Nutraceuticals in the Modulation of the Intestinal Microbiota: Current Status and Future Directions

Pharmaceutical interest in the human intestinal microbiota has increased considerably, because of the increasing number of studies linking the human intestinal microbial ecology to an increasing number of non-communicable diseases. Many efforts at modulating the gut microbiota have been made using probiotics, prebiotics and recently postbiotics. However, there are other, still little-explored opportunities from a pharmaceutical point of view, which appear promising to obtain modifications of the microbiota structure and functions. This review summarizes all in vitro, in vivo and clinical studies demonstrating the possibility to positively modulate the intestinal microbiota by using probiotics, prebiotics, postbiotics, essential oils, fungus and officinal plants. For the future, clinical studies investigating the ability to impact the intestinal microbiota especially by using fungus, officinal and aromatic plants or their extracts are required. This knowledge could lead to effective microbiome modulations that might support the pharmacological therapy of most non-communicable diseases in a near future

Antioxidant, anti-inflammatory, and microbial-modulating activities of essential oils: Implications in colonic pathophysiology

Essential oils (EOs) are a complex mixture of hydrophobic and volatile compounds synthesized from aromatic plants, most of them commonly used in the human diet. In recent years, many studies have analyzed their antimicrobial, antioxidant, anti-inflammatory, immunomodulatory and anticancer properties in vitro and on experimentally induced animal models of colitis and colorectal cancer. However, there are still few clinical studies aimed to understand their role in the modulation of the intestinal pathophysiology. Many EOs and some of their molecules have demonstrated their efficacy in inhibiting bacterial, fungi and virus replication and in modulating the inflammatory and oxidative processes that take place in experimental colitis. In addition to this, their antitumor activity against colorectal cancer models makes them extremely interesting compounds for the modulation of the pathophysiology of the large bowel. The characterization of these EOs is made difficult by their complexity and by the different compositions present in the same oil having different geographical origins. This review tries to shift the focus from the EOs to their individual compounds, to expand their possible applications in modulating colon pathophysiology

Ulk4 regulates GABAergic signaling and anxiety-related behavior

Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4(+/tm1a) mice, demonstrating that Ulk4(+/tm1a) mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4(+/tm1a) mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67⁺ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4(+/tm1a) mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments

Helplessness: a systematic translational review of theory and evidence for its relevance to understanding and treating depression

Helplessness is a major concept in depression and a major theme in preclinical and clinical depression research. For example, in rodents and humans, the learned helplessness (LH) effect describes a specific deficit in behaviour to control aversive stimuli that is induced by prior exposure to uncontrollable aversive stimuli. The LH effect is objective and valid in that the cause of the behavioural deficit, namely uncontrollability, is clear; furthermore, the deficit induced is underlain by emotional, motivational and cognitive processes that are relevant to depression psychopathology. As a further example, helplessness, hopelessness, external locus of control and causal attribution are inter-related and major themes in psychological theories (primarily cognitive theories) of depression. Despite this broad interest in helplessness, it can be argued that its potential usefulness as a scientific and clinical concept has so far not been investigated optimally, including with respect to its application in research aimed at development of improved anti-depressant pharmacotherapy. The first aim of this review was to describe and integrate the psychological evidence and the neurobiological evidence for the LH effect in rodents and healthy humans and for helplessness in depressed patients. The second aim was to conduct three systematic reviews, namely of rodent studies of the LH effect, rodent studies of effects of psychopharmacological agents on the LH effect, and human studies of efficacy of pharmacotherapeutic and psychotherapeutic treatment on helplessness in depressed patients. With respect to the first aim, the major findings are: the specificity of the LH effect in otherwise non-manipulated rodents and healthy humans has been under-estimated, and the LH effect is a specific learned aversive uncontrollability (LAU) effect. There is theoretical and empirical support for a model in which a specific LAU effect induced by a life event of major emotional significance can function as an aetiological factor for generalised helplessness which can in turn function as an aetiological and maintenance factor for depression. However, to date such models have focused on cognitive mediating processes whereas it is emotional-motivational-cognitive processes (as proposed for the LAU effect) that need to be invoked and understood. The evidence is for analogous neural processes underlying the LAU effect in rodents and healthy humans and helplessness in depression, with the ventro-medial prefrontal cortex exhibiting aversive uncontrollability-dependent activity. With respect to the second aim, the major findings are: the LAU effect is demonstrated quite consistently using a number of different paradigms in rat but is poorly studied in mouse. The rat LAU effect can be reversed by chronic administration of monoamine reuptake inhibitors. The effects of antidepressants on human helplessness have been scarcely studied to-date. The major conclusion is that the LAU effect and generalised helplessness constitute major neuropsychological concepts of high value to future translational research aimed at increased understanding of depression and development of novel, improved antidepressant treatments

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/- ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/- mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/- and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders. Keywords: amygdala; cell deconvolution; depression; differential gene expression; gray and white matter; inflammation; mouse; myelin transcriptome; myelin-axon integrity; oligodendrocyte; social stress

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/− ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/− mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/− and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders