ensuing oxidative stress, physical barrier dysfunction, and extensive microbiome reconfiguration. Rather than strict, isolated events, these insults interact in a self-perpetuating feedback loop. On a cellular level, nano-sized particles translocate across the intestinal lining via paracellular transport, persorption, or transcytosis, embedding into cell membranes and downregulating key tight junction (TJ) proteins (ZO-1, occludin, claudins). This mechanical and chemical disruption yields an overproduction of reactive oxygen species (ROS) and a concomitant reduction in anti-inflammatory, short-chain fatty acid (SCFA)-producing bacterial taxa (e.g., Bacteroidetes, Faecalibacterium, Roseburia). Crucially, this resulting mucosal disruption converges on the enteric nervous system (ENS). MNPs induce neuroendocrine derangements by perturbing cholinergic neurotransmission—characterized by acetylcholinesterase (AChE) inhibition, aberrant synaptic acetylcholine dynamics, and subsequent downregulation of muscarinic acetylcholine receptors (mAChRs)—ultimately resulting in uncoordinated smooth muscle contractility and delayed transit. In murine models, this enteric neuropathy manifests phenotypically as structural intestinal shortening, delayed gastric emptying, and chronic constipation. The intestinal defense network is susceptible to MNP bioaccumulation, wherein particle-induced barrier failure and microbial dysbiosis may contribute to downstream neuromuscular dysmotility. Understanding this interconnected oxidative-barrier–microbiome–neuromuscular axis is essential, positioning environmental plastic contamination as an emerging, potentially modifiable factor in the pathogenesis of functional bowel disorders. Full article

Sleep and the gastrointestinal (GI) tract interact in a complex and reciprocal relationship, although the molecular and physiological pathways underlying this interaction remain only partially defined. Communication between the central (CNS) and enteric nervous systems (ENS) spans neural, immune, endocrine, and metabolic pathways, including vagal nerve signaling, the hypothalamic–pituitary–adrenal (HPA) axis, gut-resident microbiota, and circulating microbial metabolites, such as bile acids with neuroinflammatory or neurotransmitter activity. In this narrative review, we synthesize evidence from animal models, observational cohorts, and intervention trials to map this bidirectional axis, focusing on several underexamined modulatory mechanisms including the interaction between the gut microbiome and the glymphatic system, the brain’s perivascular waste-clearance network, which is implicated in the removal of amyloid-β (Aβ) and tau in Alzheimer’s disease; neuroendocrine regulation and sex-related differences in gut microbiome composition and sleep patterns, which may help explain the divergent neurodegenerative disease risks between men and women; and age-related parallel trajectories of microbiome senescence and sleep fragmentation in older adults. We discuss melatonin, cortisol, estrogen, and ghrelin as endocrine mediators linking circadian biology to gut physiology, and we consider how environmental and lifestyle factors further perturb this system. These mechanisms form an integrative framework of the gut–brain–sleep axis and highlight priority directions for mechanistic and translational research, including significant nodes in this pathway where targeted interventions may help cognitive resilience and slow the neurodegenerative disease progression. More research clarifying these mechanisms may help identify the most promising targets, potentially leading to personalized, precision-medicine-based therapeutic strategies. Full article

Glyphosate is a widely used herbicide, yet its effects on the enteric nervous system (ENS) remain poorly understood. This study investigated the effects of low-dose glyphosate exposure on substance P (SP)-immunoreactive neurons and tachykinin receptor gene expression in the porcine small intestine. Fifteen juvenile pigs were assigned to three groups (n = 5 per group): a control group and two groups receiving oral glyphosate for 28 days at doses corresponding to the estimated maximum daily intake in Europe (0.05 mg/kg BW/day) and the acceptable daily intake (0.5 mg/kg BW/day). Double immunofluorescence was used to determine the percentage of SP-immunoreactive neurons in the myenteric (MP), outer submucosal (OSP), and inner submucosal (ISP) plexuses of the duodenum, jejunum, and ileum. The expression of TACR1, TACR2, and TACR3 was analysed by RT-qPCR. Glyphosate exposure increased the percentage of SP-immunoreactive neurons in all analysed intestinal segments and plexuses, with a clear dose-related pattern. TACR2 mRNA expression was significantly increased in the duodenum in both glyphosate-exposed groups but decreased in the ileum at the higher glyphosate dose. TACR3 mRNA expression was significantly decreased in the duodenum in both exposed groups and in the jejunum at the higher dose, whereas TACR1 expression remained unchanged. SOD activity was significantly increased in the duodenum and ileum of pigs exposed to the higher glyphosate dose, whereas no significant changes were observed in the jejunum. These findings demonstrate that low-dose glyphosate exposure is associated with region-specific alterations in selected components of the enteric tachykinin system, indicating a complex neurochemical response of the ENS to glyphosate. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the deposition of Lewy bodies (LBs). The gut–brain axis has emerged as a potential route for the bidirectional dissemination of PD pathology, in which the enteric and central nervous systems may contribute to the spread of misfolded α-synuclein (α-Syn) and associated neuroinflammatory responses. However, neural pathways alone may not fully account for the widespread distribution of PD pathology across the brain and gut. As another major conduit connecting the gut and the brain, the peripheral circulation may provide an additional route for PD-related pathological processes. Nevertheless, how blood circulation contributes to the development and dissemination of pathology along the gut–brain axis remains underexplored. Accordingly, this narrative review examines peripheral blood as a potential additional route for pathological communication along the gut–brain axis, focusing on two potential mechanisms involving the transport of pathological α-Syn aggregates between the gut and the brain and the circulation of inflammatory signals associated with gut microbiota dysbiosis. Furthermore, to highlight the translational relevance of the gut–blood–brain axis, we briefly summarize recent advances in related blood-derived biomarkers and therapeutic strategies targeting these pathways. Full article

Adipose tissue secretes bioactive mediators known as adipokines. Beyond their well-established roles in energy homeostasis, appetite regulation, insulin sensitivity, and inflammation, adipokines have emerged as important modulators of inter-organ communication, influencing cardiovascular, neural, immune, and respiratory functions. Growing evidence indicates that many of these effects involve nitric oxide (NO) signaling. NO is produced by three major nitric oxide synthase (NOS) isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Experimental evidence indicates that leptin, adiponectin, and resistin can modulate NOS expression or activity and NO bioavailability in a tissue- and context-dependent manner. In the gastrointestinal tract, these adipokines can influence nitrergic signaling and motility in ex vivo rodent preparations. In this review, we compare leptin–, adiponectin–, and resistin–NOS interactions across multiple organs, evaluating direct findings and their possible involvement in enteric nitrergic neurotransmission and gastrointestinal motor regulation. We highlight an emerging three-way regulatory pattern in which leptin appears to exert context-dependent actions, adiponectin predominantly preserves constitutive nitrergic signaling, and resistin shows acute versus chronic effects that may depend on exposure duration. Although direct enteric evidence remains limited and human studies are needed, a better understanding of adipokine-dependent NOS regulation might provide potential therapeutic approaches for gastrointestinal dysmotility. Full article

Recent years have seen growing medical interest in the influence of crosstalk between the gut microbiota and the endocannabinoidome (eCBome) on inflammation and pain modulation. Growing evidence indicates that gut microbiota can modify the effects of several marketed drugs, including analgesics. Cannabigerol (CBG) is an overlooked phytocannabinoid with a broad pharmacological spectrum and no psychotropic effects, which has anti-inflammatory and antinociceptive properties. This review aims to provide a comprehensive exploration of CBG and its role at the intersection of gut microbiota and eCBome, detailing the pharmacological mechanisms by which it acts as a promising therapeutic agent to modulate chronic inflammation and pain. Our data review suggests that CBG could act on the eCBome by activating CB2, PPARs, TRPV1, TRPA1, and α2-adrenergic receptors, while suppressing cellular and molecular mechanisms of inflammation, such as TNFα, COX-2, iNOS, IL-1β, and IL-6, and increasing antioxidant factors. These receptors and enzymes are distributed across neurons, glial, immune, and epithelial cells, which can also positively modulate gut microbiota and its metabolites, producing neurotransmitters, cytokines, and enzymes that regulate eCBome tone, and generating cannabinoid-mimetic compounds as part of pleiotropic functions. Nevertheless, CBG may exert direct effects on gut microbiota, promoting eubiosis and symbiotic bacteria. Moreover, there are no specific preclinical assays that demonstrate how CBG modulates the bidirectional communication between the gut microbiota and eCBome, addressing the specific mechanism involved in eCBome activation, and determining whether its anti-inflammatory and analgesic effects are dependent on gut microbiota type. Therefore, studies are required to evaluate this hypothesis to achieve translational medicine impact. Full article

Oxygen availability is a key regulator of organ maturation during the perinatal period. Disruption of physiological oxygen homeostasis contributes to prematurity-associated disorders, yet its effects on the coordinated maturation of the enteric nervous system (ENS) and gut microbiome remain poorly understood. Because β3-adrenergic receptor (β3-AR) signaling has emerged as a mediator of tissue adaptation to oxygen, we investigated whether activation of this pathway modulates hyperoxia-induced alterations in the developing colon. Newborn rats were exposed to normoxia or hyperoxia (85% O₂) from birth to postnatal day 14 and treated with the β3-AR agonist BRL37344 (1 or 3 mg/kg). Enteric neuronal and glial populations were evaluated by quantitative immunofluorescence, whereas the colonic microbiome (CM) was characterized by 16S rRNA gene sequencing. Hyperoxia reduced neuronal density and altered neurochemical coding within the submucosal plexus, disrupted enteric glial organization in both the colonic submucosal plexus and mucosa, and remodeled the intestinal microbiome without affecting overall community diversity. BRL37344 treatment partially preserved submucosal neurochemical coding, modulated neuron–glia organization within the submucosal plexus, prevented the loss of mucosal enteric glial cells, and reshaped microbial composition. Collectively, these findings demonstrate that neonatal hyperoxia disrupts coordinated postnatal maturation of the ENS and CM and indicate that β3-AR signaling may contribute to postnatal intestinal adaptation to neonatal oxygen imbalance. Full article

Background/Objectives: Antiseizure drugs (ASDs) are the primary therapeutic approach for epilepsy in small animals. Although ASDs are primarily used to modulate central neuronal excitability, they are commonly administered systemically, most often by the oral route, and may therefore influence neuronal populations outside the central nervous system. Nevertheless, their functional effects on peripheral neuronal populations, including enteric and dorsal root ganglion (DRG) neurons, remain incompletely characterized at a comparative pharmacological level. This study aimed to perform a comparative functional neuropharmacological profiling of commonly used ASDs in primary cultured myenteric and DRG neurons. Methods: Changes in neuronal activity were assessed in primary cultured guinea pig myenteric and DRG neurons using voltage-sensitive dye imaging with Di-8-ANEPPS following direct ASD application under standardized in vitro conditions. Results: ASDs exerted distinct drug- and neuron-type-specific effects on peripheral neuronal excitability. Topiramate induced the most pronounced reduction in neuronal excitability in myenteric neurons, whereas phenobarbital and levetiracetam produced only minor changes compared with buffer control. Potassium bromide induced mainly excitatory effects in both enteric and DRG neurons. Overall, most ASDs predominantly increased neuronal excitability in DRG neurons. Conclusions: These findings demonstrate distinct functional response profiles of ASDs in enteric and sensory neuronal populations. This comparative in vitro approach may provide a basis for future studies investigating peripheral neuronal drug effects and may help relate experimental pharmacological profiling to clinically relevant challenges associated with ASD treatment across different disorders. Full article

Background/Objectives: Gastroparesis is a disorder in which individuals experience dysfunctional gastric motor symptoms, but the underlying etiology is unclear. This exploratory study investigates autoimmune, inflammatory, metabolic, autonomic, and enteric (AIMAE) abnormalities in patients with gastroparesis symptoms to provide new insights into pathophysiology. The aim of this study is to further elucidate the potential associations between the different AIMAE measurements. Methods: Twenty-one patients with gastroparesis symptoms underwent a series of testing including assays for measurement of autoimmune, inflammatory, and metabolic markers; measurement of the autonomic nervous system; electrogastrography recordings; and gastric emptying measurements. Associations were evaluated using Spearman’s rank correlation with pairwise-complete observations. Benjamini–Hochberg false-discovery-rate correction was applied separately within each prespecified statistical family, with q ≤ 0.05 defining statistical significance. Results: Across 3432 planned correlations in 10 prespecified families, four associations met the false-discovery-rate threshold. DFS-70 was positively associated with C-peptide (q= 0.000330). Low-resolution EGG S1 mean amplitude was positively associated with insulin (q = 0.000172). IL-6 was inversely associated with baseline sympathetic LFa modulation (q = 0.000172) and standing sympathetic LFa modulation (q = 0.000172). Conclusions: This prospective pilot study identified strong associations among autoimmune, inflammatory, metabolic, enteric, and autonomic measurements. The findings were robust to leave-one-out analyses and generally retained their direction and magnitude after excluding participants with diabetes or a gastric electrical stimulator. However, the results of this study should be interpreted as hypothesis-generating rather than causal due to its limitations including a small cohort and incomplete confounder information. Full article

Diabetes mellitus is frequently associated with gastrointestinal dysfunction, in which alterations in the enteric nervous system (ENS) are considered important contributing factors. Neuropeptide Y (NPY) is a key enteric neuromodulator involved in the regulation of gastrointestinal motility, secretion, and blood flow; however, its response to diabetes remains insufficiently characterized, particularly in large animal models. This study investigated the effect of experimental diabetes on the distribution of NPY-immunoreactive enteric neurons in the porcine gastrointestinal tract. Diabetes was induced in juvenile female pigs by streptozotocin administration. Six weeks later, the stomach, duodenum, jejunum, ileum, and descending colon were collected, and the population of NPY-immunoreactive neurons in the myenteric and submucosal plexuses was evaluated by double-label immunofluorescence. Experimental diabetes significantly increased the population of NPY-immunoreactive neurons in the myenteric plexus of the stomach, jejunum, ileum, and descending colon, whereas no statistically significant changes were detected in the duodenum after correction for multiple comparisons. In the submucosal plexuses, significant increases were restricted to the inner and outer submucosal plexuses of the descending colon. These findings demonstrate that diabetes induces region- and plexus-specific neurochemical plasticity of NPY-immunoreactive enteric neurons in pigs. Given the predominantly inhibitory effects of NPY on gastrointestinal motility and secretion, together with its vasoconstrictive actions, the observed changes may contribute to altered neural regulation of gastrointestinal function during diabetes and may represent one of the mechanisms involved in diabetic gastroenteropathy. Full article

Background/Objectives: Microplastics (MPs) and nanoplastics (NPs) have emerged as ubiquitous environmental contaminants resulting from the extensive production, use, and degradation of plastic materials. Human exposure occurs primarily through contaminated food and drinking water, with inhalation representing an additional important route. Growing concern has focused on the ability of these particles, particularly NPs, to cross biological barriers, enter the systemic circulation, and reach human tissues. The aim of this review was to summarize current evidence on dietary exposure to MPs and NPs, their gastrointestinal bioavailability and toxicokinetics, and their potential systemic health effects, with particular emphasis on organ-specific responses, underlying biological mechanisms, and the strength and limitations of the available evidence. Methods: A comprehensive narrative review of the scientific literature published between 2000 and 2026 was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Original research articles and review papers addressing dietary exposure, occurrence in food and drinking water, migration from food-contact materials, gastrointestinal absorption, translocation, biodistribution, bioaccumulation, elimination, molecular mechanisms, and potential organ-specific or systemic health effects were included. Publications without full-text availability, conference proceedings, editorials, commentaries, duplicate publications, and studies without relevance to human exposure or health were excluded. Results: Food, drinking water, beverages, and food-contact materials represent important sources of human exposure to MPs and NPs. Following ingestion, most larger particles are eliminated through the gastrointestinal tract, whereas smaller MPs and particularly NPs may cross biological barriers and potentially reach the systemic circulation and distant tissues. Experimental studies consistently identify interconnected biological responses involving oxidative stress, inflammation, mitochondrial dysfunction, barrier impairment, immune dysregulation, genotoxicity, apoptosis, and endocrine disruption. These mechanisms have been associated with alterations in the gastrointestinal, respiratory, cardiovascular, nervous, urinary, reproductive, endocrine, and skeletal systems and with biological processes relevant to carcinogenesis. However, most mechanistic evidence derives from in vitro and animal models, whereas human evidence remains limited and predominantly observational. Consequently, the extent to which these experimental findings translate into clinically significant effects in humans remains uncertain. Conclusions: Current evidence supports the biological plausibility of systemic effects associated with MNP exposure but is insufficient to establish causal relationships between chronic dietary exposure and specific human diseases. The detection of MNPs in human tissues and reported associations with pathological conditions should therefore be interpreted cautiously. Standardized analytical methods, improved characterization of realistic human exposure, and well-designed longitudinal epidemiological studies integrating quantitative exposure assessment with validated clinical outcomes are required to clarify dose–response relationships, long-term health effects, and the clinical significance of MNP exposure. Full article

Prenatal alcohol exposure (PAE) leads to fetal alcohol spectrum disorder (FASD), the most common preventable cause of neurodevelopmental impairment. The classical narrative attributes the clinical picture of FASD exclusively to direct ethanol-induced brain injury. In the present review, we argue that this perspective is incomplete and leads to diagnostic errors, most often to the misdiagnosis of ADHD in children who in fact have FASD. We propose that, alongside the direct neurotoxicity of ethanol, an important and clinically under-recognized complementary mechanism is gut–brain axis dysfunction: alcohol damages the enteric nervous system and enteric glial cells, induces dysbiosis with deep deficits of butyrate and other short-chain fatty acids (SCFAs), damages the enterochromaffin cells responsible for 90% of peripheral serotonin production, and—through translocation of lipopolysaccharide (LPS) and activation of the Toll-like receptor 4 (TLR4)—sustains a neuroinflammatory brain signature. This cascade—superimposed on direct ethanol neurotoxicity—may account for the high rates of depression, anxiety, self-injurious behavior, and suicide attempts observed in individuals with FASD and for the limited efficacy of traditional interventions focused solely on the central nervous system. The 2024 Polish Institute of Mother and Child (Okulicz-Kozaryn et al.) study showed that 50.3% of pregnant women consumed alcohol, and 11% did so regularly, against only 7% who admitted so in questionnaires. The real clinical picture of children with FASD is further complicated by three factors to which we devote separate sections in this paper: prenatal co-exposure to nicotine, cannabinoids, and opioids; the loss of vertical microbiota transmission and breastfeeding in children transferred to foster care (where the prevalence of FASD is 18.8% and in children’s homes in some regions reaches up to 80%); and the substantial over-representation of preterm and small-for-gestational-age (SGA) infants (in the Hasken et al. cohort, 18.4% of children with FASD were born preterm and 51.4% were born SGA). In the final section, we present a structured, staged protocol for nutritional and microbiological intervention grounded in a hierarchy of evidence: from interventions supported by randomized controlled trials (RCT-level; choline) through interventions supported by strong mechanistic rationale and RCTs in related populations (sodium butyrate, Lactobacillus rhamnosus GG, GOS/FOS prebiotics—galacto-oligosaccharides and fructo-oligosaccharides, and omega-3 fatty acids) to experimental interventions. The protocol also covers the window before 2 years of age: we argue that, given the over-representation of preterm and SGA infants among children with FASD, the analogy to preterm infants on parenteral nutrition and to post-institutional infants applies in substantial part to the same patients, which justifies extending the indications for choline and other nutritional interventions. The paper includes a compact table of dosing proposals for each age window (from pregnancy to school-age child) and provides clinicians with concrete answers: where to start, what to avoid, and what to monitor, with explicit signposting of regulatory limitations for individual substances in Poland and the European Union. Full article