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The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?
Supplementary resource (1)
... They can regulate gut barrier integrity and mucosal immunity through various molecular mechanisms involving G protein-coupled receptors such as free fatty acid receptors 2 and 3 or hydrocarboxylic acid receptors [45]. Butyrate has been shown to promote the upregulation of proteins constituting tight junctions, such as zonula occludens-1, claudin-5, and occulin, and the inhibition of zonulin to reduce intestinal permeability and maintain gut barrier integrity [46][47][48][49][50][51][52]. A decrease in the abundance of butyrate can lead to leaky gut syndrome, thereby influencing the immune response, as well as the integrity of both the gut and the blood-brain barrier (BBB) [53][54][55][56][57]. Indeed, the expression of claudin and occludin has also been shown to be reduced in the BBB of germ-free mice, leading to the increased permeability of the BBB from intrauterine life to adulthood [58]. ...
... The LPS-induced pro-inflammatory cascades have been shown to be inhibited by the butyrate inhibition of histone deacetylase (HDAC) [98]. This intracellular signaling has been found not only in the gut and associated immune tissue but also in the peripheral nervous system and CNS [51,[99][100][101][102]. Perturbations of the gut microbiota caused by antibiotics in experimental animal models systemically produced altered immune responses with pro-inflammatory profiles [103]. ...
Obsessive–compulsive disorder (OCD) is a debilitating mental health disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions). Dysbiosis, an imbalance in the gut microbial composition, has been associated with various health conditions, including mental health disorders, autism, and inflammatory diseases. While the exact mechanisms underlying OCD remain unclear, this review presents a growing body of evidence suggesting a potential link between dysbiosis and the multifaceted etiology of OCD, interacting with genetic, neurobiological, immunological, and environmental factors. This review highlights the emerging evidence implicating the gut microbiota in the pathophysiology of OCD and its potential as a target for novel therapeutic approaches. We propose a model that positions dysbiosis as the central unifying element in the neurochemical, immunological, genetic, and environmental factors leading to OCD. The potential and challenges of microbial reprogramming strategies, such as probiotics and fecal transplants in OCD therapeutics, are discussed. This review raises awareness of the importance of adopting a holistic approach that considers the interplay between the gut and the brain to develop interventions that account for the multifaceted nature of OCD and contribute to the advancement of more personalized approaches.
... On the other hand, the present result confirmed previous observations regarding the role of butyric acid in the pathogenesis of both depressive and anxiety symptoms 25,41,42 SCFAs such as butyric acid cross the blood-brain barrier and upregulate several neurotrophic factor expressions in the hippocampus and frontal cortex. Thus, SCFAs were found to further regulate mood 42,43 , modulating serotonergic, and dopaminergic neurotransmission 20,43 . ...
... On the other hand, the present result confirmed previous observations regarding the role of butyric acid in the pathogenesis of both depressive and anxiety symptoms 25,41,42 SCFAs such as butyric acid cross the blood-brain barrier and upregulate several neurotrophic factor expressions in the hippocampus and frontal cortex. Thus, SCFAs were found to further regulate mood 42,43 , modulating serotonergic, and dopaminergic neurotransmission 20,43 . ...
Eating disorders (EDs) are syndromes with a multifactorial etiopathogenesis, involving childhood traumatic experiences, as well as biological factors. Human microbiome has been hypothesised to play a fundamental role, impacting on emotion regulation, as well as with eating behaviours through its metabolites such as short chain fatty acids (SCFAs). The present study investigated the interactions between psychopathology of EDs, the gut microbiome and SCFAs resulting from bacterial community metabolic activities in a population of 47 patients with Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder and in healthy controls (HCs). Bacterial gut microbiota composition differences were found between subjects with EDs and HCs, especially in association with different pathological behaviours (binge-purge vs restricting). A mediation model of early trauma and ED-specific psychopathology linked reduction of microbial diversity to a typical microbiota-derived metabolite such as butyric acid. A possible interpretation for this model might be that childhood trauma represents a risk factor for gut dysbiosis and for a stable modification of mechanisms responsible for SCFAs production, and that this dysfunctional community is inherited in the passage from childhood to adulthood. These findings might open the way to novel interventions of butyric acid-like compounds as well as faecal transplant.
... It promotes histone acetylation and stimulation of gene expression. Receptors such as GPR43/FFAR2, GPR41/ FFAR3, and GPR109a/HCAR2 and transporters including MCT1/SLC16A1 and SMCT1/SLC5A8 are important for its operations [22,23]. ...
... Butyric acid may be involved with other SCFAs such as acetate, propionate, acetoacetate, and d-β-hydroxybutyrate in the pathogenesis of many diseases, including those of a neurological type (e.g., AD) and diabetes, arrhythmogenic cardiomyopathy. Butyrate as an experimental drug has been used in experimental models of neurological disorders, from depression to neurodegenerative diseases of old age [23]. ...
Neurological
diseases can be broadly divided according to causal factors into circulatory system disorders leading to ischemic stroke; degeneration of the nerve cells leading to neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, and immune system disorders; bioelectric activity (epileptic) problems; and genetically determined conditions as well as viral and bacterial infections developing inflammation. Regardless of the cause of neurological diseases, they are usually accompanied by disturbances of the central energy in a completely unexplained mechanism. The brain makes up only 2% of the human body’s weight; however, while working, it uses as much as 20% of the energy obtained by the body. The energy requirements of the brain are very high, and regulatory mechanisms in the brain operate to ensure adequate neuronal activity. Therefore, an understanding of neuroenergetics is rapidly evolving from a “neurocentric” view to a more integrated picture involving cooperativity between structural and molecular factors in the central nervous system. This article reviewed selected molecular biomarkers of oxidative stress and energy metabolism disorders such as homocysteine, DNA damage such as 8-oxo2dG, genetic variants, and antioxidants such as glutathione in selected neurological diseases including ischemic stroke, AD, PD, and epilepsy. This review summarizes our and others’ recent research on oxidative stress in neurological disorders. In the future, the diagnosis and treatment of neurological diseases may be substantially improved by identifying specific early markers of metabolic and energy disorders.
... These are organic acids derived from the microbial fermentation of dietary fibers and starch in the intestines. While anaerobic fermentation is the largest source, SCFAs can also result from amino acid metabolism [37,38] and are found in high quantities in dairy products, hence, the SCFA concentration can vary strongly with diet [38]. In addition to their known roles as trophic factors and energy supply substrates to the gut [39], SCFAs are thought to play a major role in stress and anxiety modulation [28], and reduced levels of SCFAs have been found to be associated with chronic stress. ...
... These are organic acids derived from the microbial fermentation of dietary fibers and starch in the intestines. While anaerobic fermentation is the largest source, SCFAs can also result from amino acid metabolism [37,38] and are found in high quantities in dairy products, hence, the SCFA concentration can vary strongly with diet [38]. In addition to their known roles as trophic factors and energy supply substrates to the gut [39], SCFAs are thought to play a major role in stress and anxiety modulation [28], and reduced levels of SCFAs have been found to be associated with chronic stress. ...
Maternal prenatal stress exposure affects the development of offspring. We searched for articles in the PubMed database and reviewed the evidence for how prenatal stress alters the composition of the microbiome, the production of microbial-derived metabolites, and regulates microbiome-induced behavioral changes in the offspring. The gut–brain signaling axis has gained considerable attention in recent years and provides insights into the microbial dysfunction in several metabolic disorders. Here, we reviewed evidence from human studies and animal models to discuss how maternal stress can modulate the offspring microbiome. We will discuss how probiotic supplementation has a profound effect on the stress response, the production of short chain fatty acids (SCFAs), and how psychobiotics are emerging as novel therapeutic targets. Finally, we highlight the potential molecular mechanisms by which the effects of stress are transmitted to the offspring and discuss how the mitigation of early-life stress as a risk factor can improve the birth outcomes.
... At the genus level, the abundance of Romboutsia, Roseburia, Lachnospiraceae_NK4A136_group, Prevotella_9, and Eubac-terium_coprostanoligenes_group was significantly lower in the CUMS group compared to the NC group, which has already been reported to be related to the maintenance of intestinal barrier function and the alleviation of inflammatory response. Romboutsia, Roseburia, Lach-nospiraceae_NK4A136_group, and Prevotella_9 can produce SCFAs [34][35][36][37], and the intestinal epithelial oxidative and inflammatory damage of mice rich in these four bacteria has been found to be lower than that of control mice [38]. Lachnospiraceae_NK4A136_group has also been found to be positively correlated with factors related to the maintenance of intestinal barrier integrity and negatively correlated with pro-inflammatory factors (LPS and IL-6) and neurotoxic quinolone [39,40]. ...
Polygalae radix (PR) is a well-known traditional Chinese medicine that is used to treat depression, and polygalae radix oligosaccharide esters (PROEs) are the main active ingredient. Although gut microbiota are now believed to play key role in depression, the effects of PROEs on depression via modulation of gut microbiota remain unknown. In this article, we investigate the effect of PROEs on the gut microbiota of a depression rat and the possible mechanism responsible. The depression rat model was induced by solitary rearing combined with chronic unpredictable mild stress (CUMS). The depression-like behavior, the influence on the hypothalamic–pituitary–adrenal (HPA) axis, the contents of monoamine neurotransmitter in the hippocampus, and the quantity of short-chain fatty acids (SCFAs) in the feces were each assessed, and the serum levels of lipopolysaccharide (LPS) and interleukin-6 (IL-6) were measured by ELISA. Additionally, ultrastructural changes of the duodenal and colonic epithelium were observed under transmission electron microscope, and the gut microbiota were profiled by using 16S rRNA sequencing. The results show that PROEs alleviated the depression-like behavior of the depression model rats, increased the level of monoamine neurotransmitters in the brain, and reduced the hyperfunction of the HPA axis. Furthermore, PROEs regulated the imbalance of the gut microbiota in the rats, relieving intestinal mucosal damage by increasing the relative abundance of gut microbiota with intestinal barrier protective functions, and adjusting the level of SCFAs in the feces, as well as the serum levels of LPS and IL-6. Thus, we find that PROEs had an antidepressant effect through the restructuring of gut microbiota that restored the function of the intestinal barrier, reduced the release of intestinal endotoxin, and constrained the inflammatory response.
... The main hypothesis is that the active ingredient in HFCG (gluconate) acts as a precursor for acetate and/or butyrate in the hindgut (Asano et al., 1994;Tsukahara et al., 2002Tsukahara et al., , 2006. Some groups have investigated the potential impacts of gluconate supplementation on gut health & morphological measures with mixed results (Poeikhampha and Bunchasak, 2011;Michiels et al., 2020;Watanabe et al., 2022), while others have proposed that luminal VFAs may act as signaling molecules to affect extragastrointestinal responses (Stilling et al., 2016;O'Riordan et al., 2022), such as energy partitioning. In previous studies with HFCG, we have proposed that responses in milk protein yield were likely supported by improved voluntary dry matter intake , while responses in milk fat yield were most likely supported by increased uptake of preformed fatty acids of endogenous origin by the mammary gland (Seymour et al., 2021). ...
Prebiotic compounds may be supplemented in the diet to improve animal health and performance in a variety of ways. In dairy cattle, the transition from pregnancy through parturition and lactation represents a critical life stage with many concurrent stressors. The objectives of this study were to evaluate responses to the provision of a hindgut-targeted prebiotic compound (calcium gluconate; HFCG) when supplemented prepartum and/or postpartum in a 2 × 2 factorial design. One hundred and sixty-four multiparous Holstein cattle were enrolled and followed from approximately 21 d prior to calving until 100 d of lactation. Treatments were administered as a pelleted compound feed offered in the rotary milking parlor once daily prepartum and thrice daily postpartum. Information pertaining to milk production and body weight were automatically recorded by the milking equipment, and information pertaining to reproductive and health performance was recorded by farm staff. Cattle that received HFCG prepartum were confirmed pregnant approximately 21 d earlier (P = 0.024). Cattle that received HFCG both pre- and postpartum had 9% to 10% higher yields of milk protein, fat, and energy-corrected milk (P ≤ 0.037) from weeks 4 to 9 of lactation relative to those that received HFCG exclusively prepartum. Conversely, cattle that received HFCG exclusively postpartum had 9% to 10% higher yields of milk protein, fat, and energy-corrected milk (P ≤ 0.037) from weeks 9 to 14 of lactation relative to those that received exclusively the negative control in both periods. The mechanism underlying these responses remains unclear, however, we hypothesize that these responses are due to localized reductions in inflammation in the gut and/or signaling to extragastrointestinal tissues altering energy partitioning and balance.
... 21 Se ha encontrado el butirato y propionato tienen la capacidad de afectar los comportamientos y la función neuronal, en una serie de acciones metabólicas que parecen regular la expresión génica de la tirosina hidroxilasa, enzima clave para la síntesis de noradrenalina y dopamina. 22 Estos ácidos grasos también han demostrado que juegan un papel crítico en el desarrollo y maduración de las microglias, macrófagos residentes del sistema nervioso, afectando la densidad y el tamaño de sus ramificaciones, disminuyendo la síntesis enzimática y alterando la capacidad de polarización de perfil M1 a M2, entorpeciendo su función. 23 La expresión de las proteínas presentes en las uniones estrechas, zónula occludens y claudinas en la barrera hematoencefálica y del epitelio gastrointestinal, está modulada por la cantidad disponible de ácidos grasos de cadena corta, favoreciendo en altas cantidades una menor permeabilidad intercelular, evitando la difusión y transporte de lipopolisacáridos (LPS) hacia la submucosa 24 y por ende evitando la generación de un proceso inflamatorio a distancia. ...
El rol del eje cerebro-intestino en las enfermedades neurodegenerativas. RESUMEN En los últimos años se ha investigado fuertemente el papel de la microbiota del tracto digestivo y su relación con el sistema nervioso central, en el denominado eje intestino-cerebro, que establece interacciones de manera bidireccional. Los estudios científicos han proporcionado datos que contribuyen a la comprensión de este eje, que parece mantenerse a través de la vinculación vía nervio vago y a través de la vía circulatoria, por las cuales pueden liberarse y difundir neurotransmisores, hormonas, citoquinas y otros metabolitos, entre ellos toxinas. Estos sistemas de comunicación se ven determinados por la composición de la microbiota y a su vez, la composición de la misma se ve afectada por procesos centrales. Todos estos procesos incluyen al sistema inmunológico, que interactúa íntimamente con el sistema nervioso entérico y el intestino. Aunque se trata de mecanismos que no han sido totalmente dilucidados, este eje se postula como una posible base patógena para numerosos trastornos neurológicos de gran impacto, como la enfermedad de Alzheimer, la enfermedad de Parkinson y la epilepsia. Esta revisión recoge información sobre estudios recientes que apoyan y aportan a la descripción de la participación del eje cerebro-intestino en la aparición de estas entidades neurodegenerativas. Palabras clave: Eje cerebro-intestino, microbiota intestinal, disbiosis, enfermedades neurodegenerativas, Parkinson, Alzheimer, epilepsia ABSTRACT In recent years, the role of the microbiota in the digestive tract and its relationship with the central nervous system has been heavily researched, in what is known as the gut-brain axis, establishing bidirectional interactions. Scientific studies have provided data that contribute to the understanding of this axis, which appears to be maintained through connections via the vagus nerve and through the circulatory system, through which neurotransmitters, hormones, cytokines, and other metabolites, including toxins, can be released and spread. These communication systems are influenced by the composition of the microbiota, which, in turn, is affected by central processes. All these processes involve the immune system, which intimately interacts with the enteric nervous system and the gut. Although these mechanisms have not been fully elucidated, this axis is proposed as a possible pathological basis for numerous neurological disorders of great impact, such as Alzheimer's disease, Parkinson's disease, and epilepsy. This review gathers information from recent studies that support and contribute to the description of the involvement of the brain-gut axis in the development of these neurodegenerative conditions.
... Several tissues and organs including the brain, intestine and glands, as well as immune cells and intestinal microbiota, have been proposed to be critical herein (for an overview, see [8,9]). The results of several studies further suggest that the intestinal microbiota, be it directly through an activation of the vagus nerve or the activation of immune cells and an induction of the synthesis and release of neurotransmitters (for an overview, see [10]) or through metabolites derived from it [11] might influence the nervous system. For instance, both increases and decreases in prevalence and relative proportion of Bacteroides have been found in patients with dementia and AD [12][13][14]. ...
Emerging evidence implicate the ‘microbiota–gut–brain axis’ in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like receptor (TLR) 2 and TLR4, in blood and different brain regions, and depending signaling cascades are paralleling aging associated alterations of cognition in healthy aging mice. Cognitive function was assessed in the Y-maze and intestinal and brain tissue and blood were collected in young (4 months old) and old (24 months old) male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and TLR4 ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function, senescence and TLR2 and TLR4 signaling. Cognitive function was significantly impaired in old mice. Also, in old mice, intestinal microbiota composition was significantly altered, while the relative abundance of Gram-negative or Gram-positive bacteria in the small and large intestines at different ages was not altered. Moreover, intestinal barrier function was impaired in small intestine of old mice, and the levels of TLR2 and TLR4 ligands were also significantly higher in both portal and peripheral blood. Furthermore, levels of TLR2 and TLR4 ligands, and downstream markers of TLR signaling were higher in the hippocampal and prefrontal cortex of old mice compared to young animals. Taken together, our results suggest that even in ‘healthy’ aging, cognitive function is impaired in mice going along with an increased intestinal translocation of TLR ligands and alterations of TLR signaling in several brain regions.
... SCFAs, particularly butyrate, inhibit the activity of HDAC (Dalile et al., 2019). Signaling inhibition of intracellular HDAC is reported in the remote organs and gut (Stilling et al., 2016). In line with this, Henagan et al., (2015) explored the anti-obesity property of sodium butyrate by inhibiting HDAC activity and chromatin remodeling. ...
The diverse populations reportedly suffer from obesity on a global scale, and inconclusive evidence has indicated that both environmental and genetic factors are associated with obesity development. Therefore, a need exists to examine potential therapeutic or prophylactic molecules for obesity treatment. Prebiotics with non-digestible oligosaccharides (NDOs) have the potential to treat obesity. A limited number of prebiotic NDOs have demonstrated their ability as a convincing therapeutic solution to encounter obesity through various mechanisms, viz., stimulating beneficial microorganisms, reducing the population of pathogenic microorganisms, and also improving lipid metabolism and glucose homeostasis. NDOs include pectic-oligosaccharides, fructo-oligosaccharides, xylo-oligosaccharides, isomalto-oligosaccharides, manno-oligosaccharides and other oligosaccharides which significantly influence the overall human health by different mechanisms. This review provides the treatment of obesity benefits by incorporating these prebiotic NDOs, according to established scientific research, which shows their good effects extend beyond the colon.
... Butyrate is another SCFA and a secondary metabolite of the gut microbiome which acts as an endogenous inhibitor of class I HDACs, a well-known class of epigenetic modulatory genes [174,175]. Neuroprotective effects of butyrate against ASD have been linked to positive modulation of mitochondrial functions like enhancing oxidative phosphorylation and beta-oxidation, suppressing microglia-mediated neuroinflammation, regulating the microbiome-gut-brain axis, reducing oxidative stress-induced transport deficits of tryptophan or its activity as a histone deacetylase inhibitor [176][177][178][179]. Moreover, butyrate as an HDAC inhibitor can enhance acetylation around the promoters of neurotrophic factors such as BDNF and consequently promote their transcription [180,181]. ...
Nutrition and metabolism modify epigenetic signatures like histone acetylation and DNA methylation. Histone acetylation and DNA methylation in the central nervous system (CNS) can be altered by bioactive nutrients and gut microbiome via the gut–brain axis, which in turn modulate neuronal activity and behavior. Notably, the gut microbiome, with more than 1000 bacterial species, collectively contains almost three million functional genes whose products interact with millions of human epigenetic marks and 30,000 genes in a dynamic manner. However, genetic makeup shapes gut microbiome composition, food/nutrient metabolism, and epigenetic landscape, as well. Here, we first discuss the effect of changes in the microbial structure and composition in shaping specific epigenetic alterations in the brain and their role in the onset and progression of major mental disorders. Afterward, potential interactions among maternal diet/environmental factors, nutrition, and gastrointestinal microbiome, and their roles in accelerating or delaying the onset of severe mental illnesses via epigenetic changes will be discussed. We also provide an overview of the association between the gut microbiome, oxidative stress, and inflammation through epigenetic mechanisms. Finally, we present some underlying mechanisms involved in mediating the influence of the gut microbiome and probiotics on mental health via epigenetic modifications.
... Mechanisms of HDACi include blocking the active site in HDAC and activation of GPCRs (which reduces expression of HDAC-encoding genes) [10][11][12] and (ii) modifying cell gene activity (where butyrate binds to butyrate-responsive elements in cellular gene promoters). This may explain the pleiotropic effects of butyrate [13,14] (Fig. 1). ...
Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of “health,” is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a “leaky gut,” permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.
... Butyrate, a fourcarbon SCFA, has potent anti-inflammatory effects, regulates gut permeability in-vitro (Peng et al., 2009), and can modify gene expression through epigenetic mechanisms (Govindarajan et al., 2011). Butyrate has been hypothesized as playing a potential role in the regulation of the gut-brain axis potentially via increases in production of colonic serotonin, a neurotransmitter important for regulating mood and behavior (Fukumoto et al., 2003;Yadav et al., 2013;Stilling et al., 2016). Furthermore, research conducted on rodents has proposed that butyrate might exhibit antidepressant-like properties by augmenting the expression of brain-derived neurotrophic factor (BDNF), a protein crucial for neuronal growth and survival (Intlekofer et al., 2013). ...
Short-chain fatty acids (SCFAs), produced by the metabolism of dietary fibers in the gut, have wide-ranging effects locally and throughout the body. They modulate the enteric and central nervous systems, benefit anti-inflammatory pathways, and serve as energy sources. Recent research reveals SCFAs as crucial communicators between the gut and brain, forming the gut-brain axis. This perspective highlights key findings and discusses signaling mechanisms connecting SCFAs to the brain. By shedding light on this link, the perspective aims to inspire innovative research in this rapidly developing field.
... Pathobionts themselves can also produce Aβ-like metabolites able to cross-seeding with human Aβ; resulting amyloid deposition in the brain stimulates an inflammatory response by the local microglia, with plaques formation and neuronal loss [58][59][60][61][62]. (2) Many other bacterial toxins may influence Aβ plaques deposition as well, like saxitoxin, anatoxin-alfa or beta-N-methylamino-alanine [63]. On the other hand, short-chain fatty acids (SCFAs), especially butyrate, and histamine may have a neuroprotective role [64,65]. (3) It is possible that the lack of probiotic strains may affect the secretion of neurotrophic factors, such as BDNF, NMDA and GABA [66]. ...
In the context of neurodegenerative disorders, cognitive decline is frequently reported in older population. Recently, numerous metabolic pathways have been implicated in neurodegen-eration, including signaling disruption of insulin and other glucose-regulating hormones. In fact, Alzheimer's disease has now been considered as "type-3 diabetes". In this review, we tried to clarify the role of sleep impairment as the third major player in the complex relationship between metabolic and neurodegenerative diseases. Altered sleep may trigger or perpetuate these vicious mechanisms, leading to the development of both dementia and type 2 diabetes mellitus. Finally, we analyzed these reciprocal interactions considering the emerging role of the gut microbiota in modulating the same processes. Conditions of dysbiosis have been linked to circadian rhythm disruption, metabolic alterations, and release of neurotoxic products, all contributing to neurodegeneration. In a future prospective, gut microbiota could provide a major contribution in explaining the tangled relationship between sleep disorders, dementia and diabetes.
... In complex interactions with the brain, the microbiome-gut-brain axis has received a lot of attention as a complex bidirectional route of communication between the gut microbiota, brain functioning and mental health (Clapp et al., 2017;Cryan and Dinan, 2012;Foster et al., 2017;Foster and McVey Neufeld, 2013). Such communication occurs via metabolites and other neuroactive signalling molecules released from the gut microbiome (Banks, 2005;Stilling et al., 2016), activation of the enteric, systemic and brain immune system (Dantzer et al., 2000;Geuking et al., 2014;Giunti et al., 2003;Hopkins, 2007;Schedlowski et al., 2014), and stimulation of the vagus nerve (Dockray, 2013;Kuwahara et al., 2020). The gut microbiota composition substantially differs between MDD patients and healthy individuals (Bastiaanssen et al., 2020;Foster et al., 2021). ...
Animal models of selective breeding for extremes in emotionality are a strong experimental approach to model psychopathologies. They became indispensable in order to increase our understanding of neurobiological, genetic, epigenetic, hormonal, and environmental mechanisms contributing to anxiety disorders and their association with depressive symptoms or social deficits. In the present review, we extensively discuss Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze. After 30 years of breeding, we can confirm the prominent differences between HAB and LAB rats in trait anxiety, which are accompanied by consistent differences in depressive-like, social and cognitive behaviours. We can further confirm a single nucleotide polymorphism in the vasopressin promotor of HAB rats causative for neuropeptide overexpression, and show that low (or high) anxiety and fear levels are unlikely due to visual dysfunctions. Thus, HAB and LAB rats continue to exist as a reliable tool to study the multiple facets underlying the pathology of high trait anxiety and its comorbidity with depression-like behaviour and social dysfunctions.
... Gut microbiota metabolites can also impact host gene expression through epigenetic mechanisms. Butyrate can inhibit histone deacetylase, thereby promoting histone acetylation and subsequent chromatin relaxation and gene expression (reviewed in Stilling et al., 2016). A recent clinical study found that reduced amounts of fecal butyrate, and butyrate-producing bacteria, were associated with increased depression symptoms in individuals with Parkinson's disease (Xie et al., 2022). ...
Alcohol exposure in adulthood can result in inflammation, malnutrition, and altered gastroenteric microbiota, which may disrupt efficient nutrient extraction. Clinical and preclinical studies have documented convincingly that prenatal alcohol exposure (PAE) also results in persistent inflammation and nutrition deficiencies, though research on the impact of PAE on the enteric microbiota is in its infancy. Importantly, other neurodevelopmental disorders, including autism spectrum and attention deficit/hyperactivity disorders, have been linked to gut microbiota dysbiosis. The combined evidence from alcohol exposure in adulthood and from other neurodevelopmental disorders supports the hypothesis that gut microbiota dysbiosis is likely an etiological feature that contributes to negative developmental, including neurodevelopmental, consequences of PAE and results in fetal alcohol spectrum disorders. Here, we highlight published data that support a role for gut microbiota in healthy development and explore the implication of these studies for the role of altered microbiota in the lifelong health consequences of PAE.
... it is unclear or little that butyrate acts on brain directly. However, butyrate could stimulate enteroendocrine cells(EEC) to release neuropeptide and neurotransmitter like serotonin in role of controlling immune cells like Treg cell in anti-inflammation, else, and regulating nervi vagus to adjust permeability of intestinal barrier and blood-brain barrier(BBB) for better regulation of interaction among gut microbiome, metabolism, and human body (Stilling et al., 2016). Furthermore, butyrate is a key to reduce inflammation, improve macrophage development and restrain the excessive growth of intestinal epithelium by inhibting histone deacetylase(HDAC) (Salvi and Cowles, 2021;Liu et al., 2023; Park et al., 2023). ...
Background and aims
Gastrointestinal microbial metabolomics is closely related to the state of the organism and has significant interaction with the pathogenesis of many diseases. Based on the publications in Web of Science Core Collection(WoSCC) from 2004 to 2022, this study conducted a bibliometric analysis of this field, aiming to understand its development trend and frontier, and provide basic information and potential points for in-depth exploration of this field.
Methods
All articles on gastrointestinal flora and metabolism published from 2004 to 2022 were collected and identified in WoCSS. CiteSpace v.6.1 and VOSviewer v.1.6.15.0 were used to calculate bibliometric indicators, including number of publications and citations, study categories, countries/institutions, authors/co-cited authors, journals/co-cited journals, co-cited references, and keywords. A map was drawn to visualize the data based on the analysis results for a more intuitive view.
Results
There were 3811 articles in WoSCC that met our criteria. Analysis results show that the number of publications and citations in this field are increasing year by year. China is the country with the highest number of publications and USA owns the highest total link strength and citations. Chinese Acad Sci rank first for the number of institutional publications and total link strength. Journal of Proteome Research has the most publications. Nicholson, Jeremy K. is one of the most important scholars in this field. The most cited reference is “Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease”. Burst detection indicates that Urine, spectroscopy, metabonomic and gut microflora are long-standing hot topics in this field, while autism spectrum disorder and omics are likely to be at the forefront of research. The study of related metabolic small molecules and the application of gastrointestinal microbiome metabolomics in various diseases are currently emerging research directions and frontier in this field.
Conclusion
This study is the first to make a bibliometric analysis of the studies related to gastrointestinal microbial metabolomics and reveal the development trends and current research hotspots in this field. This can contribute to the development of the field by providing relevant scholars with valuable and effective information about the current state of the field.
... Recent breakthroughs in schizophrenia have demonstrated that the gut microbiota can cause neurodevelopmental and neurodegenerative conditions by communicating with the brain via the gut-brain axis, which includes tryptophan metabolism [118], neurotransmitters, immunomodulatory pathways, and bioactive microbial metabolites [119,120]. There is also a relationship between antidepressants, and microbiota. ...
It is well-known that probiotics have key roles in the crosstalk between the gut and brain in terms of nutrition and health. However, when investigating their role in nutrition and health, it can be important to discriminate probiotics used as foods, food supplements, or drugs. For clarification of this terminology, the Food and Drug Administration (FDA) has established a new “live biotherapeutic products” (LBP) category, expressing pharmaceutical expectations and to reduce confusion in the literature. Growing evidence advises that the community of microorganisms found in the gut microbiota is associated with psychological conditions. Hence, it is thought that LBPs may positively affect depression, anxiety, bipolar disorder, and schizophrenia by reducing inflammation, improving gut microbiota, and balancing gut neurometabolites. This review focuses on the specific position of probiotics as LBPs in psychological conditions. Condition-specific potential pathways and mechanisms of LBPs and the prominent strains are discussed in the light of novel studies for future research, dietetic and pharmaceutical applications.
... SCFAs are the most crucial microbial products with anti-inflammatory potential and maintain the gastrointestinal system's homeostasis (49,50). Decreasing SCFAs could deteriorate the gut permeability (51), making it possible for the detrimental microbiota products such as LPS to leak into the circulatory system and accelerate the progression of neurodegeneration diseases (52,53). Furthermore, we found that spatial learning and memory ability are negatively related to the METH group-enriched taxa (Clostridia, Bacteroides, and Lactobacillus) but positively associated with the saline group-enriched taxon (Muribaculaceae) (Fig. 6A). ...
Methamphetamine (METH) exposure may lead to cognitive impairment. Currently, evidence suggests that METH exposure alters the configuration of the gut microbiota. However, the role and mechanism of the gut microbiota in cognitive impairment after METH exposure are still largely unknown. Here, we investigated the impact of the gut microbiota on the phenotype status of microglia (microglial phenotypes M1 and microglial M2) and their secreting factors, the subsequent hippocampal neural processes, and the resulting influence on spatial learning and memory of chronically METH-exposed mice. We determined that gut microbiota perturbation triggered the transformation of microglial M2 to M1 and a subsequent change of pro-brain-derived neurotrophic factor (proBDNF)-p75NTR-mature BDNF (mBDNF)-TrkB signaling, which caused reduction of hippocampal neurogenesis and synaptic plasticity-related proteins (SYN, PSD95, and MAP2) and, consequently, deteriorated spatial learning and memory. More specifically, we found that Clostridia, Bacteroides, Lactobacillus, and Muribaculaceae might dramatically affect the homeostasis of microglial M1/M2 phenotypes and eventually contribute to spatial learning and memory decline after chronic METH exposure. Finally, we found that fecal microbial transplantation could protect against spatial learning and memory decline by restoring the microglial M1/M2 phenotype status and the subsequent proBDNF-p75NTR/mBDNF-TrkB signaling in the hippocampi of chronically METH-exposed mice. IMPORTANCE Our study indicated that the gut microbiota contributes to spatial learning and memory dysfunction after chronic METH exposure, in which microglial phenotype status plays an intermediary role. The elucidated "specific microbiota taxa-microglial M1/M2 phenotypes-spatial learning and memory impairment" pathway would provide a novel mechanism and elucidate potential gut microbiota taxon targets for the no-drug treatment of cognitive deterioration after chronic METH exposure.
... Firmicutes in the gut flora ferments carbohydrates into short-chain fatty acids. When the abundance of Firmicutes decreases, the synthesis of these short-chain fatty acids decreases, which can lead to reduced intestinal function [28,29]. ...
Breast cancer ranks first among female cancers and has become a major public health problem in the current society. More studies indicated that these cancers are related to the change in the gut microbiome that can cause metabolic and immune system disorders in the body. However, there are few studies on the changes in gut microbiome caused by the onset of breast cancer, and the relationship between breast cancer and gut microbiome needs to be further clarified. In this study, we inoculated 4T1 breast cancer cells to induce breast cancer tumorigenesis in mice and collected their feces samples at different stages during this process. These intestinal florae were analyzed using 16S rRNA gene amplicon sequencing, and the results showed that at the phylum level, the ratio of Firmicutes/Bacteroidetes decreased with the development of the tumor; at the family level, the intestinal microbiome had obvious variations of Lachnospiraceae, Bacteroidaceae, Erysipelotrichaceae, etc. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and COG annotation demonstrated that decreased abundance of cancer-related signaling pathways. This study elucidated the relationship between breast cancer and intestinal microbiome, and the research results can be used as an important biomarker for the diagnosis of breast cancer.
... A possible conjecture is that the family Lachnospiraceae regulates the symptoms of ADHD by producing butyrate. Butyrate has anti-inflammatory, neuroplasticity-promoting, and long-term memory formation effects, and is beneficial for the treatment of neurodegenerative diseases and mental illnesses such as depression and ASD (Stilling et al., 2016). In addition to the genus LachnospiraceaeNC2004group, our study also found that there is a causal relationship between bacteria that produce butyrate such as the genus Roseburia, genus Eubacteriumhalliigroup, and genus Butyricicoccus and ADHD (Eicher and Mohajeri, 2022). ...
Previous research has suggested a link between gut microbiota and attention deficit hyperactivity disorder (ADHD), but their causal relationship has not been elucidated. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for ADHD, we conducted a two-sample Mendelian randomization (MR) analysis. Instrumental variables of 211 gut microbiota taxa were obtained from gene wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on ADHD risk from PGC GWAS (20,183 ADHD cases and 35,191 controls) and FinnGen GWAS (830 ADHD cases and 215,763 controls). Wald ratio (WR), inverse variance weighted (IVW), MR-Egger, and weighted median were the main methods to analyze causality, and MR results are verified by several sensitivity analysis analyses. At locus-wide significance level (p < 1 × 10-5), IVW results confirmed that genus Eubacteriumhalliigroup (p = 0.013) and genus RuminococcaceaeUCG013 (p = 0.049) were correlated with the risk of ADHD and genus Butyricicoccus (p = 0.009), genus Roseburia (p = 0.009), genus Desulfovibrio (p = 0.015), genus LachnospiraceaeNC2004group (p = 0.026), genus Romboutsia (p = 0.028) and family Oxalobacteraceae (p = 0.048) were protective factors of ADHD. Weighted median results indicated that genus Butyricicoccus (p = 0.018) was negatively correlated with the risk of ADHD. At genome-wide statistical significance level (p < 5 × 10-8), Wald ratio results demonstrated that genus Ruminococcustorquesgroup (p = 0.003) was a risk factor for ADHD, while genus Romboutsia (p = 0.006) and family Peptostreptococcaceae (p = 0.006) had a negative correlation with the risk of ADHD. In reverse MR analysis, IVW results showed that ADHD may lead to an increase in the abundance of genus Roseburia (p = 0.020). Analysis of heterogeneity (p > 0.05) and pleiotropy (p > 0.05) confirmed the robustness of MR results. We demonstrated that there was a potential causal relationship between gut microbiota and ADHD. Our research provides a foundation for understanding the causal relationship between gut microbiota and ADHD, and the several gut bacteria found in this study that may reduce the occurrence of ADHD may have potential in the prevention and treatment of ADHD.
... Acetate, propionic acid, and butyric acid are the most abundant SCFA in the human body and the most abundant anions in the colon (Kim et al., 2022). Because acetate, butyrate and propionate in SCFA easily cross the blood-brain barrier (BBB), and SCFA has neuroactive properties and its impact on other intestinal-brain signaling pathways, including immune and endocrine systems, SCFA may be directly or indirectly involved in the occurrence and development of cerebrovascular diseases and exert its biological role (Clarke et al., 2014;Stilling et al., 2016;Wenzel et al., 2020). SCFAs possess favorable anti-inflammatory and chemopreventive properties. ...
The gut microbiome is critically involved in maintaining normal physiological function in the host. Recent studies have revealed that alterations in the gut microbiome contribute to the development and progression of cerebrovascular disease via the microbiota-gut-brain axis (MGBA). As a broad communication network in the human body, MGBA has been demonstrated to have significant interactions with various factors, such as brain structure and function, nervous system diseases, etc. It is also believed that the species and composition of gut microbiota and its metabolites are intrinsically linked to vascular inflammation and immune responses. In fact, in fecal microbiota transplantation (FMT) research, specific gut microbiota and downstream-related metabolites have been proven to not only participate in various physiological processes of human body, but also affect the occurrence and development of cerebrovascular diseases directly or indirectly through systemic inflammatory immune response. Due to the high mortality and disability rate of cerebrovascular diseases, new treatments to improve intestinal dysbacteriosis have gradually attracted widespread attention to better ameliorate the poor prognosis of cerebrovascular diseases in a non-invasive way. This review summarizes the latest advances in the gut microbiome and cerebrovascular disease research and reveals the profound impact of gut microbiota dysbiosis and its metabolites on cerebrovascular diseases. At the same time, we elucidated molecular mechanisms whereby gut microbial metabolites regulate the expression of specific interleukins in inflammatory immune responses. Moreover, we further discuss the feasibility of novel therapeutic strategies targeting the gut microbiota to improve the outcome of patients with cerebrovascular diseases. Finally, we provide new insights for standardized diagnosis and treatment of cerebrovascular diseases.
... In our experiment, we found that HFD reduced the generation of SCFAs and the combination of PTE and IF significantly increased the content of SCFAs especially butyrate which might be due to the fact that the increasing SCFAs-producing bacteria (Akkermansia) promoted the butyrate production ( Fig. 4E-G). Butyrate can facilitate the production of mucin which serves as a defense for epithelial cells and can up-regulate the expression of epithelial tight-junction proteins, mainly ZO-1 (Stilling et al., 2016). This further supported our view that the combination of PTE and IF enhanced intestinal barrier function by increasing butyrate production. ...
Intermittent fasting (IF) could not work well in females indicating that additional interventions might be necessary to improve outcomes. We here investigated whether Pu-erh tea extract (PTE) intake could enhance anti-obesity effect of IF in female mice and explored the underlying mechanisms. The combination of PTE and IF treated obesity by reducing lipogenesis and enhancing adipose thermogenesis. This combination might decrease follicle-stimulating hormone (FSH) to reduce FSH-mediated UCP1 inhibition by AMPK/PGC1α/UCP1 pathways, finally promoting adipose thermogenesis. Based on this, we speculated increase of FSH might be a key reason for poor anti-obesity effect in female mice under IF. Besides, this combination modulated the composition of gut microbes (restored Firmicutes/Bacteroidetes and improved Akkermansia abundance) by protecting the intestinal barrier, and further promoted the production of SCFAs especially butyrate which might finally induce thermo-genesis in adipose. Our results suggested this combination could be an effective strategy to combating obesity for females.
... The linkage between depression and HIV has been well-documented [11,12]. Some studies suggest that the gut microbiota and its metabolites may contribute to depression and mood disorders via short-chain fatty acids (SCFAs), one of the gut microbiota's metabolites [13]. However, due to insufficient data, this area is understudied, particularly with regard to microbial composition and its relationship with depression in PWH. ...
Inter-individual differences in the gut microbiome are linked to alterations in inflammation and blood–brain barrier permeability, which may increase the risk of depression in people with HIV (PWH). The microbiome profile of blood, which is considered by many to be typically sterile, remains largely unexplored. We aimed to characterize the blood plasma microbiome composition and assess its association with major depressive disorder (MDD) in PWH and people without HIV (PWoH). In this cross-sectional, observational cohort, we used shallow-shotgun metagenomic sequencing to characterize the plasma microbiome of 151 participants (84 PWH and 67 PWoH), all of whom underwent a comprehensive neuropsychiatric assessment. The microbial composition did not differ between PWH and PWoH or between participants with MDD and those without it. Using the songbird model, we computed the log ratio of the highest and lowest 30% of the ranked classes associated with HIV and MDD. We found that HIV infection and lifetime MDD were enriched in a set of differentially abundant inflammatory classes, such as Flavobacteria and Nitrospira. Our results suggest that the circulating plasma microbiome may increase the risk of MDD related to dysbiosis-induced inflammation in PWH. If confirmed, these findings may indicate new biological mechanisms that could be targeted to improve treatment of MDD in PWH.
... Previously, our group investigated the anti-pathogenic and anti-inflammatory effects of the short chain fatty acid (SCFA) butyrate during C. jejuni infection in SAB IL-10 knockout mice (Du et al., 2022). Butyrate or butyric acid is known for its anti-bacterial and immunomodulatory effects, which are mainly exhibited indirectly via immunomodulation as a histone deacetylase (HDAC) inhibitor (Ricke, 2003;Stilling et al., 2016;Du et al., 2021). Although butyrate did not lower gastrointestinal enteropathogen counts, amelioration of clinical symptoms and significant anti-inflammatory effects could be detected upon treatment of C. jejuni infected mice (Du et al., 2022). ...
Introduction:
The food-borne Gram-negative bacterial pathogen Campylobacter jejuni may cause the acute enterocolitis syndrome campylobacteriosis in infected humans. Given that human C. jejuni infections are rising globally which hold also true for resistance rates against antibiotic compounds such as macrolides and fluoroquinolones frequently prescribed for the treatment of severe infectious enteritis, novel antibiotics-independent therapeutic strategies are needed. Distinct organic acids are well known for their health-beneficial including anti-microbial and immunomodulatory properties. In our present study, we investigated potential pathogen-lowering and anti-inflammatory effects of benzoic acid, butyric acid, caprylic acid, and sorbic acid either alone or in combination during acute murine campylobacteriosis.
Methods:
Therefore, secondary abiotic IL-10-/- mice were perorally infected with C. jejuni strain 81-176 and subjected to a 4-day-course of respective organic acid treatment.
Results and discussion:
On day 6 post-infection, mice from the combination cohort displayed slightly lower pathogen loads in the duodenum, but neither in the stomach, ileum nor large intestine. Remarkably, the clinical outcome of C. jejuni induced acute enterocolitis was significantly improved after combined organic acid treatment when compared to the placebo control group. In support, the combinatory organic acid treatment dampened both, macroscopic and microscopic inflammatory sequelae of C. jejuni infection as indicated by less colonic shrinkage and less pronounced histopathological including apoptotic epithelial cell changes in the colon on day 6 post-infection. Furthermore, mice from the combination as compared to placebo cohort exhibited lower numbers of innate and adaptive immune cells such as neutrophilic granulocytes, macrophages, monocytes, and T lymphocytes in their colonic mucosa and lamina propria, respectively, which also held true for pro-inflammatory cytokine secretion in the large intestines and mesenteric lymph nodes. Notably, the anti-inflammatory effects were not restricted to the intestinal tract, but could also be observed systemically given pro-inflammatory mediator concentrations in C. jejuni infected mice from the combination organic acid treatment that were comparable to basal values. In conclusion, our in vivo study provides first evidence that an oral application of distinct organic acids in combination exhibits pronounced anti-inflammatory effects and hence, constitutes a promising novel antibiotics-independent therapeutic strategy in the combat of acute campylobacteriosis.
... It can also inhibit histone deacetylase, thus aiding in the regulation of gene expression. [32,33] Propionate provides energy to the epithelial cells and also takes part in gluconeogenesis. [34] In the human body, acetate is utilized for lipogenesis and cholesterol metabolism. ...
The diversity of bacteria, viruses, eukaryotic organisms, and archaea that live in the gastrointestinal tract and have coevolved with the host over thousands of years to establish a complex and advantageous relationship is referred to as the “gut microbiota” or “gut microbiome.” The numerous and diverse gut microbiota play an important role mostly in the betterment of human health by facilitating the breakdown of food to release nutrients that would otherwise be inaccessible to the host, encouraging host cells proliferation and differentiation, defending the host against pathogen colonization, and activating or modulating the immune system. The gut microbial community plays an important role in protecting the host against pathogenic microbes, modulating immunity, and regulating metabolic processes and is even regarded as an endocrine organ. The term “dysbiosis” refers to the imbalance of the gut bacterial microbiota, which has been linked to several disorders such as cardiovascular diseases, obesity, irritable bowel syndrome, colorectal cancer, and sepsis. During cardiac surgery, intestinal ischemia-reperfusion causes an inflammatory response throughout the body. Since the intestines are an organ that is vulnerable to ischemia, germs and endotoxins can move between organs. As a consequence, the gut leads to sepsis after surgery. Next-generation sequencing technologies have enabled analysis of a large number of microorganisms. Metagenomics can be used to study intestinal microbiome diversity and dysbiosis, as well as its relationship to health and disease. Sequence-based and multifunctional metagenomics will also provide insights that will lead to greater knowledge than it is ever been of the structural and functional microbiomes.
... Not surprisingly, venlafaxine was found to affect sex hormones and aromatic amines in rats [12]. Butyricicoccus is an intestinal bacterium and its metabolite is butyrate, which is used as an experimental drug in neurological disease models from depression to neurodegenerative disorders and cognitive impairments [60], and increases 5-HT level [59]. Overall, the beneficial effects induced by venlafaxine treatment may therefore be attributed to specific alterations in the gut microbiota. ...
Depression is associated with intestinal dysbiosis. Venlafaxine is a commonly used antidepressant in clinical practice as a serotonin and noradrenaline reuptake inhibitor. However, its effects on gut bacteria in depression remain unclear. Here, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and investigated the alterations of venlafaxine on the gut microbiota and potential key bacteria. Our data show that venlafaxine exerts antidepressant effects by restoring the serotonin (5-HT) system and glutamate (Glu) levels in CUMS mice. Moreover, we revealed that venlafaxine altered the diversity of gut bacteria in CUMS mice, and at genus level, Blautia, Oscillibacter, Tyzzerella, Butyricicoccus, and Enterorhabdus are the key bacteria responsible for venlafaxine-ameliorated depression in mice. Among these potential key bacteria, Blautia, Oscillibacter, and Butyricicoccus are correlated significantly with the 5-HT and 5-hydroxyindoleacetic acid levels; while Tyzzerella is correlated markedly with Glu levels. We further show that venlafaxine affected multiple functional metabolic pathways of gut bacteria in mice with CUMS-induced depression. Our results suggest that venlafaxine possibly ameliorates depression via modulating gut bacteria, and found the potential targets of its antidepressant effects.
... Triglycerides and corresponding fatty acids are divided into three groups according to their length: short-chain fatty acids (SCFA), medium-chain FA (MCFA) and long-chain FA (LCFA) (Reviewed in (Lei et al. 2016)). SCFA (1-5 carbons: mainly acetate, butyrate and valproate) are produced by gut microbiota in the presence of dietary fibres and show neuroprotective and anti-inflammatory effects in animal models of mental and neurological disorders (Stilling et al. 2016). Saturated MCFA (6-12 carbons) are found predominantly in coconut oil and also in palm kernel oil, are absorbed and metabolized faster than LCFA (Hollis et al. 2018). ...
Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative therapeutic approaches including diets are, therefore, under investigation. Ketogenic diet (KD) is effective for treatment-resistant epilepsy and metabolic diseases, however, only a few clinical studies suggest its beneficial effect also for mental disorders. Animal models are a useful tool to uncover the underlying mechanisms of therapeutic effects. Women have a twice-higher prevalence of mood disorders but very little is known about sex differences in nutritional psychiatry. In this review, we aim to summarize current knowledge of the sex-specific effects of KD in mood disorders. Ketone bodies improve mitochondrial functions and suppress oxidative stress, inducing neuroprotective and anti-inflammatory effects which are both beneficial for mental health. Limited data also suggest KD-induced improvement of monoaminergic circuits and hypothalamus–pituitary–adrenal axis—the key pathophysiological pathways of mood disorders. Gut microbiome is an important mediator of the beneficial and detrimental effects of diet on brain functioning and mental health. Gut microbiota composition is affected in mood disorders but its role in the therapeutic effects of different diets, including KD, remains poorly understood. Still little is known about sex differences in the effects of KD on mental health as well as on metabolism and body weight. Some animal studies used both sexes but did not find differences in behavior, body weight loss or gut microbiota composition. More studies, both on a preclinical and clinical level, are needed to better understand sex-specific effects of KD on mental health.
... Short Chain Fatty Acids (SCFA), primarily butyrate, acetate, and propionate, are a class of metabolites mainly produced by the microbial fermentation of non-digestible dietary fibers in the colon (Morrison and Preston, 2016). Intriguingly, these metabolites, particularly butyrate and, to a lesser extent, propionate and acetate, have been shown to act as histone deacetylase (HDAC) inhibitors (Davie, 2003;Stilling et al., 2016;Waldecker et al., 2008). SCFA could promote the acetylation of histone proteins allowing the binding of transcription factors to DNA and eventually activating gene transcription (Thomas and Denu, 2021). ...
Neuroplasticity refers to the ability of brain circuits to reorganize and change the properties of the network, resulting in alterations in brain function and behavior. It is traditionally believed that neuroplasticity is influenced by external stimuli, learning, and experience. Intriguingly, there is new evidence suggesting that endogenous signals from the body's periphery may play a role. The gut microbiota, a diverse community of microorganisms living in harmony with their host, may be able to influence plasticity through its modulation of the gut-brain axis. Interestingly, the maturation of the gut microbiota coincides with critical periods of neurodevelopment, during which neural circuits are highly plastic and potentially vulnerable. As such, dysbiosis (an imbalance in the gut microbiota composition) during early life may contribute to the disruption of normal developmental trajectories, leading to neurodevelopmental disorders. This review aims to examine the ways in which the gut microbiota can affect neuroplasticity. It will also discuss recent research linking gastrointestinal issues and bacterial dysbiosis to various neurodevelopmental disorders and their potential impact on neurological outcomes.
... Butyrate is one of the main members of SCFA, is the main metabolite of butyrate-producing bacteria, and participates in gastrointestinal function, immune function, energy metabolism, and development and homeostasis of the central nervous system (Velázquez et al., 1997;Sitkin et al., 2021;Zhou et al., 2017b;Bridgeman et al., 2020;Sun et al., 2020;Xiong et al., 2021). It affects the central nervous system by inhibiting histone deacetylase activity or acting on SCFA receptors, preventing the occurrence and development of depression and reversing depression-like behavior (Stilling et al., 2016). Therefore, understanding the distribution and changes of butyrate-producing bacteria in the intestinal flora to regulate butyrate production is important for targeted intervention and research on the mechanism of depression. ...
Aims:
Here, regulatory effects of Xiaoyaosan polysaccharide on entire intestinal flora and butyrate-producing bacteria were investigated to reveal their pharmacological mechanism serving as bacterial-derived carbon sources for regulating intestinal microecology during the treatment of chronic unpredictable mild stress (CUMS)-induced depression in rats.
Methods and results:
The effects were measured by analyzing depression-like behavior, intestinal flora, butyrate-producing bacteria diversity, and fecal butyrate content. After intervention, CUMS rats exhibited alleviated depression and increased body weight, sugar water consumption rate, and performance index in the open-field test. The abundance of dominant phyla, such as Firmicutes and Bacteroidetes, and dominant genera, such as Lactobacillus and Muribaculaceae, was regulated to restore the diversity and abundance of the entire intestinal flora to a healthy level. The polysaccharide enriched the diversity of butyrate-producing bacteria, increased the abundance of the butyrate-producing bacteria Roseburia sp. and Eubacterium sp., reduced the abundance of Clostridium sp., increased the distribution of Anaerostipes sp., Mediterraneibacter sp., and Flavonifractor sp., and subsequently increased the content of butyrate in the intestine.
Conclusions:
These findings suggest that the Xiaoyaosan polysaccharide alleviates unpredictable mild stress-induced depression-like chronic behavior in rats by regulating the composition and abundance of the entire intestinal flora, restoring the diversity of butyrate-producing bacteria, and increasing the butyrate levels.
Background & Aims
Disorders of gut‐brain interaction (DGBI) are complex conditions that result in decreased quality of life and a significant cost burden. Linaclotide, a guanylin cyclase C (GCC) receptor agonist, is approved as a DGBI treatment. However, its efficacy has been limited and variable across DGBI patients. Microbiota and metabolomic alterations are noted in DGBI patients, provoking the hypothesis that the microbiota may impact the GCC response to current therapeutics.
Methods
Human‐derived intestinal organoids were grown from pediatric DGBI, non‐IBD colon biopsies (colonoids). Colonoids were treated with 250 nM linaclotide and assayed for cGMP to develop a model of GCC activity. Butyrate was administered to human colonoids overnight at a concentration of 1 mM. Colonoid lysates were analyzed for cGMP levels by ELISA. For the swelling assay, colonoids were photographed pre‐ and post‐treatment and volume was measured using ImageJ. Principal coordinate analyses (PCoA) were performed on the Bray–Curtis dissimilarity and Jaccard distance to assess differences in the community composition of short‐chain fatty acid (SCFA) producing microbial species in the intestinal microbiota from pediatric patients with IBS and healthy control samples.
Key Results
Linaclotide treatment induced a significant increase in [cGMP] and swelling of patient‐derived colonoids, demonstrating a human in vitro model of linaclotide‐induced GCC activation. Shotgun sequencing analysis of pediatric IBS patients and healthy controls showed differences in the composition of commensal SCFA‐producing bacteria. Butyrate exposure significantly dampened linaclotide‐induced cGMP levels and swelling in patient‐derived colonoids.
Conclusions & Inferences
Patient‐derived colonoids demonstrate that microbiota‐derived butyrate can dampen human colonic responses to linaclotide. This study supports incorporation of microbiota and metabolomic assessment to improve precision medicine for DGBI patients.
Lifestyle modifications that include adherence to healthy dietary patterns that are low in saturated fat have been associated with reduced risk for cardiovascular disease, the leading cause of death globally. Whole-milk dairy foods including milk, cheese, and yogurt, are leading sources of saturated fat in the diet. Dietary guidelines around the world recommend the consumption of low-fat and fat-free dairy foods to obtain overall healthy dietary patterns that help meet nutrient recommendations while keeping within recommended calorie and saturated fat limitations. A body of observational and clinical evidence indicates, however, that whole-milk dairy food consumption, despite saturated fat content, does not increase risk for cardiovascular disease. This review describes the proposed biological mechanisms underlying inverse associations between whole-milk dairy food consumption and risk markers for cardiometabolic health, such as altered lipid digestion, absorption, and metabolism; influence on the gut microflora; and regulation of oxidative stress and inflammatory responses. The dairy food matrix, a term used to describe how the macro- and micronutrients and other bioactive components of dairy foods are differentially packaged and compartmentalized among fluid milk, cheese, and yogurt, may dictate how each affects cardiovascular risk. Current evidence indicates consideration of dairy foods as complex food matrices, rather than delivery systems for isolated nutrients, such as saturated fatty acids, is warranted.
Soil microbiomes continue to evolve and shape the human microbiota according to external anthropogenic and climate change effects. Ancient microbes are being exposed as a result of glacier melting, soil erosion and poor agricultural practices. Soil microbes subtly regulate greenhouse gas emissions and undergo profound alterations due to poor soil maintenance. This review highlights how the soil microbiome influences human digestion processes, mineral and vitamin production, mental health and mood stimulation. Although much about microbial functions remains unknown, increasing evidence suggests that beneficial soil microbes are vital for enhancing human tolerance to diseases and pathogens. Further research is essential to delineate the specific role of the soil microbiome in promoting human health, especially in light of the increasing anthropogenic pressures and changing climatic conditions.
There is increasing evidence that mental health problems such as schizophrenia, depression and anxiety are linked with poor nutrition. At present, very few psychiatrists provide nutritional advice for their patients, despite such advice complimenting drug and psychological therapies. This edited volume is the first book to provide a comprehensive overview of the relationship between nutrition and mental health, for mental health professionals. Featuring contributions from leading authorities in the field, the book examines the link between diet and the microbiome-gut brain axis and how this correlates with a variety of psychiatric disorders. The book explores how enhancing the beneficial bacteria in the gut, through the use of psychobiotics, prebiotics or dietary change can improve mood and reduce anxiety. The book will appeal to psychiatrists and psychologists, behavioural scientists, neuroscientists and nutritionists.
The gut–brain axis refers to a bidirectional communication pathway linking the gastrointestinal system to the central nervous system. The hardware of this multifaceted pathway takes many forms, at once structural (neurons, microglia, intestinal epithelial cell barrier), chemical (neurotransmitters, enteroendocrine hormones, bacterial metabolites), and cellular (immune signaling, inflammatory pathways). The gut–brain axis is exquisitely influenced by our environment, diet, and behaviors. Here, we will describe recent progress in understanding the gut–brain axis in neurological disease, using Parkinson's disease as a guide. We will see that each component of the gut–brain axis is heavily mediated by intestinal microbiota and learn how gut–brain communication can go awry in microbial dysbiosis.
The enteric nervous system is largely autonomous, and the central nervous system is compartmentalized behind the blood-brain barrier. Yet the intestinal microbiota shapes gut function, local and systemic immune responses, and central nervous system functions including cognition and mood. In this review, we address how the gut microbiota can profoundly influence neural and immune networks. Although many of the interactions between these three systems originate in the intestinal mucosa, intestinal function and immunity are modulated by neural pathways that connect the gut and brain. Furthermore, a subset of microbe-derived penetrant molecules enters the brain and regulates central nervous system function. Understanding how these seemingly isolated entities communicate has the potential to open up new avenues for therapies and interventions.
Long-term exposure to chronic stress increases the incidence of depression. However, chronic stress is an associated risk factor in only a subset of individuals. Inflammation has been identified as a putative mechanism promoting stress vulnerability. Because of the gut microbiota's potential role as a source of inflammatory substances, short-chain fatty acids (SCFAs) may exert their influence on inflammation, emotional states, and cognition via the gut-brain axis. In this study, Classic behavioral tests were used to categorize C57BL/6 J mice into a CUMS-vulnerable and a CUMS-resilient group after they were exposed to chronic unpredictable mild stress (CUMS). We compared the 16S ribosomal RNA (rRNA) gene sequences retrieved from fecal samples between control, CUMS-vulnerable, and CUMS-resilient mice. SCFAs in fecal samples were detected by liquid chromatography and gas chromatography-mass spectrometry. Hippocampal cytokine production and TLR4/MYD88/NF-κB inflammatory pathway activation were evaluated using enzyme-linked immunosorbent assays (ELISAs) and western blotting. Then, we supplemented SCFAs in CUMS mice. we observed depression-like behavior and the expression of TLR4/MYD88/NF-κB inflammatory pathway in hippocampus of SCFAs supplementation mice. Susceptible mice to CUMS showed more severe symptoms of depression and anxiety, α diversity was significantly different, as well as higher expression of interleukin (IL)-1β and TLR4/MYD88/NF-κB inflammatory pathway components in the hippocampus. SCFA levels in the feces were significantly higher in CUMS-resilient mice than in control mice. Depressive behavior was reversed in CUMS-SCFAs group, and the protein level of TLR4/MYD88/NF-κB in hippocampus was decreased. Overall, these results provide new light on the possible involvement of the microbiome in the gut-brain axis development in depressive disorder and provide a theoretical basis for identifying novel therapeutic targets.
Introduction
Small intestinal bacterial overgrowth (SIBO) is common in irritable bowel disease (IBS) and has been proposed as an etiologic factor. This study aimed to identify potential fecal microbiota profiles in patients with IBS and SIBO.
Methods
Patients with IBS were divided into two groups: IBS with SIBO (IBS.SIBO+) and IBS without SIBO (IBS.SIBO-). SIBO was identified using a standard glucose hydrogen breath test. A total of 52 subjects were enrolled in this study, of whom 18 were normal controls (NCs), 17 had IBS with SIBO, and 17 had IBS without SIBO. The IBS symptom severity scale, abdominal pain, and health-related quality of life (QoL) were evaluated using questionnaires. Rectal balloon distension was used to measure the visceral sensitivity. Fresh fecal samples were collected, and 16S rRNA gene sequencing analysis was performed to evaluate the structure and diversity of the microbiota among different groups. Correlation analysis was performed to assess the relationship between specific flora and abdominal pain, visceral sensitivity, and QoL.
Results
The richness of the intestinal microbiota in the IBS without SIBO group was significantly lower than that in the IBS with SIBO group (P = 0.012). At the phylum level, the relative abundance of Firmicutes decreased significantly in fecal samples collected from patients with IBS and SIBO compared to those in the NC and IBS groups. No significant difference was found between the IBS with SIBO and IBS without SIBO groups, although the phylum type showed a decreasing trend in the latter. At the genus level, Fusobacterium (P = 0.01) was significantly less abundant in the IBS with SIBO group than in the NC group; however, no significant difference was found between the IBS with SIBO and IBS without SIBO groups. The relative abundance of Firmicutes correlated negatively with the abdominal pain scale (r = 0.436, P = 0.026) and the IBS symptom severity scale (r = 0.494, P = 0.010), whereas a positive correlation was found between the defecation distress threshold and Firmicutes (r = 0.458, P = 0.019).
Conclusions
Fecal microbiota showed obvious dysbiosis in patients with IBS and SIBO compared to those without SIBO. The decreased abundance of Firmicutes may be related to IBS symptoms and abdominal pain, rather than visceral sensitivity.
Stroke is a significant public health concern for elderly individuals. However, the majority of pre-clinical studies utilize young and healthy rodents, which may result in failure of candidate therapies in clinical trials. In this brief review/perspective, the complex link between circadian rhythms, aging, innate immunity, and the gut microbiome to ischemic injury onset, progression, and recovery is discussed. Short-chain fatty acids and nicotinamide adenine dinucleotide+ (NAD+ ) production by the gut microbiome are highlighted as key mechanisms with profound rhythmic behavior, and it is suggested to boost them as prophylactic/therapeutic approaches. Integrating aging, its associated comorbidities, and circadian regulation of physiological processes into stroke research may increase the translational value of pre-clinical studies and help to schedule the optimal time window for existing practices to improve stroke outcome and recovery.
A fundamental shift in neuroscience suggests bidirectional interaction of gut microbiota with the healthy and dysfunctional brain. This microbiota-gut-brain axis has mainly been investigated in stress-related psychopathology (e.g. depression, anxiety). The hippocampus, a key structure both the healthy brain and these psychopathologies, is implicated by work in rodents that suggests gut microbiota substantially impact hippocampal-dependent learning and memory. However, understanding microbiota-hippocampus mechanisms in health and disease, and translation to humans, is hampered by the absence of a coherent evaluative approach. We review the current knowledge regarding four main gut microbiota-hippocampus routes in rodents: through the vagus nerve; via the hypothalamus-pituitary-adrenal-axis; by metabolism of neuroactive substances; and through modulation of host inflammation. Next, we suggest an approach including testing (biomarkers of) the four routes as a function of the influence of gut microbiota (composition) on hippocampal-dependent (dys)functioning. We argue that such an approach is necessary to proceed from the current state of preclinical research to beneficial application in humans to optimise microbiota-based strategies to treat and enhance hippocampal-dependent memory (dys)functions.
Short-chain fatty acids (SCFAs, especially butyric acid) have been demonstrated to play a promising role in the development of autism spectrum disorders (ASD). Recently, the hypothalamic–pituitary–adrenal (HPA) axis is also suggested to increase the risk of ASD. However, the mechanism underlying SCFAs and HPA axis in ASD development remains unknown. Here, we show that children with ASD exhibited lower SCFA concentrations and higher cortisol levels, which were recaptured in prenatal lipopolysaccharide (LPS)-exposed rat model of ASD. These offspring also showed decreased SCFA-producing bacteria and histone acetylation activity as well as impaired corticotropin-releasing hormone receptor 2 (CRHR2) expression. Sodium butyrate (NaB), which can act as histone deacetylases inhibitors, significantly increased histone acetylation at the CRHR2 promoter in vitro and normalized the corticosterone as well as CRHR2 expression level in vivo . Behavioral assays indicated ameliorative effects of NaB on anxiety and social deficit in LPS-exposed offspring. Our results imply that NaB treatment can improve ASD-like symptoms via epigenetic regulation of the HPA axis in offspring; thus, it may provide new insight into the SCFA treatment of neurodevelopmental disorders like ASD.
IMPORTANCE
Growing evidence suggests that microbiota can affect brain function and behavior through the “microbiome–gut–brain’’ axis, but its mechanism remains poorly understood. Here, we show that both children with autism and LPS-exposed rat model of autism exhibited lower SCFA concentrations and overactivation of HPA axis. SCFA-producing bacteria, Lactobacillus , might be the key differential microbiota between the control and LPS-exposed offspring. Interestingly, NaB treatment contributed to the regulation of HPA axis (such as corticosterone as well as CRHR2) and improvement of anxiety and social deficit behaviors in LPS-exposed offspring. The potential underlying mechanism of the ameliorative effect of NaB may be mediated via increasing histone acetylation to the CRHR2 promoter. These results enhance our understanding of the relationship between the SCFAs and the HPA axis in the development of ASD. And gut microbiota-derived SCFAs may serve as a potential therapeutic agent to neurodevelopmental disorders like ASD.
Huntington's disease (HD) is a complex progressive neurodegenerative disorder affected by genetic, environmental, and metabolic factors contributing to its pathogenesis. Gut dysbiosis is termed as the alterations of intestinal microbial profile. Emerging research has highlighted the pivotal role of gut dysbiosis in HD, focusing on the gut-brain axis as a novel research parameter in science. This review article provides a comprehensive overview of gut microbiota dysbiosis and its relationship with HD and its pathogenesis along with the future challenges and opportunities. The focuses on the essential mechanisms which link gut dysbiosis to HD pathophysiology including neuroinflammation, immune system dysregulation, altered metabolites composition, and neurotransmitter imbalances. We also explored the impacts of gut dysbiosis on HD onset, severity, and symptoms such as cognitive decline, motor dysfunction, and psychiatric symptoms. Furthermore, we highlight recent advances in therapeutics including microbiota-based therapeutic approaches, including dietary interventions, prebiotics, probiotics, fecal microbiota transplantation, and combination therapies with conventional HD treatments and their applications in managing HD. The future challenges are also highlighted as the heterogeneity of gut microbiota, interindividual variability, establishing causality between gut dysbiosis and HD, identifying optimal therapeutic targets and strategies, and ensuring the long-term safety and efficacy of microbiota-based interventions. This review provides a better understanding of the potential role of gut microbiota in HD pathogenesis and guides the development of novel therapeutic approaches.
Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
Introduction
Females in the perimenopausal period are susceptible to mood disorders. Perimenopausal panic disorder (PPD) is characterized by repeated and unpredictable panic attacks during perimenopause, and it impacts the patient's physical and mental health and social function. Pharmacotherapy is limited in the clinic, and its pathological mechanism is unclear. Recent studies have demonstrated that gut microbiota is strongly linked to emotion; however, the relation between PPD and microbiota is limitedly known.
Methods
This study aimed to discover specific microbiota in PPD patients and the intrinsic connection between them. Gut microbiota was analyzed in PPD patients ( n = 40) and healthy controls ( n = 40) by 16S rRNA sequencing.
Results
The results showed reduced α-diversity (richness) in the gut microbiota of PPD patients. β-diversity indicated that PPD and healthy controls had different intestinal microbiota compositions. At the genus level, 30 species of microbiota abundance had significantly different between the PPD and healthy controls. In addition, HAMA, PDSS, and PASS scales were collected in two groups. It was found that Bacteroides and Alistipes were positively correlated with PASS, PDSS, and HAMA.
Discussion
Bacteroides and Alistipes dysbiosis dominate imbalanced microbiota in PPD patients. This microbial alteration may be a potential pathogenesis and physio-pathological feature of PPD. The distinct gut microbiota can be a potential diagnostic marker and a new therapeutic target for PPD.
Phellinus linteus polysaccharide (PLP) had received increasing attention due to its multiple biological activities. Herein, the extraction, characterization and in vitro fermentation of PLP were studied to explore its physiochemical properties and the interaction mechanism between the gut microbiota and PLP. The results obtained demonstrated that PLP was mainly composed of 9 monosaccharides, with three gel chromatographic peaks and molecular weights (Mw) of 308.45 kDa, 13.58 kD and 3.33 kDa, respectively. After 48 h fermentation, the Mw, total sugar, reducing sugar, pH and monosaccharides composition were decreased. Furthermore, PLP regulated the composition of gut microbiota, such as promoting the proliferation of beneficial bacteria such as Bacteroides, Prevotella and Butyricimonas, while preventing the growth of pathogenic bacteria such as Escherichia-Shigella, Morganella and Intestinimonas. Gut microbiota metabolites regulated by PLP such as short-chain fatty acids were the main regulators that impact the host health. Bioinformatics analysis indicated that butyrate, bile acid and purine metabolism were the main metabolic pathways of PLP regulating host health, and the Bacteroides was the key genus to regulate these metabolic pathways. In conclusion, our finding suggested that PLP may be used as a prebiotic agent for human health because of its ability to regulate gut microbiota.
Alzheimer’s disease (AD) is the most common neurodegenerative disease, yet it currently lacks effective treatment due to its complex etiology. The pathological changes in AD have been linked to the neurotoxic immune responses following aggregation of Aβ and phosphorylated tau. The gut microbiota (GM) is increasingly studied for modulating neuroinflammation in neurodegenerative diseases and in vivo studies emerge for AD. This critical review selected 7 empirical preclinical studies from 2019 onwards assessing therapy approaches targeting GM modulating microglia neuroinflammation in AD mouse models. Results from probiotics, fecal microbiota transplantation, and drugs were compared and contrasted, including for cognition, neuroinflammation, and toxic aggregation of proteins. Studies consistently reported significant amelioration or prevention of cognitive deficits, decrease in microglial activation, and lower levels of pro-inflammatory cytokines, compared to AD mouse models. However, there were differences across papers for the brain regions affected, and changes in astrocytes were inconsistent. Aβ plaques deposition significantly decreased in all papers, apart from Byur dMar Nyer lNga Ril Bu (BdNlRB) treatment. Tau phosphorylation significantly declined in 5 studies. Effects in microbial diversity following treatment varied across studies. Findings are encouraging regarding the efficacy of study but information on the effect size is limited. Potentially, GM reverses GM derived abnormalities, decreasing neuroinflammation, which reduces AD toxic aggregations of proteins in the brain, resulting in cognitive improvements. Results support the hypothesis of AD being a multifactorial disease and the potential synergies through multi-target approaches. The use of AD mice models limits conclusions around effectiveness, as human translation is challenging.
Introduction:
As a chronic encephalopathy, drug addiction is responsible for millions of deaths per year around the world. The gut microbiome is a crucial component of the human microbiome. Through dynamic bidirectional communication along the 'gut-brain axis,' gut bacteria cooperate with their hosts to regulate the development and function of the immune, metabolic, and nervous systems.
Method:
These processes may affect human health because some brain diseases are related to the composition of gut bacteria, and disruptions in microbial communities have been implicated in neurological disorders.
Result:
We review the compositional and functional diversity of the gut microbiome in drug addiction. We discuss intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems and possible contributions by the gut microbiota to neurological disorders.
Conclusion:
Finally, the treatment of probiotics and fecal transplantation was summarized. This was done to further understand the role of intestinal microecology in the pathogenesis of drug addiction and to explore new methods for the treatment of drug addiction.
Multiple factors affect cognitive health, such as age-related changes in the brain, injuries, mood disorders, substance abuse, and diseases. While some cannot be changed, evidence exists of many potentially possibly modifiable lifestyle factors: diet, physical activity, cognitive and social engagement, smoking and alcohol consumption which may stabilize or improve declining cognitive function. In nutrition, the focus has been mainly on its role in brain development in the early years. There is a strong emerging need to identify the role of diet and nutrition factors on age-related cognitive decline, which will open up the use of new approaches for prevention, treatment or management of age-related disorders and maintaining a good quality of life among older adults. While data on effect of high protein diets is not consistent, low-fat diets are protective against cognitive decline. Several micronutrients like B group vitamins and iron, as well as many polyphenols play a crucial role in cognitive health. Mediterranean, Nordic, DASH, and MIND diets are linked to a lower risk of cognitive decline and dementia. The relationship between the gut microbiome and brain function through the gut-brain axis has led to the emergence of data on the beneficial effects of dietary fibers and probiotics through the management of gut microbes. A “whole diet” approach as well as macro- and micro-nutrient intake levels that have protective effects against cardiovascular diseases are most likely to be effective against neurodegenerative disorders too. Young adulthood and middle age are crucial periods for determining cognitive health in old age. The importance of cardio metabolic risk factors such as obesity and hypertension, smoking and physical inactivity that develop in middle age suggest that preventive approaches are required for target populations in their 40s and 50s, much before they develop dementia. The commonality of dementia risk with cardiovascular and diabetes risk suggests that dementia could be added to present non-communicable disease management programs in primary healthcare and broader public health programs.
Background:
Evidence suggests that intake of blueberry (poly)phenols is associated with improvements in vascular function and cognitive performance. Whether these cognitive effects are linked to increases in cerebral and vascular blood flow or changes in the gut microbiota is currently unknown.
Methods:
A double-blind, parallel randomized controlled trial was conducted in 61 healthy older individuals aged 65-80 y. Participants received either 26g of freeze-dried wild blueberry (WBB) powder (302 mg anthocyanins) or a matched placebo (0 mg anthocyanins). Endothelial function measured by flow-mediated dilation (FMD), cognitive function, arterial stiffness, blood pressure (BP), cerebral blood flow (CBF), gut microbiome and blood parameters were measured at baseline and 12 weeks following daily consumption. Plasma and urinary (poly)phenol metabolites were analyzed using micro-elution solid phase-extraction coupled with LC-MS.
Results:
A significant increase in FMD and reduction in 24 h ambulatory systolic BP were found in the WBB group compared to placebo (0.86%; 95% CI 0.56, 1.17, p<0.001; -3.59 mmHg; 95% CI -6.95, -0.23, p=0.037; respectively). Enhanced immediate recall on the auditory verbal learning task, alongside better accuracy on a task-switch task were also found following WBB treatment compared to placebo (p<0.05). Total 24 h urinary (poly)phenol excretion increased significantly in the WBB group compared to placebo. No changes in CBF or gut microbiota composition were found.
Conclusions:
Daily intake of WBB powder, equivalent to 178 g fresh weight, improves vascular and cognitive function, and decreases 24h ambulatory systolic BP in healthy older individuals. This suggests that WBB (poly)phenols may reduce future cardiovascular disease (CVD) disease risk in an older population, and may improve episodic memory processes and executive functioning in older adults at risk of cognitive decline. CLINICAL TRIAL REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT04084457.
Hippocampal dysregulation might be a key pathophysiological factor for memory impairments in psychosis. Contemporary models particularly postulate that an imbalance of hippocampal glutamate and GABA leads to impaired memory and may thus serve as a therapeutic target to improve memory deficits. However, currently available interventions in early stages of psychosis do not explicitly target hippocampal pathology. A novel approach for manipulating hippocampus-dependent memory processes is provided via the gut microbiota. In this perspective article, we first recapitulate compelling evidence for emerging hippocampus pathology during the development of psychosis. The following sections emphasize the critical role of the gut microbiota in hippocampus plasticity and memory, and summarize existing evidence of gut microbiota alterations in different stages of psychosis. Finally, we propose a novel conceptual roadmap for future studies deciphering gut microbiota–hippocampus synergisms in emerging psychosis and argue that specific microbial supplementation might be promising for improving hippocampus-dependent memory deficits in early stages of psychosis.
The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.
Major depressive disorder (MDD) is the result of complex gene-environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with 'depression microbiota' derived from MDD patients resulted in depression-like behaviors compared with colonization with 'healthy microbiota' derived from healthy control individuals. Mice harboring 'depression microbiota' primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host's metabolism.Molecular Psychiatry advance online publication, 12 April 2016; doi:10.1038/mp.2016.44.
As interest in the gut microbiome has grown in recent years, attention has turned to the impact of our diet on our brain. The benefits of a high fiber diet in the colon have been well documented in epidemiological studies, but its potential impact on the brain has largely been understudied. Here, we will review evidence that butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, can improve brain health. Butyrate has been extensively studied as a histone deacetylase (HDAC) inhibitor but also functions as a ligand for a subset of G protein-coupled receptors and as an energy metabolite. These diverse modes of action make it well suited for solving the wide array of imbalances frequently encountered in neurological disorders. In this review, we will integrate evidence from the disparate fields of gastroenterology and neuroscience to hypothesize that the metabolism of a high fiber diet in the gut can alter gene expression in the brain to prevent neurodegeneration and promote regeneration.
Human skin emits a variety of volatile metabolites, many of them odorous. Much previous work has focused upon chemical structure and biogenesis of metabolites produced in the axillae (underarms), which are a primary source of human body odour. Nonaxillary skin also harbours volatile metabolites, possibly with different biological origins than axillary odorants.
To take inventory of the volatile organic compounds (VOCs) from the upper back and forearm skin, and assess their relative quantitative variation across 25 healthy subjects.
Two complementary sampling techniques were used to obtain comprehensive VOC profiles, viz., solid-phase microextraction and solvent extraction. Analyses were performed using both gas chromatography/mass spectrometry and gas chromatography with flame photometric detection.
Nearly 100 compounds were identified, some of which varied with age. The VOC profiles of the upper back and forearm within a subject were, for the most part, similar, although there were notable differences.
The natural variation in nonaxillary skin odorants described in this study provides a baseline of compounds we have identified from both endogenous and exogenous sources. Although complex, the profiles of volatile constituents suggest that the two body locations share a considerable number of compounds, but both quantitative and qualitative differences are present. In addition, quantitative changes due to ageing are also present. These data may provide future investigators of skin VOCs with a baseline against which any abnormalities can be viewed in searching for biomarkers of skin diseases.
Butyrate is one of the major short chain fatty acids produced in the gut via microbial fermentation and a preferred energy source for gut epithelial cells. Butyrate exerts a broad range of biological effects, mainly as a potent histone deacetylase inhibitor. Butyrate also binds to its own receptors on the cell membrane. Recent RNA-seq analysis reveals that butyrate significantly alters the expression of 11,443 genes in vitro, representing ~65% of all genes transcribed in the epithelial transcriptome. Numerous butyrate-producing bacteria from phylogenetically diverse groups have been isolated from host-associated habitats. Luminal butyrate concentrations, which vary tremendously along the gastrointestinal tract, result from the balance between its biosynthesis, absorption, and utilization by intestinal epithelial cells, and excretion. Mounting evidence indicates that reduced butyrate production has important physiological and pathological implications. Moreover, intracellular butyrate concentrations are suggested to be a key determinant of its biological functions. Extensive research over the past decades has identified numerous butyrogenic carbohydrate substrates. The potency of these substrates in stimulating butyrate biosynthesis depends on their structural features, including polymer chain lengths. Many of these butyrogenic compounds have the potential to be prebiotics. Selected bifidogenic and butyrogenic bacterial strains, especially those hyperbutyrate producers, possess the ability to increase butyrate production. Furthermore, the capacity of butyrate biosynthesis in the gut microbiota is readily inducible. The effects of different combinations of various prebiotics or pre- and pro-biotics (synbiotics) on butyrate biosynthesis have proven to be additive or even synergistic. Alternative approaches to enhance butyrate bioavailability will also be discussed in this chapter.
GPR41 and GPR43 are a pair of mammalian G-protein coupled receptors (GPCRs) expressed in human adipocytes, colon epithelial cells and peripheral blood mononuclear cells. These receptors are activated by short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate– which are produced during dietary fiber fermentation by resident gut bacteria. This unique ligand specificity suggests that GPR41 and GPR43 may mediate the interaction between the human host and the gut microbiome. Indeed, studies on knockout mice implicate GPR41 and GPR43 in chronic inflammatory disorders such as obesity, colitis, asthma and arthritis. However, whether GPR41 and GPR43 are protective or causative is inconsistent between studies. This discrepancy may be due to differences in the disease models used, the inbred mouse strains or non-specific knockout effects. Here, we review the latest findings on GPR41 and GPR43, highlighting contradictory observations. With GPR41 and GPR43 being considered as drug targets, it is pertinent that their role is fully elucidated. We propose that future studies on human tissues, ex vivo, may allow us to confirm the role of GPR41 and GPR43 in humans, be it protective or causative.
Despite its negative impact on performances because of lower protein and energy digestibility, increasing attention has been paid in the past decade to dietary fibre in swine nutrition due to its multiple functionalities. The present review examines the influence of dietary fibre on the digestive processes and the consequences on pig protein and energy nutrition, health concerns and environmental issues. Dietary fibre is defined as the plant polysaccharides that are resistant to digestive secretions and are potentially available for bacterial fermentation in the intestines of single-stomached animals. Resistant starch is also considered as a dietary fibre. The short-chain fatty acids released by bacteria contribute to the host energy supply and both regulate the composition of the flora and the growth of epithelial cells, especially in the case of butyrate. The bacterial growth supported by the fermentation induces a shift of N excretion from urine to faeces. Beside the fermentability, the physical properties of dietary fibre such as the water-holding capacity, the viscosity and the solubility influence the digestion, the satiety and the transit time. In relationship with the mechanisms of dietary fibre interaction with the digestive processes exposed in this review, the opportunities and treats of dietary fibre inclusion in swine rations for intensified and for more extensive tropical production systems are discussed. Dietary fibre is indeed a possible means to reduce nitrogen losses of production units and to improve pig intestinal health and animal welfare. Finally, the potential role of in vitro fermentation methods to investigate the fate of dietary fibre in the digestive system is discussed. © 2008 FAC UNIV SCIENCES AGRONOMIQUES GEMBLOUX. All rights reserved.
Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how cellular metabolism and protein acetylation change during early aging in Drosophila melanogaster. Contrary to common assumptions, we find that flies increase oxygen consumption and become less sensitive to histone deacetylase inhibitors as they reach midlife. Further, midlife flies show changes in the metabolome, elevated acetyl-CoA levels, alterations in protein-notably histone-acetylation, as well as associated transcriptome changes. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL) or the levels of the histone H4 K12-specific acetyltransferase Chameau. We find that these targeted interventions both alleviate the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal life span.
Despite some block-buster G protein-coupled receptor (GPCR) drugs only a small fraction (~15%) of the more than 390 non-odorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent de-orphanization programmes that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short chain fatty acids acetate, propionate and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic β-cells, FFA3 on neurons and FFA2 on leukocytes and adipocytes means that the biological role of these receptors likely extends beyond that of the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here we review the physiological roles of FFA2 and FFA3, the recent development and use of receptor selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.
Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
G protein-coupled receptor 109A (GPR109A) activation by its ligand nicotinic acid (NA) in immune cells increases Ca2+ levels, and Ca2+ induces glutamate release, and oxidative stress in central blood pressure (BP) regulating nuclei e.g. the rostral ventrolateral medulla (RVLM) leading to sympathoexcitation. Despite NA ability to reach the brain, the expression and function of its receptor GPR109A in the RVLM remains unknown. We hypothesized that NA activation of RVLM GPR109A causes Ca2+ dependent L-glutamate release, and subsequently increases neuronal oxidative stress, sympathetic activity, and BP. To test this hypothesis, we adopted a multilevel approach, which included pharmacological in vivo studies along with ex vivo and in vitro molecular studies in PC12 cells (exhibit neuronal phenotype). We present the first evidence for GPR109A expression in the RVLM and in PC12 cells. Next, we showed that RVLM GPR109A activation (NA) caused pressor and bradycardic responses in conscious rats. The resemblance of these responses to those caused by intra-RVLM glutamate, and their attenuation by NMDA receptor (NMDAR) blockade (2-amino-5-phosphonopentanoic acid; AP5) and enhancement by L-glutamate uptake inhibition (L-trans-Pyrrolidine-2,4-dicarboxylic acid; PDC) supported our hypothesis. NA increased Ca2+, glutamate, nitric oxide (NO) and reactive oxygen species (ROS) levels in PC12 cells and increased RVLM ROS levels. The inactive NA analog iso-nicotinic acid (IsoNA) failed to replicate the cardiovascular and biochemical effects of NA. Further, GPR109A knockdown (siRNA) abrogated the biochemical effects of NA in PC12 cells. These novel findings yield new insight into the role of RVLM GPR109A in central BP control.
The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a "leaky gut" may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function.
Cross-feeding is an important metabolic interaction mechanism of bacterial groups inhabiting the human colon and includes features such as the utilization of acetate by butyrate-producing bacteria as may occur between Bifidobacterium and Faecalibacterium genera. In this study we assessed the utilization of different carbon sources (glucose, starch, inulin and fructo-oligosaccharides) by strains of both genera and selected the best suited combinations for evidencing this cross-feeding phenomenon. Co-cultures of B. adolescentis L2-32 with F. prausnitzii S3/L3 with fructo-oligosaccharides as carbon source, as well as with F. prausnitzii A2-165 in starch, were carried out and the production of short chain fatty acids was determined. In both co-cultures acetate levels decreased between 8 to 24 h of incubation and were lower than in the corresponding B. adolescentis monocultures. In contrast, butyrate concentrations were higher in co-cultures as compared to the respective F. prausnitzii monocultures, indicating enhanced formation of butyrate by F. prausnitzii in the presence of the bifidobacteria. Variations in the levels of acetate and butyrate were more pronounced in the co-culture with fructo-oligosaccharides than with starch. Our results provide a clear demonstration of cross-feeding between B. adolescentis and F. prausnitzii.
Probiotics actively participate in neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and vascular dementia (VaD) is poorly understood. Here, we used a mouse model of VaD induced by a permanent right unilateral common carotid arteries occlusion (rUCCAO) to investigate the neuroprotective effects and possible underlying mechanisms of Clostridium butyricum. Following rUCCAO, C. butyricum was intragastrically administered for 6 successive weeks. Using the Morris water maze, cognitive function was assessed in mice. Histopathological changes in the hippocampus were also assessed. Using Western blot analysis and immunohistochemistry, the expression of BDNF-PI3K/Akt pathway-related proteins (BDNF, Akt, p-Akt, Bcl-2, Bax) in the brain were analyzed. In addition, the diversity of gut microbiota was assessed and the levels of butyrate in the caecal content and the brain were determined. Our data demonstrate that C. butyricum treatment significantly attenuated the cognitive dysfunction and histopathological changes that normally occur in mice with VaD. C. butyricum treatment not only increased the levels of BDNF and Bcl-2 and decreased Bax expression, but also induced Akt phosphorylation (p-Akt), and ultimately reduced apoptosis in the hippocampus of mice with VaD. In addition, C. butyricum treatment could regulate the gut microbiota leading to an improved production of metabolic short chain fatty acids (SCFAs) resulting in a butyrate neuroprotective effect. These findings suggest that the altered gut microbiota, especially of those with the ability to influence the probiotic-gut microbiota-butyrate-brain axis, stimulated the differential production of butyrate that in turn elevated butyrate levels in the brain to protect against VaD in mice. These results open new avenues for viable therapeutic options against VaD by gut microbiota modulation.
The relevance of the butyrate-sensing olfactory receptor OR51E1 for gastrointestinal (GIT) functioning has not been considered so far. We investigated in young pigs the distribution of OR51E1 along the GIT, its relation with some endocrine markers, its variation with age and after interventions affecting the gut environment and intestinal microbiota. Immuno-reactive cells for OR51E1 and chromogranin A (CgA) were counted in cardial (CA), fundic (FU), pyloric (PL) duodenal (DU), jejunal (JE), ileal (IL), cecal (CE), colonic (CO) and rectal (RE) mucosae. OR51E1 co-localization with serotonin (5HT) and peptide YY (PYY) were evaluated in PL and CO respectively. FU and PL tissues were also sampled from 84 piglets reared from sows receiving either or not oral antibiotics (amoxicillin) around parturition, and sacrificed at days 14, 21, 28 (weaning) and 42 of age. JE samples were also obtained from 12 caesarean-derived piglets that were orally associated with simple (SA) or complex (CA) microbiota in the postnatal phase, and of which on days 26-37 of age jejunal loops were perfused for 8 h with enterotoxigenic Escherichia coli F4 (ETEC), Lactobacillus amylovorus or saline (CTRL). Tissue densities of OR51E1+ cells were in decreasing order: PL=DU>FU=CA>JE=IL=CE=CO=RE. OR51E1+ cells showed an enteroendocrine nature containing gastrointestinal hormones such as PYY or 5HT. OR51E1 gene expression in PL and FU increased during and after the suckling period (p
Available evidence on the bioactive, nutritional and putative detrimental properties of gut microbial metabolites has been evaluated to support a more integrated view of how prebiotics might affect host health throughout life. The present literature inventory targeted evidence for the physiological and nutritional effects of metabolites, for example, SCFA, the potential toxicity of other metabolites and attempted to determine normal concentration ranges. Furthermore, the biological relevance of more holistic approaches like faecal water toxicity assays and metabolomics and the limitations of faecal measurements were addressed. Existing literature indicates that protein fermentation metabolites (phenol,
p
-cresol, indole, ammonia), typically considered as potentially harmful, occur at concentration ranges in the colon such that no toxic effects are expected either locally or following systemic absorption. The endproducts of saccharolytic fermentation, SCFA, may have effects on colonic health, host physiology, immunity, lipid and protein metabolism and appetite control. However, measuring SCFA concentrations in faeces is insufficient to assess the dynamic processes of their nutrikinetics. Existing literature on the usefulness of faecal water toxicity measures as indicators of cancer risk seems limited. In conclusion, at present there is insufficient evidence to use changes in faecal bacterial metabolite concentrations as markers of prebiotic effectiveness. Integration of results from metabolomics and metagenomics holds promise for understanding the health implications of prebiotic microbiome modulation but adequate tools for data integration and interpretation are currently lacking. Similarly, studies measuring metabolite fluxes in different body compartments to provide a more accurate picture of their nutrikinetics are needed.
Over the last 20 years there has been an increasing interest in the influence of the gastrointestinal tract on appetite regulation. Much of the focus has been on the neuronal and hormonal relationship between the gastrointestinal tract and the brain. There is now mounting evidence that the colonic microbiota and their metabolic activity play a significant role in energy homeostasis. The supply of substrate to the colonic microbiota has a major impact on the microbial population and the metabolites they produce, particularly short chain fatty acids (SCFAs). SCFAs are produced when non-digestible carbohydrates, namely dietary fibres and resistant starch, undergo fermentation by the colonic microbiota. Both the consumption of fermentable carbohydrates and the administration of SCFAs have been reported to result in a wide range of health benefits including improvements in body composition, glucose homeostasis, blood lipid profiles, and reduced body weight and colon cancer risk. However, published studies tend to report the effects that fermentable carbohydrates and SCFAs have on specific tissues and metabolic processes, and fail to explain how these local effects translate into systemic effects and the mitigation of disease risk. Moreover, studies have tended to investigate SCFAs collectively and neglect to report the effects associated with individual SCFAs. Here, we bring together the recent evidence and suggest an overarching model for the effects of SCFAs on one of their beneficial aspects: appetite regulation and energy homeostasis.International Journal of Obesity accepted article preview online, 14 May 2015. doi:10.1038/ijo.2015.84.
Dimethyl fumarate (DMF), recently approved as an oral immunomodulatory treatment for relapsing-remitting multiple sclerosis (MS), metabolizes to monomethyl fumarate (MMF) which crosses the blood–brain barrier and has demonstrated neuroprotective effects in experimental studies. We postulated that MMF exerts neuroprotective effects through modulation of microglia activation, a critical component of the neuroinflammatory cascade that occurs in neurodegenerative diseases such as MS. To ascertain our hypothesis and define the mechanistic pathways involved in the modulating effect of fumarates, we used real-time PCR and biochemical assays to assess changes in the molecular and functional phenotype of microglia, quantitative Western blotting to monitor activation of postulated pathway components, and ex vivo whole-cell patch clamp recording of excitatory post-synaptic currents in corticostriatal slices from mice with experimental autoimmune encephalomyelitis (EAE), a model for MS, to study synaptic transmission. We show that exposure to MMF switches the molecular and functional phenotype of activated microglia from classically activated, pro-inflammatory type to alternatively activated, neuroprotective one, through activation of the hydroxycarboxylic acid receptor 2 (HCAR2). We validate a downstream pathway mediated through the AMPK–Sirt1 axis resulting in deacetylation, and thereby inhibition, of NF-κB and, consequently, of secretion of pro-inflammatory molecules. We demonstrate through ex vivo monitoring of spontaneous glutamate-mediated excitatory post-synaptic currents of single neurons in corticostriatal slices from EAE mice that the neuroprotective effect of DMF was exerted on neurons at pre-synaptic terminals by modulating glutamate release. By exposing control slices to untreated and MMF-treated activated microglia, we confirm the modulating effect of MMF on microglia function and, thereby, its indirect neuroprotective effect at post-synaptic level. These findings, whereby DMF-induced activation of a new HCAR2-dependent pathway on microglia leads to the modulation of neuroinflammation and restores synaptic alterations occurring in EAE, represent a possible novel mechanism of action for DMF in MS.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-015-1422-3) contains supplementary material, which is available to authorized users.
G-protein coupled receptor 41 (GPR41) also called free fatty acid receptor 3 (FFAR3) is a Gαi-coupled receptor activated by short chain fatty acids (SCFAs) mainly produced from dietary complex carbohydrate fibers in the large intestine as products of fermentation by the microbiota. FFAR3 is expressed in enteroendocrine cells, but has recently also been shown to be present in sympathetic neurons of the superior cervical ganglion. The aim of this study was to investigate whether the FFAR3 is present in other autonomic and sensory ganglia possibly influencing gut physiology. Cryostat sections were cut of autonomic and sensory ganglia of a transgenic reporter mouse expressing the monomeric red fluorescent protein (mRFP) gene under the control of the FFAR3 promoter. Control for the specific expression was also done by immunohistochemistry with an antibody against the reporter protein. mRFP expression was as expected found in neurons of the superior cervical ganglion, but also in sympathetic ganglia of the thoracic and lumbar sympathetic trunk. Further, neurons in prevertebral ganglia expressed the mRFP reporter. FFAR3-mRFP expressing neurons were also present in both autonomic and sensory ganglia such as the vagal ganglion, the spinal dorsal root ganglion and the trigeminal ganglion. No expression was observed in the brain or spinal cord. By use of radioactive labeled antisense DNA probes, mRNA encoding the FFAR3 was found to be present in cells of the same ganglia. Further, the expression of the FFAR3 in the ganglia of the transgenic mice was confirmed by immunohistochemistry using an antibody directed against the receptor protein, and double labelling colocalized mRFP and the FFAR3-protein in the same neurons. Finally, qRT-PCR on extracts from the ganglia supported the presence mRNA encoding the FFAR3 in most of the investigated tissues. These data indicate that FFAR3 is expressed on postganglionic sympathetic and sensory neurons in both the autonomic and somatic peripheral nervous system and that SCFAs act not only through the enteroendocrine system but also directly by modifying physiological reflexes integrating the peripheral nervous system and the gastro-intestinal tract.
Copyright © 2015. Published by Elsevier Ltd.
Epigenetic drugs like sodium butyrate (NaB) show antidepressant-like effects in preclinical studies, but the exact molecular mechanisms of the antidepressant effects remain unknown. While research using NaB has mainly focused on its role as a histone deacetylase inhibitor (HDACi), there is also evidence that NaB affects DNA methylation.
The purpose of this study was to examine NaB's putative antidepressant-like efficacy in relation to DNA methylation changes in the prefrontal cortex of an established genetic rat model of depression (the Flinders Sensitive Line [FSL]) and its controls (the Flinders Resistant Line).
The FSL rats had lower levels of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which catalyzes the conversion of DNA methylation to hydroxymethylation. As indicated by the behavioral despair test, chronic administration of NaB had antidepressant-like effects in the FSL and was accompanied by increased levels of TET1. The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity. These epigenetic changes were associated with a corresponding BDNF overexpression.
Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1.
© The Author 2015. Published by Oxford University Press on behalf of CINP.
Acute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.
Freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.
Butyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.
In agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.
Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis.-Reigstad, C. S., Salmonson, C. E., Rainey, III, J. F., Szurszewski, J. H., Linden, D. R., Sonnenburg, J. L., Farrugia, G., Kashyap, P. C. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells.
© FASEB.
Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota–BBB communication is initiated during gestation and propagated throughout life.
A much-anticipated revision of a benchmark resource, written by a renowned author, professor, and researcher in food flavors, Flavor Chemistry and Technology, Second Edition provides the latest information and newest research developments that have taken place in the field over the past 20 years. New or expanded coverage includes: Flavor and the Information Age. Food/Flavor interactions. Flavoring materials and flavor potentiators. Changes to food flavors during processing. Off-Flavors in foods. Performance of flavors during processing and storage. Applications of flavorings in processing. One of the many highlights of the new edition is the chapter on food/flavor interactions and flavor release in the mouth. Addressing one of the hottest topics in flavor today, the chapter presents current knowledge on criical issues such as why low-calorie foods do not taste as good as their full-calorie counterparts. The greatest changes in the book have been made to the chapter on food applications. The author supplies a compelling explanation of how flavors interact with basic food components and how these perform during processing and storage. The chapter on flavor production has been updated to include the latest information on the controlled release of flavorings. Actively involved in flavor research for 35 years, author Gary Reineccius is an award-winning flavor chemist. Drawing on his years of academic and practical experience, he focuses on the technology of flavors and applications in processing to provide a complete overview of the field.
A polyclonal affinity-purified antibody to the carboxyl-terminal end of the rat monocarboxylate transporter 1 (MCT1) was generated in chickens and used in immunocytochemical studies of brain tissue sections from adult and suckling rats. The antibody identified a 48-kDa band on immunoblots and stained tissue sections of heart, cecum, kidney, and skeletal muscle, consistent with the reported molecular mass and cellular expression for this transporter. In tissue sections from adult brains, the antibody labeled brain microvessel endothelial cells, ependymocytes, glial-limiting membranes, and neuropil. In brain sections from 3- to 14-day-old rats, microvessels were much more strongly labeled and neuropil was weakly labeled compared with sections from adults. Immunoelectron microscopy indicated that labeling was present on both luminal and abluminal endothelial cell plasma membranes. These results suggest that MCT1 may play an important role in the passage of lactate and other monocarboxylates across the blood-brain barrier and that suckling rats may be especially dependent on this transporter to supply energy substrates to the brain.
Cognitive flexibility is the ability to switch between different rules or concepts and behavioral flexibility is the overt physical manifestation of these shifts. Behavioral flexibility is essential for adaptive responses and commonly measured by reversal learning and set-shifting performance in rodents. Both tasks have demonstrated vulnerability to stress with effects dependent upon stressor type and number of repetitions. This review compares the effects of stress on reversal learning and set-shifting to provide insight into the differential effect of stress on cognition. Acute and short-term repetition of stress appears to facilitate reversal learning whereas the longer-term repetition of stress impair reversal learning. Stress facilitated intradimensional set-shifting within a single, short-term stress protocol but otherwise generally impaired set-shifting performance in acute and repeated stress paradigms. Chronic unpredictable stress impairs reversal learning and set-shifting whereas repeated cold intermittent stress selectively impairs reversal learning and has no effect on set-shifting. In considering the mechanisms underlying the effects of stress on behavioral flexibility, pharmacological manipulations performed in conjunction with stress are also reviewed. Blocking corticosterone receptors does not affect the facilitation of reversal learning following acute stress but the prevention of corticosterone synthesis rescues repeated stress-induced set-shifting impairment. Enhancing post-synaptic norepinephrine function, serotonin availability, and dopamine receptor activation rescue behavioral flexibility performance following stress. While this review highlights a lack of a standardization of stress paradigms, some consistent effects are apparent. Future studies are necessary to specify the mechanisms underlying the stress-induced impairments of behavioral flexibility, which will aid in alleviating these symptoms in patients with some psychiatric disorders.