Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson's disease.

Parkinson's disease (PD) is the most common progressive neurological disorder compromising motor functions. However, nonmotor symptoms, such as gastrointestinal (GI) dysfunction, precede those affecting movement. Evidence of an early involvement of the GI tract and enteric nervous system highlights the need for better understanding of the role of gut microbiota in GI complications in PD. Here, we investigate the gut microbiome of patients with PD using metagenomics and serum metabolomics. We integrate these data using metabolic modeling and construct an integrative correlation network giving insight into key microbial species linked with disease severity, GI dysfunction, and age of patients with PD. Functional analysis reveals an increased microbial capability to degrade mucin and host glycans in PD. Personalized community-level metabolic modeling reveals the microbial contribution to folate deficiency and hyperhomocysteinemia observed in patients with PD. The metabolic modeling approach could be applied to uncover gut microbial metabolic contributions to PD pathophysiology.

Vascular Protection of TPE-CA on Hyperhomocysteinemia-induced Vascular Endothelial Dysfunction through AA Metabolism Modulated CYPs Pathway.

A high concentration of homocysteine (Hcy) in plasma induces vascular endothelial dysfunction, and it may ultimately accelerate the development of cardiovascular diseases (CVDs). Although several B vitamins have been clinically applied for hyperhomocysteinemia (HHcy) treatment, the outcomes are not satisfied due to their limited therapeutic mechanism. Hence, in order to improve the curative effect, development of new effective therapeutic strategies should be put on the agenda. Total phenolic extracts of Citrus aurantium L. (TPE-CA) is a naturally obtained phenolic mixture, mainly containing flavones, flavanones and their glycosyl derivatives, flavonols, polymethoxyflavones and coumarins. Previous reports indicated that bioactive phenolic compounds possessed potent vascular protective effects and regarded as a protective agent against CVDs. Intriguingly, the exact mechanism underlying the suppressed effects of TPE-CA on HHcy could assist in revealing their therapy on CVDs. Here, the multi-targeted synergistic mechanism of TPE-CA on HHcy-induced vascular endothelial dysfunction was uncovered in a deduced manner. TPE-CA treatment exhibited an obvious superiority than that of B vitamins treatment. Network pharmacology was employed to identify the interrelationships among compounds, potential targets and putative pathways. Further experimental validation suggested that the treatment of TPE-CA for HHcy could not only effectively reduce the Hcy level in plasma through up-regulating transsulfuration pathway in Hcy metabolism, but also restore the HHcy-induced vascular endothelial dysfunction by activating cytochrome P450 enzymes (CYPs) epoxygenase signal cascades and inhibiting CYPs hydroxylase signal cascades in arachidonic acid (AA) metabolism.

Association of hyperhomocysteinemia and Chlamydia pneumoniae infection with carotid atherosclerosis and coronary artery disease in Japanese patients.

An elevated plasma level of homocysteine (Hcy) and infection by Chlamydia pneumoniae (C. pneumoniae) have been suggested as independent risk factors for carotid atherosclerosis (CA) and coronary artery disease (CAD), but the mechanisms involved are unclear. We investigated the correlation between positivity for antibody to C. pneumonia (anti-C. pneumoniae) and the Hcy level in patients with CA and CAD. The total plasma homocysteine (tHcy) concentration was determined in 99 patients with CA and 31 patients with CAD, as well as 119 controls with matched risk factors for atherosclerosis. The tHcy level was measured with a Bio-Rad microplate enzyme immunoassay. In the CAD group, the tHcy level (13.67 micromol/l) was significantly higher than that in other groups (CA group, 10.96 micromol/l; control group, 9.95 micromol/l; ANOVA, P = 0.0006). Positivity for anti-C. pneumoniae IgG was significantly more common in the CAD group (77.4%) than in the other groups (CA group, 53.5%; control group, 54.6%; ANOVA, P = 0.0490). There was no association between anti-C. pneumoniae IgA positivity or tHcy and conventional risk factors. However, anti-C. pneumoniae IgG positivity was significantly more common in subjects with higher tHcy levels than in those with low tHcy levels from each of the 3 groups. The CAD group had significantly higher tHcy levels, and tHcy was significantly associated with anti-C. pneumoniae IgG positivity. These findings indicate that elevation of tHcy is related to positivity for anti-C. pneumoniae IgG in patients with CAD.

Adverse event associated with methionine loading test: a case report.

The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer's disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care.