Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia?

Growing interest in gut and digestive processes and their potential link to brain and peripheral based inflammation or biobehavioral phenotypes has led to an increasing number of basic and translational scientific reports focused on the role of gut microbiota within the context of neuropsychiatric disorders. However, the effect of dietary modification on specific gut metabolites, in association with immune, metabolic, and psychopathological functioning in schizophrenia spectrum disorders has not been well characterized. The short chain fatty acids (SCFA) acetate, butyrate, and propionate, major metabolites derived from fermentation of dietary fibers by gut microbes, interact with multiple immune and metabolic pathways. The specific pathways that SCFA are thought to target, are dysregulated in cardiovascular disease, type II diabetes, and systemic inflammation. Most notably, these disorders are consistently linked to an attenuated lifespan in schizophrenia. Although, unhealthy dietary intake patterns and increased prevalence of immune and metabolic dysfunction has been observed in people with schizophrenia; dietary interventions have not been well utilized to target immune or metabolic illness. Prior schizophrenia patient trials primarily focused on the effects of gluten free diets. Findings from these studies indicate that a diet avoiding gluten benefits a limited subset of patients, individuals with celiac disease or non-celiac gluten sensitivity. Therefore, alternative dietary and nutritional modifications such as high-fiber, Mediterranean style, diets that enrich the production of SCFA, while being associated with a minimal likelihood of adverse events, may improve immune and cardiovascular outcomes linked to premature mortality in schizophrenia. With a growing literature demonstrating that SCFA can cross the blood brain barrier and target key inflammatory and metabolic pathways, this article highlights enriching dietary intake for SCFA as a potential adjunctive therapy for people with schizophrenia.

Modifying resilience mechanisms in at-risk individuals: a controlled study of mindfulness training in Marines preparing for deployment.

OBJECTIVE: Military deployment can have profound effects on physical and mental health. Few studies have examined whether interventions prior to deployment can improve mechanisms underlying resilience. Mindfulness-based techniques have been shown to aid recovery from stress and may affect brain-behavior relationships prior to deployment. The authors examined the effect of mindfulness training on resilience mechanisms in active-duty Marines preparing for deployment. METHOD: Eight Marine infantry platoons (N=281) were randomly selected. Four platoons were assigned to receive mindfulness training (N=147) and four were assigned to a training-as-usual control condition (N=134). Platoons were assessed at baseline, 8 weeks after baseline, and during and after a stressful combat training session approximately 9 weeks after baseline. The mindfulness training condition was delivered in the form of 8 weeks of Mindfulness-Based Mind Fitness Training (MMFT), a program comprising 20 hours of classroom instruction plus daily homework exercises. MMFT emphasizes interoceptive awareness, attentional control, and tolerance of present-moment experiences. The main outcome measures were heart rate, breathing rate, plasma neuropeptide Y concentration, score on the Response to Stressful Experiences Scale, and brain activation as measured by functional MRI. RESULTS: Marines who received MMFT showed greater reactivity (heart rate [d=0.43]) and enhanced recovery (heart rate [d=0.67], breathing rate [d=0.93]) after stressful training; lower plasma neuropeptide Y concentration after stressful training (d=0.38); and attenuated blood-oxygen-level-dependent signal in the right insula and anterior cingulate. CONCLUSIONS: The results show that mechanisms related to stress recovery can be modified in healthy individuals prior to stress exposure, with important implications for evidence-based mental health research and treatment.

Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y(2) receptor promoter disrupt multiple transcriptional response motifs.

OBJECTIVES: The neuropeptide Y(2) G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10,000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter. METHODS AND RESULTS: Twin pair studies indicated substantial heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were associated with both BMI (P = 3.75E-04) and PYY (P = 4.01E-06). Computational approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In neuroendocrine cells transfected with NPY2R promoter/luciferase reporter plasmids, all three variants and their resulting haplotypes influenced transcription (G-1606A, P < 2.97E-06; C-599T, P < 1.17E-06; A-224G, P < 2.04E-06), and transcription was differentially augmented or impaired by coexpression of either the cognate full-length transcription factors or their specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) of a rodent model of hypertension and the metabolic syndrome, the spontaneously hypertensive rat. CONCLUSION: We conclude that common genetic variation in the proximal NPY2R promoter influences transcription factor binding so as to alter gene expression in neuroendocrine cells, and consequently cardiometabolic traits in humans. These results unveil a novel control point, whereby cis-acting genetic variation contributes to control of complex cardiometabolic traits, and point to new transcriptional strategies for intervention into neuropeptide actions and their cardiometabolic consequences.

Cell-bound complement activation products (CB-CAPs) as a source of lupus biomarkers.

Measurement of serum C3 and C4 has been used for several decades to monitor disease activity in patients with SLE. Despite the limited utility and recognized weaknesses of these assays, they have remained the gold standard during an era of unprecedented discovery in the complement field. The current urgent need for lupus biomarkers warrants efforts to mine the complement system for assays superior to serum C3 and C4. Recent studies of soluble and cell-bound complement activation products hold promise for achieving this goal.