International Journal of Molecular Sciences

Inflammation and gut dysbiosis are increasingly recognized as important contributors to the pathophysiology of Parkinson’s disease (PD). Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic strategy aimed at restoring gut microbial balance and modulating inflammatory pathways. The aim of the study was to evaluate the effect of single fecal microbiota transplantation on systemic and gut-related inflammatory biomarkers in patients with PD. This exploratory analysis was conducted as part of the randomized, double-blind, placebo-controlled EFFACE-PD study. Fifty-nine participants with PD were randomized to receive either donor-derived FMT or placebo. Serum levels of IL-18 and calprotectin were measured using ELISA before intervention and 3 months after the procedure. Ferritin, leukocyte count, neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio (NLR) were assessed at baseline and after twelve months. No statistically significant between-group differences in changes in inflammatory biomarker concentrations were observed. Broader inflammatory markers, including ferritin and leukocyte parameters, also did not differ significantly between groups. We conclude that single FMT did not induce significant changes in systemic inflammatory biomarkers in this exploratory cohort of PD patients. Larger studies with standardized inflammatory assessments are needed to clarify the immunomodulatory effects of FMT in PD.

The ileal ASBT bile acid transporter is a critical mediator of bile acid and cholesterol homeostasis and is modulated by fatty acids via S-acylation. We investigated mechanisms underlying differential regulation of ASBT by saturated and polyunsaturated fatty acids. Using a prenylation mimetic with a CAAX box at the C-terminus of ASBT, we showed that transport activity in transfected HEK293 cells increased significantly, suggesting that direct attachment of a saturated fatty acid stimulates ASBT function. Furthermore, siRNA-mediated attenuation of DHHC21 acyltransferase expression reduced ASBT S-acylation and its function, demonstrating DHHC21 as a positive regulator of ASBT function. Conversely, treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs), like eicosapentaenoic acid (EPA), reduced ASBT function in HEK293 cells. Supplementation of fish oil, as a source of n-3 PUFAs, to a high-fat, high-cholesterol diet fed to C57BL6/J mice protected them against diet-induced hepatic steatosis, along with reduced bile acid absorption consistent with the inhibition of ASBT. This was supported by increased fecal bile acids, decreased ileal bile acid-stimulated gene expression, and increased hepatic bile acid synthesis-related gene expression. Metabolic labeling with alkyne-EPA in HEK293 cells showed, for the first time, direct binding of this n-3 PUFA to ASBT. Unlike palmitate modification, EPA binding was highly resistant to hydroxylamine retrieval, indicating a mechanism distinct from S-acylation. Our data unraveled a novel role for DHHC21 in regulating ASBT and provided evidence for distinct mechanisms by which saturated palmitate and polyunsaturated EPA fatty acids bind ASBT. The direct effect on ASBT and inhibition of bile acid absorption may partly contribute to the protective effects of n-3 PUFAs on the liver.

Cardiometabolic disorders are accompanied by persistent immune activation that links metabolic stress to vascular and organ injury. Conventional inflammatory measures capture part of this process, but they provide limited information about tissue origin, biological mechanism and disease trajectory. This narrative review examines emerging biomarkers across genetic and epigenetic regulation, metabolic and oxidative stress, gut microbial exposure, innate immune activation, adaptive immune remodeling and circulating inflammatory responses. It integrates mechanistic studies with clinical observations to consider how these signals may inform the assessment of cardiometabolic immune injury. Particular attention is given to the distinction between inherited susceptibility and acquired responses, circulating associations and tissue mechanisms, and potentially injurious versus compensatory immune activity. The evidence supports substantial biological connectivity among these domains, while the strength of clinical validation varies widely. Most candidate markers and proposed combinations require standardized measurement, longitudinal assessment and external validation before biomarker-guided prevention can be justified. We propose a mechanism-informed framework for organizing candidate immune-metabolic phenotypes, recognizing reciprocal interactions rather than a universal temporal sequence. Future studies should determine whether these biomarkers improve prediction and clinical decisions beyond established risk factors and whether changes in biomarker profiles correspond to meaningful treatment benefits.