Article

Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits

Authors:
  • CEMD - Círculo de Escritores Moçambicanos na Diáspora
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Abstract

Soluble dietary fibers promote metabolic benefits on body weight and glucose control, but underlying mechanisms are poorly understood. Recent evidence indicates that intestinal gluconeogenesis (IGN) has beneficial effects on glucose and energy homeostasis. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate, which are generated by fermentation of soluble fiber by the gut microbiota, activate IGN via complementary mechanisms. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit involving the fatty acid receptor FFAR3. The metabolic benefits on body weight and glucose control induced by SCFAs or dietary fiber in normal mice are absent in mice deficient for IGN, despite similar modifications in gut microbiota composition. Thus, the regulation of IGN is necessary for the metabolic benefits associated with SCFAs and soluble fiber.

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... The SCFAproducing microbiota are important for cardiovascular health [202]. And SCFAs also directly affect the risk of CVDs, by regulating inflammation, insulin secretion, immune response, intestinal barrier integrity, and energy metabolism [203]. ...
... For instance, acetate decreases appetite and nutrient intake [206]. Propionate activates intestinal gluconeogenesis by a gut-brain neural circuit to promote energy balance [203]. Butyrate provides energy for colon cells, maintains the integrity of intestinal walls, and improves the insulin response, which activates gluconeogenesis to maintain the balance of glucose and energy through the cAMP pathway [203]. ...
... Propionate activates intestinal gluconeogenesis by a gut-brain neural circuit to promote energy balance [203]. Butyrate provides energy for colon cells, maintains the integrity of intestinal walls, and improves the insulin response, which activates gluconeogenesis to maintain the balance of glucose and energy through the cAMP pathway [203]. And one study indicated that oral butyrate intake prevents obesity and insulin resistance [207]. ...
Article
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The gut microbiota is critical to human health, such as digesting nutrients, forming the intestinal epithelial barrier, regulating immune function, producing vitamins and hormones, and producing metabolites to interact with the host. Meanwhile, increasing evidence indicates that the gut microbiota has a strong correlation with the occurrence, progression and treatment of cardiovascular diseases (CVDs). In patients with CVDs and corresponding risk factors, the composition and ratio of gut microbiota have significant differences compared with their healthy counterparts. Therefore, gut microbiota dysbiosis, gut microbiota-generated metabolites, and the related signaling pathway may serve as explanations for some of the mechanisms about the occurrence and development of CVDs. Several studies have also demonstrated that many traditional and latest therapeutic treatments of CVDs are associated with the gut microbiota and its generated metabolites and related signaling pathways. Given that information, we summarized the latest advances in the current research regarding the effect of gut microbiota on health, the main cardiovascular risk factors, and CVDs, highlighted the roles and mechanisms of several metabolites, and introduced corresponding promising treatments for CVDs regarding the gut microbiota. Therefore, this review mainly focuses on exploring the role of gut microbiota related metabolites and their therapeutic potential in CVDs, which may eventually provide better solutions in the development of therapeutic treatment as well as the prevention of CVDs.
... Some SCFAs, however, diffuse across IEC membranes and enter the circulatory system un-ionized [190]. Butyrate protects intestinal barrier function by up-regulating the tight junction protein claudin-1 [191] and is used by colonocytes as their main energy source [192]. Butyrate also induces apoptosis of colon cancer cells [192] and plays an essential role in the consumption of oxygen in epithelial cells. ...
... Butyrate protects intestinal barrier function by up-regulating the tight junction protein claudin-1 [191] and is used by colonocytes as their main energy source [192]. Butyrate also induces apoptosis of colon cancer cells [192] and plays an essential role in the consumption of oxygen in epithelial cells. A balanced state of oxygen prevents dysbiosis [193]. ...
... Consistent with this, propionate feeding induces fos (fos proto-oncogene, AP-1 transcription factor subunit) expression in the dorsal vagal complex of the brainstem, the hypothalamus, and the spinal cord [190], raising the question as to whether SCFA-induced stimulation of peripheral sensory neuronal activity could mediate the effects of SCFAs on host feeding behavior. SCFAs regulate several other physiological functions in the body, e.g., the maturation and functioning of microglia in the CNS [203], the transmission of signals generated by serotonin, GABA and DA signals to neurons [217,218] and the secretion of anions in the colon [192,219,220]. The latter is due to the stimulation of nicotinic Ach receptors in the colon that leads to an increase in Ach production and the stimulation of goblet cells to secrete more mucus [221]. ...
Article
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Gut bacteria play an important role in the digestion of food, immune activation, and regulation of entero-endocrine signaling pathways, but also communicate with the central nervous system (CNS) through the production of specific metabolic compounds, e.g., bile acids, short-chain fatty acids (SCFAs), glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), norepinephrine (NE), serotonin (5-HT) and histamine. Afferent vagus nerve (VN) fibers that transport signals from the gastro-intestinal tract (GIT) and gut microbiota to the brain are also linked to receptors in the esophagus, liver, and pancreas. In response to these stimuli, the brain sends signals back to entero-epithelial cells via efferent VN fibers. Fibers of the VN are not in direct contact with the gut wall or intestinal microbiota. Instead, signals reach the gut microbiota via 100 to 500 million neurons from the enteric nervous system (ENS) in the submucosa and myenteric plexus of the gut wall. The modulation, development, and renewal of ENS neurons are controlled by gut microbiota, especially those with the ability to produce and metabolize hormones. Signals generated by the hypothalamus reach the pituitary and adrenal glands and communicate with entero-epithelial cells via the hypothalamic pituitary adrenal axis (HPA). SCFAs produced by gut bacteria adhere to free fatty acid receptors (FFARs) on the surface of intestinal epithelial cells (IECs) and interact with neurons or enter the circulatory system. Gut bacteria alter the synthesis and degradation of neurotransmitters. This review focuses on the effect that gut bacteria have on the production of neurotransmitters and vice versa.
... (155) Obese people's microbiota may have a larger capacity to convert food into energy, than lean people's microbiota (164,165), and many studies have found that HFD have a significant impact on the gut microbiota composition in rats (165)(166)(167)(168). Furthermore, a recent study in obese people found that certain microbiome compositions are linked to impaired glucose control. (169,170) In humans and animals, obesity and insulin resistance are linked to shifting in gut microbial composition. The Firmicutes/Bacteroidetes ratio is commonly used as a marker for obesity dysbiosis. ...
... (172,173) SCFAs (especially propionate) have also been shown to reduce glucose levels because SCFA can activate intestinal gluconeogenesis and sensitizing systemic insulin. (170) While acetate, may pass the blood-brain barrier in both rats and humans (174,175), and send their anorexigenic effects by brain GPCR activation via the periportal neural system. SCFAs also inhibit hunger by increasing the production of leptin from WAT (176,177) and peptide YY (PYY) and GLP1 from the stomach (162,(178)(179)(180). Therefore, lean, healthy human donors transplantation enhance insulin sensitivity and increase the number of butyrate-producing bacteria in obese people. ...
Article
BACKGROUND: Metabolism impairment in obese condition usually initially triggered by inflammation and insulin signaling impairment. The involvement of metabolites, including lipids, amino acids, and ketone bodies, in altering insulin sensitivity has been revealed after massive data sets were provided by the studies regarding metabolomics and lipidomics. CONTENT: Metabolites were now understood to serve more than just the metabolism products, but also as active signaling molecules including in insulin and immunological actions. Different lipid metabolites can serve as signaling molecules to induce insulin resistance of sensitivity through a similar pathway, and impact on the inflammation status. Branched Chain Amino Acids (BCAA) and many amino acids have been correlated with mitochondrial dysfunction and insulin impairment. Ketogenic diet, supplementation and microbiota transplantation become the current strategies to set a preferable metabolites composition to modulate insulin sensitivity. SUMMARY: Thousands of metabolites can now be measured using technical and bioinformatics developments. Different types of amino acids, fatty acids, and bile acids are being studied in relation to altered metabolic states, particularly obesity and type 2 diabetes mellitus. A thorough knowledge of the metabolic changes that contribute to insulin resistance might lead to the discovery of new targets for enhancing insulin sensitivity and preventing and treating many metabolic disorders. KEYWORDS: metabolites, insulin resistance, lipids, amino acids, ketone bodies
... Conversely, Muller et al. [15] found that circulating, but not fecal, SCFAs were associated with BMI. Experimental studies [7,10,40] and clinical trials [11,12] have suggested that oral supplementation with SCFA can be effective in reducing body weight. improve the production and liberation of GLP-1 [10] and glycemia [41][42][43]. ...
... [46], the administration of a mixture containing the three main SCFA in the distal colon increased fat oxidation in fasting and REE, measured by indirect calorimetry, which was also correlated with increased plasma acetate concentrations. Vadder et al. [40] pointed out that the explanation for these potential effects is intestinal gluconeogenesis, in which propionate can induce intestinal gluconeogenesis through the brain-intestine axis, with this communication being mediated by the FFA3 receptor present in the portal vein. Finally, increased fat oxidation by SCFA and increased oxidative capacity of the skeletal muscle can improve metabolic exibility, resulting in possible partial inhibition of intracellular lipolysis in adipocytes, induced mainly by acetate, and causing reduced fat accumulation and an improvement in insulin action in peripheral tissues [46]. ...
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Purpose: The gut microbiome is associated with obesity, mainly mediated by bacteria-produced short-chain fatty acids (SCFAs). It is unknown how SCFA concentrations are associated among the phenotypes metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese/overweight (MHO), and metabolically unhealthy obese/overweight (MUO). We compared plasma and fecal SCFA concentrations among adult women categorized according to the metabolic phenotypes mentioned above and examined associations between SCFA and adiposity and components of energy and glucose homeostasis. Methods: This was a cross-sectional study involving 111 participants. Body composition was assessed by DEXA. Energy and glycemic homeostasis were assessed by the standard mixed-meal tolerance test coupled with indirect calorimetry. SCFAs were quantified by gas chromatography and mass spectrometry. Results: Only plasma propionate was increased in the MHNW phenotype compared to the MHO and MUO phenotypes [p<0.05]. Fecal propionate and butyrate concentrations and plasma propionate concentrations were inversely associated with total and visceral adiposity [p<0.05]. Fecal and plasma SCFA concentrations were associated with reduced glucose, insulin, and HbA1c levels, increased fasting and postprandial GLP-1 levels and more preserved beta-cell function [p<0.05]. Fecal and plasma SCFA concentrations were positively correlated with resting energy expenditure and lipid oxidation rate and inversely correlated with oxidation rate of carbohydrates [p<0.05]. Conclusion: These findings reinforce the concept that fecal and plasma SCFA concentrations are linked to specific components of energy and glucose homeostasis and body adiposity. On the other hand, it was not possible to discriminate the different metabolic phenotypes of adiposity based on the determination of fecal SCFA concentration.
... These GPCRs are found in both CNS and peripheral system and are most dense in peripheral organs (Lagerström et al., 2006;Meslin et al., 2015). SCFAs also communicate with the brain via the afferent vagus nerve, leading to the activation of neurons in the CNS area (De Vadder et al., 2014). However, the type of interaction of SCFAs with the vagus nerve, being direct or indirect, is unknown. ...
... The presence of FFAR3 in the vagus nerve and its influence on feeding behavior may indicate the possibility of SCFA mediated signaling to the central serotonergic system. Additionally, FFAR3 plays an important role in propionate-mediated signals to peripheral and CNS areas for intestinal gluconeogenesis and enhanced noradrenaline secretion by sympathetic neurons respectively (Kimura et al., 2011;De Vadder et al., 2014). Synaptic levels of both neurotransmitters noradrenaline and serotonin are responsible for depressive behavior (Thor et al., 2007). ...
Article
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The chicken gastrointestinal tract has a diverse microbial community. There is increasing evidence for how this gut microbiome affects specific molecular pathways and the overall physiology, nervous system and behavior of the chicken host organism due to a growing number of studies investigating conditions such as host diet, antibiotics, probiotics, and germ-free and germ-reduced models. Systems-level investigations have revealed a network of microbiome-related interactions between the gut and state of health and behavior in chickens and other animals. While some microbial symbionts are crucial for maintaining stability and normal host physiology, there can also be dysbiosis, disruptions to nutrient flow, and other outcomes of dysregulation and disease. Likewise, alteration of the gut microbiome is found for chickens exhibiting differences in feather pecking (FP) behavior and this alteration is suspected to be responsible for behavioral change. In chickens and other organisms, serotonin is a chief neuromodulator that links gut microbes to the host brain as microbes modulate the serotonin secreted by the host’s own intestinal enterochromaffin cells which can stimulate the central nervous system via the vagus nerve. A substantial part of the serotonergic network is conserved across birds and mammals. Broader investigations of multiple species and subsequent cross-comparisons may help to explore general functionality of this ancient system and its increasingly apparent central role in the gut-brain axis of vertebrates. Dysfunctional behavioral phenotypes from the serotonergic system moreover occur in both birds and mammals with, for example, FP in chickens and depression in humans. Recent studies of the intestine as a major site of serotonin synthesis have been identifying routes by which gut microbial metabolites regulate the chicken serotonergic system. This review in particular highlights the influence of gut microbial metabolite short chain fatty acids (SCFAs) on the serotonergic system. The role of SCFAs in physiological and brain disorders may be considerable because of their ability to cross intestinal as well as the blood-brain barriers, leading to influences on the serotonergic system via binding to receptors and epigenetic modulations. Examinations of these mechanisms may translate into a more general understanding of serotonergic system development within chickens and other avians.
... Another potential mechanism could be the production of SCFAs through fermentation of RS by the gut microbiota, which are substrates of gluconeogenesis in the intestine. By synthesizing glucose in the intestine, hepatic gluconeogenesis could be reduced, contributing to an overall improvement of glycemic control [40]. The absorption of SCFAs in the colon may also induce a reduction in free fatty acids and glycerol released from adipocytes during lipolysis, which contributes to enhanced insulin sensitivity [41]. ...
Article
Resistant starch (RS) is the indigestible portion of starch and can escape the small intestine and be fermented in the colon. The potential health benefits of RS have been widely studied in both animal studies and human clinical trials. The objective of this perspective review is to summarize and discuss recent evidence on multiple levels of health benefits from RS, including its influence on food intake, satiety, body weight and composition, glucose and insulin response, blood lipids profile, inflammation and oxidative status, and gut microflora and health. While more and more promising results have been reported, especially, on controlling postprandial glycemic response and modulating gut health, some uncertainties still exist regarding the effect of each specific type of RS. Additionally, more research is needed to maximize the beneficial effects of RS in the human diet.
... An intraperitoneal glucose tolerance test (ipGTT) was performed after 11 weeks of dietary intervention. 26 Mice were fasted in clean cages for 6 h prior to the test. Thirty minutes prior to the test, blood was collected from the tip of the tail to measure fasting glucose concentration using a glucose meter (ACCU-CHEK, Aviva Plus system, Indianapolis, IN, USA). ...
Article
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Little is known about how interactions among grain processing, grain type, and carbohydrate utilization (CU) by the microbiome influence the health benefits of whole grains. Therefore, two whole grains – brown rice and whole wheat – and two processing methods – boiling (porridge) and extrusion – were studied for their effects on host metabolic outcomes in mice harboring human microbiomes previously shown in vitro to have high or low CU. Mice carrying either microbiome experienced increases in body weight and glycemia when consuming Western diets supplemented with extruded grains versus porridge. However, mice with the high but not low CU microbiome also gained more weight and fat over time and were less glucose tolerant when consuming extruded grain diets. In high CU microbiome mice, the exacerbated negative health outcomes associated with extrusion were related to altered abundances of Lachnospiraceae and Ruminococcaceae as well as elevated sugar degradation and colonic acetate production. The amplicon sequence variants (ASVs) associated with extruded and porridge diets in this in vivo study were not the same as those identified in our prior in vitro study; however, the predicted functions were highly correlated. In conclusion, mice harboring both high and low CU microbiomes responded to the whole grain diets similarly, except the high CU microbiome mice exhibited exacerbated effects due to excessive acetate production, indicating that CU by the microbiome is linked to host metabolic health outcomes. Our work demonstrates that a greater understanding of food processing effects on the microbiome is necessary for developing foods that promote rather than diminish host health.
... SCFA enters the central nervous system through the blood-brain barrier and stimulates immunity (Figure 8). Amino acids and their derivatives induce several neurotransmitters (De Vadder et al., 2014;Li et al., 2020). ...
Article
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Pectin oligosaccharides (POS) are pectin‐derived prebiotics that exerts anti‐inflammatory effects on the host and stimulates an innate immune response. The role of POS in protective immunity against viral infections is not very obvious. Therefore, the prophylactic effect of POS in the mouse model induced by Poly I: C mimicking viral infection was examined. Mice fed POS showed a significant (p ≤ .05) increase in IgG, sIgA, IgA, IL‐12, and a significant (p ≤ .05) decrease in the concentration of pro‐inflammatory cytokines IL‐5, IL‐6, IL‐13 and IL‐17 in lung and blood serum after Poly I: C stimulation. However, the control group could not inhibit pro‐inflammatory cytokines. POS also promoted the growth of the Lactobacillus, Prevotella, Rilenellaceae, and Lachanospiraceae groups. Therefore, this study demonstrate that POS has the potiential to protect against viral inflammation by altering gut microbiota and activating mucosal immunity. Practical applications POS is 2–10 mer oligomers of pectin. The human gastrointestinal tract lacks the enzyme to break down POS. They are fermented by gut bacteria in the colon and stimulate the proliferation of specific gut bacteria that are positively correlated with the production of anti‐inflammatory cytokines and SCFA. POS also stimulates the secretion of IgA, which inhibits bacterial and viral adhesion and protects the host. Therefore, POS can be used as a functional food ingredient in food to stimulate a specific group of gut bacteria and enhance preventive immunity.
... It has been estimated that, in pigs, 5-12% of the energy requirement is provided by bacterial fermentation end-products [8,10]. A previous study also found that SCFAs, especially butyrate, positively influenced host metabolism by activating intestinal gluconeogenesis, both in insulinsensitive and insulin-insensitive states, promoting glucose and energy homeostasis [48]. Marques et al. found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria [17]. ...
Article
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Dietary fiber plays an important role in porcine gut health and welfare. Fiber is degraded by microbial fermentation in the intestine, and most gut microbiota related to fiber digestibility in pigs are worth pursuing. The aim of this study was to identify gut microbiota associated with the apparent total tract digestibility (ATTD) of neutral detergent fiber (NDF) and of acid detergent fiber (ADF) in pigs. Large phenotypic variations in the ATTD of NDF and of ADF were separately found among 274 Suhuai pigs. Microbial community structures were significantly different between high and low fiber digestibility groups. Fourteen genera separately dominated the communities found in the high ATTD (H-AD) of NDF and ADF samples and were in very low abundance in the low ATTD (L-AD) of NDF and ADF samples. In conclusion, norank_f__Bacteroidales_S24-7_group (p < 0.05), Ruminococcaceae_UCG-005 (p < 0.05), unclassified_f__Lachnospiraceae (p < 0.05), Treponema_2 (p < 0.01), and Ruminococcaceae_NK4A214_group (p < 0.01) were the main genera of gut microbiota affecting the ATTD of NDF in pigs. Christensenellaceae_R-7_group (p < 0.01), Treponema_2 (p < 0.05), Ruminococcaceae_NK4A214_group (p < 0.05), Ruminococcaceae_UCG-002 (p < 0.05), and [Eubacterium]_coprostanoligenes_group (p < 0.05) were the main genera of gut microbiota affecting the ATTD of ADF in pigs. The most important functions of the above different potential biomarkers were: carbohydrate transport and metabolism, general function prediction only, amino acid transport and metabolism, cell wall/membrane/envelope biogenesis, translation, transcription, replication, energy production and conversion, signal transduction mechanisms, and inorganic ion transport and metabolism. The most important metabolic pathways of the above different potential biomarkers were: membrane transport, carbohydrate metabolism, amino acid metabolism, replication and repair, translation, cell motility, energy metabolism, poorly characterized, nucleotide metabolism, metabolism of cofactors and vitamins, and cellular processes and signaling.
... Conversely, butyrate and propionate are anti-obesogenic, both increasing the expression of the anorexigenic adipokine leptin [69,70] and gut hormones peptide tyrosinetyrosine (PYY) and glucagon-like peptide-1 (GLP-1) [71] . Butyrate enhances energy expenditure by promoting mitochondrial activity and upregulating genes for lipolysis and fatty acid oxidation [72] . Propionate directly induces intestinal gluconeogenesis, which abrogates adiposity and weight gain, independently of food intake, through the activation of gut-brain neural circuits mediated by portal vein glucose sensors [73] . ...
Article
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Obesity, the metabolic syndrome, and metabolic dysfunction-associated fatty liver disease (MAFLD) can be portrayed as transmissible diseases. Indeed, they can be induced, in animal models, by cohabitation or by transplantation of fecal microbiota from other animals or humans with those diseases. As such, to get a 10,000-foot view, we need to see under the lens the microbes that populate our gut. Gut microbiota participates in the harvesting of energy from nutrients, it allows the digestion of otherwise indigestible nutrients such as fibers, and it also produces short chain fatty acids and some vitamins while emitting different compounds that can regulate whole-body metabolism and elicit proinflammatory responses. The metabolic syndrome and MAFLD share physiopathology and also patterns of gut dysbiota. Moreover, MAFLD also correlates with dysbiota patterns that are associated with direct steatogenic or fibrogenic effects. In the last decade, a tremendous effort has allowed a fair understanding of the dysbiota patterns associated with MAFLD. More recently, research is moving towards the delineation of microbiota-targeted therapies to manage metabolic dysfunction and MAFLD. This review provides in-depth insight into the state-of-the-art of gut dysbiosis in MAFLD, targeting clinical hepatologists.
... Furthermore, evidence exists in mice that acetate can alter the levels of glutamate, glutamine, and GABA (Frost et al., 2014), and some studies have shown that SCFAs and their metabolites can stimulate vagus nerve signaling (De Vadder et al., 2014;Li et al., 2018). Moreover, other studies have correlated changes in SCFAs and some BCFAs such as iso-butyrate with effects on behavior through the liver-gut-brain axis (Golubeva et al., 2017). ...
Article
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Gut microbiota dysbiosis plays a significant role in the progression of liver disease, and no effective drugs are available for the full spectrum. In this study, we aimed to explore the dynamic changes of gut microbiota along the liver disease spectrum, together with the changes in cognition and brain metabolism. Sprague-Dawley rats were divided into four groups reflecting different stages of liver disease: control diet (NC); high-fat, high-cholesterol diet (HFHC), emulating non-alcoholic steatohepatitis; control diet + thioacetamide (NC + TAA), simulating acute liver failure; and high-fat, high-cholesterol diet + thioacetamide (HFHC + TAA) to assess the effect of the superimposed damages. The diet was administered for 14 weeks and the thioacetamide was administrated (100 mg/kg day) intraperitoneally over 3 days. Our results showed changes in plasma biochemistry and liver damage across the spectrum. Differences in gut microbiota at the compositional level were found among the experimental groups. Members of the Enterobacteriaceae family were most abundant in HFHC and HFHC + TAA groups, and Akkermansiaceae in the NC + TAA group, albeit lactobacilli genus being dominant in the NC group. Moreover, harm to the liver affected the diversity and bacterial community structure, with a loss of rare species. Indeed, the superimposed damage group (HFHC + TAA) suffered a loss of both rare and abundant species. Behavioral evaluation has shown that HFHC, NC + TAA, and HFHC + TAA displayed a worsened execution when discriminating the new object. Also, NC + TAA and HFHC + TAA were not capable of recognizing the changes in place of the object. Furthermore, working memory was affected in HFHC and HFHC + TAA groups, whereas the NC + TAA group displayed a significant delay in the acquisition. Brain oxidative metabolism changes were observed in the prefrontal, retrosplenial, and perirhinal cortices, as well as the amygdala and mammillary bodies. Besides, groups administered with thioacetamide presented an increased oxidative metabolic activity in the adrenal glands. These results highlight the importance of cross-comparison along the liver spectrum to understand the different gut-microbiota-brain changes. Furthermore, our data point out specific gut microbiota targets to design more effective treatments, though the liver-gut-brain axis focused on specific stages of liver disease.
... SCFAs, as an end-product of carbohydrate fermentation in the gut microbiome, have been identified to be involved in ameliorating host metabolic syndrome [12]. The role of SCFAs as an additional energy source is contrary to adipogenic factors, demonstrating that SCFAs have some beneficial effects in obesity prevention, including regulating lipid metabolism [13], promoting energy homeostasis [14], anticancer activity [15], and controlling appetite [16]. Intestinal microbiota is an emerging factor affecting obesity and metabolic homeostasis in mammals [17,18]. ...
Article
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Plant polysaccharide intervention has shown significant potential to combat obesity. However, studies on animal polysaccharides are indeed rare. The aim of this study was to investigate the potential functions of CIP (IL) on obesity, intestinal microflora dysbiosis, and the possible protection of intestinal barrier in mice fed with high-fat diet (HFD). Our results revealed that after 13 weeks, the HFD+L (high-fat diet + 25 mg/kg CIP) group showed significantly more weight loss and fat accumulation relative to the HFD+H (high-fat diet + 50 mg/kg CIP) group. Furthermore, CIP intervention modulated lipid metabolism and mRNA levels of inflammatory mediators in liver. Overall, CIP clearly improved the intestinal barrier in HFD-fed mice. Additionally, we observed that CIP intervention improved intestinal microbiota community richness and diversity in HFD-fed mice. The CIP intervention mice group showed a relatively low Firmicutes to Bacteroidetes ratio compared to the HFD group. This study concluded that CIP could be used as a functional food to prevent adipocyte accumulation, reduce systemic inflammation, and protect the intestinal barrier.
... Dietary fiber supplements can significantly increase the concentration of succinate in the cecum of mice and participate in the process of small intestinal gluconeogenesis, thus playing an important role in maintaining glucose homeostasis [17] . Succinate levels in the cecum may also increase with dietary fiber supplements during a high-fat diet (HFD) [18] . In the intestinal flora, there are also some succinate-consuming bacteria, such as P. faecium and Ruminococcus, which convert succinate into propionate [19] . ...
Article
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Cardiovascular disease (CVD) refers to a class of diseases related to the heart or blood vessels that have high global incidence. Succinate is generally considered an important intermediate product of the tricarboxylic acid cycle. Recent studies have shown that succinate is related to the pathophysiology of CVD, such as atherosclerosis, acute aortic dissection, hypertension, myocardial ischemia-reperfusion injury, and heart failure. It may represent a potential target or biomarker for CVD. It has been demonstrated that succinate not only participates in various energy metabolic pathways but also plays an important role in various pathophysiological activities as a signaling molecule. Given the significance of metabolism in CVD, it is important to focus on the metabolic regulation mechanism of succinate in CVD. This review outlines the latest evidence pointing to the potential role of succinate in CVD, along with its mechanisms, and updates the current understanding on the role of succinate in CVD. Further studies may focus on identifying succinate, its receptor, and its downstream signaling molecules as new targets for the prevention and treatment of CVD.
... Collectively, SCFAs play a variety of roles that protect body homeostasis(Skaarud et al., 2021;Zhang, Dogan, et al., 2020). SCFAs' functional roles regulate the host's metabolism, immune system, and cell proliferation(Adebowale et al., 2019), and acts as an intestinal gluconeotroph improving glucose homeostasis and inhibiting hepatic lipid synthesis(De Vadder et al., 2014;Frost et al., 2014). In rodents, a large amount of acetic acid stimulates the hypothalamic center inhibiting appetite, thereby increasing energy consumption. ...
Article
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Capsaicin (CAP) and dietary fibers are natural active ingredients that given separately do positively affect obesity and metabolic diseases. However, it was unknown whether their combined administration might further improve blood lipids and gut flora composition. To test this hypothesis we administered capsaicin plus dietary fibers (CAP + DFs) to male rats on a high‐fat diet and analyzed any changes in the intestinal microbiota make up, metabolites, and blood indexes. Our results showed that combining CAP with dietary fibers more intensely reduced total cholesterol (TC) and low‐density lipoprotein cholesterol (LDL‐C). CAP + DFs also increased gut bacteria variety, and the abundance of several beneficial bacterial strains, including Allobaculum and Akkermansia, while reducing harmful strains such as Desulfovibrio. Additionally, CAP + DFs significantly increased arginine levels and caused short‐chain fatty acids accumulation in the contents of the cecal portion of rats' gut. In conclusion, notwithstanding the rats were kept on a high‐fat diet, adding CAP + DFs to the chow further improved, as compared with CAP alone, the lipidemia and increased the gut beneficial bacterial strains, while reducing the harmful ones. In conclusion, notwithstanding the rats were fed a high‐fat diet, adding CAP plus fibers to the chow improved the lipidemia and increased the gut beneficial bacterial strains, while reducing the harmful ones as compared with CAP alone.
... These SCFAs have been associated with T2DM and many diseases. Butyrate, for example, has been shown to improve glucose metabolism by boosting gluconeogenesis in the intestines (De Vadder et al., 2014). In addition, studies claim that butyrate can induce apoptosis in cancer cells and protect the host (Candido, Reeves, & Davie, 1978). ...
Article
Konjac glucomannan’s influence on the regulation of diabetes mellitus, hyperlipidemia, and gut microbial flora was evaluated in this study. In addition, a high-fat diet and streptozotocin were used to induce type 2 diabetes mellitus in rats. At the end of the study, we analyzed various parameters such as body weight, plasma lipid profile, insulin levels by immunohistochemistry, degree of fibrosis in the liver, protein expression of PPAR-γ and p-SREBP-1C and gut microbial changes using 16S rRNA sequencing. The results of our study suggest that KGM supplementation significantly reduced the plasma lipid profile (TC, TG, VLDL, LDL, etc.). In addition, KGM has improved insulin levels, which were visualized using immunohistochemistry. Furthermore, KGM also regulated the protein expression of key regulatory proteins of lipid metabolism PPAR-γ and p-SREBP-1C (Group 3). Similar results were seen in the groups treated with the standard drug rosiglitazone (group 4). Finally, the 16S rRNA sequencing shows that KGM contributes to gut microbiota composition alterations, and it was observed using the Simpson, Shannon, Chao-1, and actual otus indices (group 3). KGM further alters the production of beneficial SCFAs and helps host good health. Furthermore, several metabolic pathways have been activated in T2DM rats. As a result, it becomes apparent that the digestive system's microbiome will play a role in T2DM. KGM has various health advantages but is particularly useful in treating hyperlipidemia and diabetes.
... LPS can destroy the tight junction between epithelial cells, thus reducing the tight junction proteins (occludin and occlusive zone-1) and CB2 (Hasain et al., 2020). The decomposition products of GM can be used as the energy substrate of the intestinal epithelium to promote the renewal metabolism and damage repair of the intestinal epithelium (De Vadder et al., 2014). Short-chain fatty acids (SCFAs), mainly propionic acid, butyric acid, etc.), the products of cellulose and carbohydrate decomposed by GM, can help maintain the integrity of the intestinal epithelium by inducing mucin synthesis and improve the intestinal barrier by promoting tight connection assembly (Burger-van Paassen et al., 2009). ...
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There is a strong link between fecal microbiota and the development of type 1 diabetes. As an emerging therapeutic modality, fecal microbiota transplantation has been shown to be safe and effective in the treatment of many intestinal and extraintestinal diseases. Various studies have found that fecal microbiota transplantation can treat diseases by correcting patients’ immune disorders. Besides, many studies have found that fecal microbiota transplantation can improve glycemic control and insulin resistance in diabetic patients. Therefore, this paper reviews the mechanism of action of fecal microbiota transplantation on autoimmune-mediated T1DM and the current research progress, feasibility, and issues that need to be addressed in the future development of fecal microbiota transplantation in the treatment of autoimmune-mediated T1DM.
... In addition, by binding to G protein-coupled receptor-43/free fatty acid receptor 2 (GPR43/FFAR2) and to G protein-coupled receptor-41/free fatty acid receptor 3 (GPR41/ FFAR3), SCFA can suppress the nuclear factor-κB (NF-κB) pathway, further decreasing inflammation [10]. Signaling through GPR43 and GPR41, SCFA can also induce lipolysis in the white adipose tissue [11] and can modulate glucose metabolism by stimulating intestinal gluconeogenesis [12] and by increasing the release of satiety-mediating hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) from the gut [13]. Short-chain fatty acids are also associated with enhanced expression of tight junction (TJ) proteins (zonulin and occludin) that strengthen the intestinal barrier, thus decreasing inflammation [14] (Fig. 1). ...
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Obesity is a systemic disease and represents one of the leading causes of death worldwide by constitutingthe main risk factor for a series of non-communicable diseases such as type 2 diabetes mellitus (T2DM),cardiovascular diseases and dyslipidemia. Lifestyle interventions have been attempting to prevent T2DM andobesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiotaand its important role in the host’s metabolism provides a new key for improving metabolic health. Modulatingthe composition of the gut microbiota was proposed as a method to manage these metabolic diseases andmost frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action ofmetformin, the most commonly prescribed drug for treating T2DM, is mediated in part by the gut microbiota,although this interplay may also be responsible for the frequent gastrointestinal adverse effects of metformin.Thus, adding a gut microbiota modulator (GMM), such as probiotics or prebiotics, to metformin therapy couldamplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the varioustherapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolicparameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existingclinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.
... Furthermore, gut microbiota provide essential capacities for the fermentation of nondigestible substrates (dietary fibers and endogenous intestinal mucus), thus supporting the growth of specialized species that produce short chain fatty acids (SCFAs) and gases [34]. The major SCFAs produced are: butyrate, which is the main energy source for human colonocytes and which activates intestinal gluconeogenesis [35]; propionate, which is transferred to the liver where it regulates gluconeogenesis and satiety signaling; acetate, which is the most abundant and is, essential for bacterial growth and is a participant in cholesterol metabolism and lipogenesis [36]. Additionally, a higher production of SCFAs correlates with lower diet-induced obesity and with reduced insulin resistance [37]. ...
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Foods high in carbohydrates are an important part of a healthy diet, since they provide the body with glucose to support bodily functions and physical activity. However, the abusive consumption of refined, simple, and low-quality carbohydrates has a direct implication on the physical and mental pathophysiology. Then, carbohydrate consumption is postulated as a crucial factor in the development of the main Western diseases of the 21st century. We conducted this narrative critical review using MedLine (Pubmed), Cochrane (Wiley), Embase, and CinAhl databases with the MeSH-compliant keywords: carbohydrates and evolution, development, phylogenetic, GUT, microbiota, stress, metabolic health, consumption behaviors, metabolic disease, cardiovascular disease, mental disease, anxiety, depression, cancer, chronic kidney failure, allergies, and asthma in order to analyze the impact of carbohydrates on health. Evidence suggests that carbohydrates, especially fiber, are beneficial for the well-being and growth of gut microorganisms and consequently for the host in this symbiotic relationship, producing microbial alterations a negative effect on mental health and different organic systems. In addition, evidence suggests a negative impact of simple carbohydrates and refined carbohydrates on mood categories, including alertness and tiredness, reinforcing a vicious circle. Regarding physical health, sugar intake can affect the development and prognosis of metabolic disease, as an uncontrolled intake of refined carbohydrates puts individuals at risk of developing metabolic syndrome and subsequently developing metabolic disease.
... In order to investigate how L-serine protects neurons, we utilized hippocampal neuronal cells treated with propionic acid (PPA) as an in vitro model of neurotoxicity in this study. PPA is a short-chain fatty acid (SCFA) that an essential role in the human body, including increasing enteric smooth muscle contractions [12,13] and the stimulation of host defense peptide expression [14]. However, excess levels of PPA cause propionic acidemia (PA), which has been associated with brain atrophy, dementia, cognitive disorders, and motor impairment [15,16]. ...
Article
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L-serine is a non-essential amino acid endogenously produced by astrocytes and is abundant in human diets. Beneficial roles of the metabolic products from L-serine in various conditions in the brain including neuronal development have been reported. Through several preclinical studies, L-serine treatment was also shown to offer beneficial therapeutic effects for brain damage such as ischemic stroke, amyotrophic lateral sclerosis, and Parkinson’s disease. Despite evidence for the value of L-serine in the clinic, however, its beneficial effects on the propionic acid (PPA)-induced neuronal toxicity and underlying mechanisms of L-serine-mediated neuroprotection are unknown. In this study, we observed that PPA-induced acidic stress induces abnormal lipid accumulation and functional defects in lysosomes of hippocampal neurons. L-serine treatment was able to rescue the structure and function of lysosomes in PPA-treated hippocampal neuronal cells. We further identified that L-serine suppressed the formation of lipid droplets and abnormal lipid membrane accumulations inside the lysosomes in PPA-treated hippocampal neuronal cells. Taken together, these findings indicate that L-serine can be utilized as a neuroprotective agent for the functionality of lysosomes through restoration of cathepsin D in disease conditions.
... These studies suggest that the gut microbiota regulates inflammation partly through PDEs signaling. The gut microbiota generates the short-chain fatty acids butyrate and propionate, which activate intestinal gluconeogenesis gene expression through the cAMPdependent pathway and the gut-brain neural circuit involving the free fatty acid receptor 3, respectively (De Vadder et al., 2014). In addition, butyrate activates cAMP-protein kinase A (PKA)-cAMP response element-binding protein signaling (Wang et al., 2012a), while free fatty acid receptor 3 modulates cAMP (Mizuta et al., 2020). ...
Article
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Alcohol abuse is one of the most significant public health problems. Chronic, excessive alcohol consumption not only causes alcohol use disorder (AUD), but also changes the gut/lung microbiota, including bacterial and non-bacterial types. Both types of microbiota can release toxins, further damage the gastrointestinal/respiratory tracts, cause inflammation, and impair the functions of the liver, lung and brain, which in turn deteriorates AUD. Phosphodiesterases (PDEs) are critical in the control of intracellular cyclic nucleotides, including cyclic AMP (cAMP) and cyclic GMP (cGMP). Inhibition of certain host PDEs reduces alcohol consumption and attenuates alcohol-related impairment. PDEs are also expressed in the microbiota and may play a potential role in controlling microbiota-associated inflammation. Here, we first summarize the influences of alcohol on gut/lung bacterial and non-bacterial microbiota, as well as on the gut-liver/brain/lung axis. We then discuss the relationship between gut/lung microbiota-mediated PDE signaling and AUD consequences, in addition to highlighting PDEs as potential targets for treatment of AUD.
... 17,18 Gastrointestinal (GI) microbiota has been shown to affect the gut-brain axis by their involvement in inflammatory and metabolic responses. 19,20 Studies have reported that there is a change in GI microbiota in patients undergoing BS. 21,22 This change in microbiota, along with anatomic rearrangement and alteration in GI hormone levels, leads to surgery-mediated weight loss. 23,24 The oral cavity, being an integral part of the alimentary tract, is also reported to have altered microbiota in patients undergoing BS. 13,15,16,[25][26][27][28] These oral microbial changes can alter the oral environment which along with other factors (changes in salivary flow 12,15 and salivary composition 13,16 ) can increase the risk of oral diseases. ...
Article
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The study aims to systematically review the available literature to evaluate the changes in oral microbiota in patients after bariatric surgery (BS) and correlates these alterations in microorganisms with common oral manifestations. Relevant Electronic databases were systematically searched for indexed English literature. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed for framework designing, application, and reporting of the current systematic review. The focused PICO question was: “Is there any change in oral microbiota (O) of patients (P) who underwent BS (I) when compared with non-BS groups (C)?' Seven articles were selected for qualitative synthesis. On application of the National Institutes of Health (NIH) quality assessment tool, six studies were found to be of fair quality and one was of good quality. All the seven included studies evaluated the effect of BS on oral microbiota in humans. The outcomes of this review suggest that considerable changes take place in oral microbiota after BS which can be correlated with common oral manifestations. These changes are mainly due to the indirect effect of BS and may vary with the individuals. Due to variations in the included studies, it is difficult to proclaim any persistent pattern of oral microbiota found after BS.
... Butyrate activates gut gluconeogenesis, which has controlling effects on glucose and energy homeostasis [92]. Butyrate is necessary for epithelial cells to consume large amounts of oxygen by beta-oxidation, creating a hypoxic state that maintains oxygen balance in the intestine and prevents dysbiosis in the gut flora [93]. ...
Article
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Diet and lifestyle are crucial factors that influence the susceptibility of humans to nonalcoholic fatty liver disease (NAFLD). Personalized diet patterns chronically affect the composition and activity of microbiota in the human gut; consequently, nutrition-related dysbiosis exacerbates NAFLD via the gut–liver axis. Recent advances in diagnostic technology for gut microbes and microbiota-derived metabolites have led to advances in the diagnosis, treatment, and prognosis of NAFLD. Microbiota-derived metabolites, including tryptophan, short-chain fatty acid, fat, fructose, or bile acid, regulate the pathophysiology of NAFLD. The microbiota metabolize nutrients, and metabolites are closely related to the development of NAFLD. In this review, we discuss the influence of nutrients, gut microbes, their corresponding metabolites, and metabolism in the pathogenesis of NAFLD.
... Thus, apoC 3 reduces the uptake of VLDL and chylomicron remnants by hepatocytes and maintains high plasma TAG levels [54]. Several studies report that XOS and other oligosaccharides could lower the serum TAG concentrations through increasing the production of SCFAs in the large intestine [55][56][57], where they serve as major signaling molecules and act as ligands for several receptors, such as free fatty acid receptor 2 (FFAR2) and FFAR3 [58]. The activation of these receptors leads to an increased release of some anorectic peptides, such as glucagonlike peptide-1 (GLP-1) and peptide YY, which results in decreased levels of TAG and TC [59,60]. ...
Article
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Type 1 diabetes mellitus is characterized with decreased microbial diversity. Gut microbiota is essential for the normal physiological functioning of many organs, especially the brain. Prebiotics are selectively fermentable oligosaccharides [xylooligosaccharides (XOS), galactooligosaccharides, etc.] that promote the growth and activity of gut microbes and influence the gut–brain axis. Aerobic exercise is a non-pharmacological approach for the control of diabetes and could improve cognitive functions. The potential beneficial effect of XOS and/or aerobic training on cognition, the lipid profile and oxidative stress markers of experimental rats were evaluated in this study. Male Wistar rats were randomly divided into three streptozotocin-induced diabetic groups and a control group. Some of the rats, either on a XOS treatment or a standard diet, underwent aerobic training. The results showed that the aerobic training independently lowered the total cholesterol levels compared to the sedentary diabetic rats ( p = 0.032), while XOS lowers the malondialdehyde levels in the trained diabetic rats ( p = 0.034). What is more the exercise, independently or in combination with XOS beneficially affected all parameters of the behavioral tests. We conclude that aerobic exercises alone or in a combination with the prebiotic XOS could ameliorate the dyslipidemia, oxidative stress, and cognitive abilities in experimental type 1 diabetic animals.
... They also observed that Bacteroides dorei and Roseburia inulinivorans were more abundant, indicating that GLP-1R agonist responders have reduced inflammation because of their role in enhancing gut barrier function and production of butyrate-derived metabolites [202]. Over last few years, scientific breakthroughs have expanded our understanding on an interesting communication circuit where microbiota, intestine, liver, and brain are interconnected to regulate metabolism and energy expenditure [203][204][205][206]. In this context, although the data are limited, they point to an interdependent relationship between microbiota and GLP-2 in metabolic disease. ...
Article
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The intestine represents the body’s largest interface between internal organs and external environments except for its nutrient and fluid absorption functions. It has the ability to sense numerous endogenous and exogenous signals from both apical and basolateral surfaces and respond through endocrine and neuronal signaling to maintain metabolic homeostasis and energy expenditure. The intestine also harbours the largest population of microbes that interact with the host to maintain human health and diseases. Furthermore, the gut is known as the largest endocrine gland, secreting over 100 peptides and other molecules that act as signaling molecules to regulate human nutrition and physiology. Among these gut-derived hormones, glucagon-like peptide 1 (GLP-1) and -2 have received the most attention due to their critical role in intestinal function and food absorption as well as their application as key drug targets. In this review, we highlight the current state of the literature that has brought into light the importance of GLP-1 and GLP-2 in orchestrating intestine–microbiota–immune system crosstalk to maintain intestinal barrier integrity, inflammation, and metabolic homeostasis.
... Remarkably, propionate supplementation was found to stimulate the release of the hormones PYY and GLP-1 in healthy adults resulting in a reduced appetite, hepatic fat, adipose tissue and a higher sensitivity to insulin [77]. Other studies also found the effects of propionate in Treg cells differentiation and production of interleukin (IL)-10 [78,79]. ...
Article
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Excessive sugar consumption is a risk factor for the development of several disorders, including metabolic, cardiovascular, neurological conditions and even some cancers, and has been linked to increased morbidity and mortality. The popularization of the typical Western diet, featured by an excessive intake of saturated fats and added sugars and a low consumption of unprocessed fruits, vegetables and fiber, may directly affect the composition and functionality of the gut microbiota, staggering the balance of the intestinal microbiome that ultimately culminates into gut dysbiosis. Although added sugars in the form of nutritive and non-nutritive sweeteners are generally considered as safe, a growing body of evidence correlate their consumption with adverse effects on gut microbial ecosystem; namely an abnormal synthesis of short-chain fatty acids, altered intestinal barrier integrity and chronic inflammation that often fuel a panoply of metabolic conditions. Accordingly, this work revisited the available preclinical evidence concerning the impact of different types of dietary sugars—nutritive and non-nutritive sweeteners—on gut microbiota and metabolic health. Future research should consider gender and species vulnerability when the impact of such substances on GM community and metabolic health is scrutinized in order to guide their adequate use at doses relevant to human use.
... PCK1 and PCK2 are regulatory genes in gluconeogenesis. Their expression has been proven to be positively correlated with the concentration of SCFAs [70,71]. ACADS can promote butyric acid metabolism, while preventing butyric acid from inhibiting the proliferation of crypt stem cells [72]. ...
Article
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The intestine is a tubular organ with multiple functions such as digestion absorption and immunity, but the functions of each intestinal segments are different. Intestinal regionalization is necessary for normal physiological function, but it also means the research results obtained at specific sites may not be applicable to other intestinal segments. In order to comprehensively describe the functional changes in the intestine, different intestinal segments and their contents (duodenum, jejunum, ileum, cecum, colon, and rectum) of guinea pigs were collected for RNA seq and 16S rRNA seq, respectively. The results showed differential genes of each intestinal segment mainly involve mucosa, digestion, absorption, and immunity. The gene sets related to fat, bill salts, vitamins, aggregates, amino acids, and water absorption were highly expressed in the small intestine, and the gene sets related to metal ions, nucleotides, and SCFAs were highly expressed in the large intestine. In terms of immunity, the CD8+ T, Th1, eosinophils, pDCs, and natural killer (NK) T cells in the small intestine showed higher scores than those in the large intestine, while the pattern-recognition receptor signaling pathway-related genes are highly expressed in the large intestine. In terms of microbial composition, Proteobacteria and Actinobacteria are abundant in the small intestine, while Firmicutes and Spirochaete are abundant in large intestine. The correlation analysis showed a high correlation between intestinal microorganisms and gene modules related to digestion and absorption. In addition, cross-species analysis showed the SCFA metabolism gene expression trends in human and rodent intestine were different. In conclusion, we analyzed the changes in substance transport, immune and microbial composition between different intestinal segments of guinea pigs, and explored the relationship between intestinal transcriptome and microorganisms, our research will provides a reference for subsequent intestinal-related research.
... Propionate and butyrate are typical representatives of SCFAs. Propionate can be used as the substrate of IGN to activate the expression of the IGN gene (free fatty acid receptor FFAR3) through the intracerebral neural circuit, and butyrate can directly stimulate the expression of the IGN gene in intestinal epithelial mucosa through the increase of intracellular cAMP (39). Importantly, SCFAs can also bind to FFAR2 and induce the release of cytoplasmic Ca 2+ from intestinal epithelial L cells, which in turn promotes the synthesis and secretion of peptide (P)YY and glucagon-like peptide (GLP-1) (40). ...
Article
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Type 2 diabetes mellitus (T2DM) and its complications are major public health problems that seriously affect the quality of human life. The modification of intestinal microbiota has been widely recognized for the management of diabetes. The relationship between T2DM, intestinal microbiota, and active ingredient berberine (BBR) in intestinal microbiota was reviewed in this paper. First of all, the richness and functional changes of intestinal microbiota disrupt the intestinal environment through the destruction of the intestinal barrier and fermentation/degradation of pathogenic/protective metabolites, targeting the liver, pancreas, visceral adipose tissue (VAT), etc., to affect intestinal health, blood glucose, and lipids, insulin resistance and inflammation. Then, we focus on BBR, which protects the composition of intestinal microbiota, the changes of intestinal metabolites, and immune regulation disorder of the intestinal environment as the therapeutic mechanism as well as its current clinical trials. Further research can analyze the mechanism network of BBR to exert its therapeutic effect according to its multi-target compound action, to provide a theoretical basis for the use of different phytochemical components alone or in combination to prevent and treat T2DM or other metabolic diseases by regulating intestinal microbiota.
... In mammals, the intestinal microbiota can affect host behavior by regulating dietary metabolic compounds like short-chain fatty acids (SCFAs). The SCFA receptors are expressed in the enteric nervous system (De Vadder et al., 2014), suggesting a role for these receptors in the activation of the nervous system by microbiota-regulated metabolic compounds. In addition, gut microbes can also directly regulate levels of host neurotransmitters (Strandwitz, 2018). ...
Article
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Alterations in the intestinal physiology caused by pathogen colonization result in immune activation. To provide insights into the mechanisms underlying the control of immune activation by changes in intestinal homeostasis, we conducted a forward genetic screen for suppressors of immune activation by intestinal distension in Caenorhabditis elegans. Our results indicate that C. elegans ACC-4, a member of a family of acetylcholine receptors, is required in immune activation by defects in the defecation motor program or by pathogen infection. ACC-4 acts postsynaptically in non-cholinergic RIM neurons to regulate several immune genes and a Wnt-mediated host immune response. These findings uncover a gut-brain-microbial axis that uses neural cholinergic signaling and the Wnt pathway to control immune activation in response to alterations in intestinal homeostasis.
... One preclinical study found that provision of propionate to healthy human-derived hepatocytes activated 5 -activated AMP kinase, which downregulated the expression of gluconeogenic enzymes and reduced gluconeogenesis, suggesting a potential benefit to glycemia (60). In a rat model, propionate decreased hepatic gluconeogenesis purportedly through stimulation of intestinal gluconeogenesis (61). However, several glucoregulatory mechanisms are disrupted in T1D, including deficient insulin, glucagon, and amylin production (62). ...
Article
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Background Comanagement of glycemia and adiposity is the cornerstone of cardiometabolic risk reduction in type 1 diabetes (T1D), but targets are often not met. The intestinal microbiota and microbiota-derived short-chain fatty acids (SCFAs) influence glycemia and adiposity but have not been sufficiently investigated in longstanding T1D. Objectives We evaluated the hypothesis that an increased abundance of SCFA-producing gut microbes, fecal SCFAs, and intestinal microbial diversity were associated with improved glycemia but increased adiposity in young adults with longstanding T1D. Methods Participants provided stool samples at ≤4 time points (NCT03651622: https://clinicaltrials.gov/ct2/show/NCT03651622). Sequencing of the 16S ribosomal RNA gene measured abundances of SCFA-producing intestinal microbes. GC-MS measured total and specific SCFAs (acetate, butyrate, propionate). DXA (body fat percentage and percentage lean mass) and anthropometrics (BMI) measured adiposity. Continuous glucose monitoring [percentage of time in range (70–180 mg/dL), above range (>180 mg/dL), and below range (54–69 mg/dL)] and glycated hemoglobin (i.e., HbA1c) assessed glycemia. Adjusted and Bonferroni-corrected generalized estimating equations modeled the associations of SCFA-producing gut microbes, fecal SCFAs, and intestinal microbial diversity with glycemia and adiposity. COVID-19 interrupted data collection, so models were repeated restricted to pre-COVID-19 visits. Results Data were available for ≤45 participants at 101 visits (including 40 participants at 54 visits pre-COVID-19). Abundance of Eubacterium hallii was associated inversely with BMI (all data). Pre-COVID-19, increased fecal propionate was associated with increased percentage of time above range and reduced percentage of time in target and below range; and abundances of 3 SCFA-producing taxa (Ruminococcus gnavus, Eubacterium ventriosum, and Lachnospira) were associated inversely with body fat percentage, of which two microbes were positively associated with percentage lean mass. Abundance of Anaerostipes was associated with reduced percentage of time in range (all data) and with increased body fat percentage and reduced percentage lean mass (pre-COVID-19). Conclusions Unexpectedly, fecal propionate was associated with detriment to glycemia, whereas most SCFA-producing intestinal microbes were associated with benefit to adiposity. Future studies should confirm these associations and determine their potential causal linkages in T1D. This study is registered at clinical.trials.gov (NCT03651622; https://clinicaltrials.gov/ct2/show/NCT03651622).
... The intestinal flora-gut-brain axis is a bidirectional information network between the intestinal flora and the brain, which consists of the gastrointestinal tract, the enteric nervous system, and the intestinal flora. It is known as the "second brain" of the human body, and plays a role in metabolic diseases such as obesity (Muscogiuri et al., 2019), IR (De Vadder et al., 2014), T2DM (Perry et al., 2016) and PCOS . The intestinal flora and its metabolites produce including SCFA, brain-gut peptides, neurotransmitters and inflammatory factors (Yano et al., 2015) as initiators of signaling pathways that initially enter the circulation via enteroendocrine cells, intestinal chromophores and the immune system or directly through the intestinal mucosal barrier, and subsequently induce central responses by signaling via the vagus nerve or the humoral circulation (Perry et al., 2016), thereby controlling the body's feeding response and the metabolism of lipids, insulin and BAs. ...
Article
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As an important part of the human intestinal microecology, the intestinal flora is involved in a number of physiological functions of the host. Several studies have shown that imbalance of intestinal flora and its regulation of the intestinal barrier, intestinal immune response, and intestinal flora metabolites (short-chain fatty acids and bile acids) can affect the development and regression of female reproductive disorders. Herbal medicine has unique advantages in the treatment of female reproductive disorders such as polycystic ovary syndrome, endometriosis and premature ovarian insufficiency, although its mechanism of action is still unclear. Therefore, based on the role of intestinal flora in the occurrence and development of female reproduction-related diseases, the progress of research on the diversity, structure and composition of intestinal flora and its metabolites regulated by botanical drugs, Chinese herbal formulas and active ingredients of Chinese herbal medicines is reviewed, with a view to providing reference for the research on the mechanism of action of Chinese herbal medicines in the treatment of female reproductive disorders and further development of new herbal medicines.
... Acetate and propionate can both localize to the liver where they stimulate lipogenesis and cholesterol production (Adak & Khan, 2019). Propionate and butyrate can also induce intestinal gluconeogenesis, which aids in proper energy homeostasis (De Vadder et al., 2014). Moreover, some essential vitamins cannot be synthetized by the host and must be either scavenged through food or synthetized by the gut microbiota. ...
Thesis
The human gut microbiota constitutes a dense multi-species anaerobic biofilm-like structure in which adhesion has been proposed to play a key role for bacterial colonization, maintenance and function. However, classical models of biofilm formation are either minor members of the gut microbiota community, often studied in presence of oxygen, or pathogenic gut bacteria. During my thesis, I have used genetic screens to identify determinants of in vitro biofilm formation in two relevant strict anaerobe gut symbionts, Bacteroides thetaiotaomicron and Veillonella parvula. B. thetaiotaomicron is one of the most abundant Gram-negative symbionts of the human gut microbiota. Although several clinical B. thetaiotaomicron isolates were shown to produce biofilms, the genetically amenable reference strain VPI 5482 is a poor biofilm former in vitro. I showed that deletion of capsule 4, one of the 8 capsular polysaccharides (CPS) of B. thetaiotaomicron, leads to the genesis of a subpopulation of acapsulated cells that have increased biofilm capacity. Whereas expression of most B. thetaiotaomicron capsules masked biofilm formation, the expression of capsule 8 induced biofilm formation, suggesting it might directly promote adhesion. Taken together, these results show that CPS expression is a major determinant of B. thetaiotaomicron biofilm formation. I also showed that addition of either bile extract or taurolithocholate induced biofilm formation in most B. thetaiotaomicron isolates. Bile-induced biofilm formation involved a putative secreted DNAse. Consistently, addition of a commercial DNAse to the culture medium complemented the lack of bile-induced biofilm formation in the DNAse mutant. V. parvula is an atypical Gram-negative Firmicute and it is a member of the oral and intestinal microbiota. Its ability to co-aggregate with multiple bacteria and to form biofilms is critical for colonization of its niches. However, molecular analysis in this species have been hampered by the lack of efficient genetic tools. Using a recently described naturally competent strain, I used random transposition and site-directed mutagenesis to show that trimeric autotransporters are the main adhesins of V. parvula SKV38, mediating cell-cell and cell-surface adhesion. Moreover, I identified a putative HD phosphohydrolase that is involved in autotransportermediated biofilm formation. The identification of biofilm formation determinants in the non-models anaerobic bacteria B. thetaiotaomicron and V. parvula constitutes a first step that will allow us to address the contribution of biofilms to gut microbiota colonization and function.
... The intestinal-brain axis provides the biochemical signaling that occurs between the gastrointestinal tract (GI tract) and the central nervous system (CNS). The term "gut-brain axis" is sometimes used to refer to the role of the gut microbiota in interaction, while the term "gut-microbiome-brain" axis explicitly includes the role of the gut microbiota in biochemical signaling events that occur between the GI tract and SNC (8). ...
Article
In order to be able to move, animals like man need the nervous and muscular system to function optimally. The brain, spine, nerves and muscles must work together. If there is a disturbance, the messages will not reach the destination and the animal will not be able to move. Depending on the location and extent of the neurological lesions, the dog may paralyze in whole or in part. Post-traumatic paralysis is a complex condition that requires proper treatment and thorough investigations to establish an accurate diagnosis. There are several conditions that can cause paralysis in the dog. The interaction between the health of the microbiome and that of the brain as well as the way it communicates immune and neuronal cells has been studied. Intestinal cells affect the cells of the central nervous system in the brain. The intestinal-brain axis may influence different neurological disorders and it is possible that dysbiosis in the intestinal tract may lead to disturbance of the transmission of nerve controls on the neuromuscular plate. By-products of microorganisms in the intestine, which appear as a result of tryptophan processing in the diet, can limit the level of inflammation in the brain by the influence they have on microglial cells. The current research focuses on the influence that the gut microbiota has on microglial cells and astrocytes that play an important role in the health of the central nervous system. To reach these observations, the authors examined how intestinal microbiota and diet influence amelioration of paralysis in dogs. In conclusion, the link between the health of the microbiome and the health of the brain, shows how the microorganisms in the intestine influence the evolution of paralysis.
... Our previous study also found that SCFAs were increased in feces of the elderly people in Bama County, compared with the elderly people from a non-longevous region [10]. SCFAs perform various physiological functions in the gut, including anti-inflammatory, antimicrobial, and antitumorigenic effects [35], associated with lower risks for some diseases [36], especially butyric acid and propionic acid, promoting metabolic benefits via gut-brain neural circuits [37]. It is therefore concluded that the relatively higher levels of SCFAs may be conducive to longevity of the centenarians, and appropriate increased dietary fibers in daily diets should be a path toward the longevity. ...
Article
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As centenarians provide a paradigm of healthy aging, investigating the comprehensive metabolic profiles of healthy centenarians is of utmost importance for the pursuit of health and longevity. However, relevant reports, especially studies considering the dietary influence on metabolism, are still limited, mostly lacking the guidance of a model of healthy aging. Therefore, exploring the signatures of the integrative metabolic profiles of the healthy centenarians from a famous longevous region, Bama County, China, should be an effective way. The global metabolome in urine and the short-chain fatty acids (SCFAs) in the feces of 30 healthy centenarians and 31 elderly people aged 60–70 from the longevous region were analyzed by non-targeted metabolomics combined with metabolic target analysis. The results showed that the characteristic metabolites related to longevity were mostly summarized into phosphatidylserine, lyso-phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, bile acids, and amino acids (p < 0.05). Six metabolic pathways were found significant relevant to longevity. Furthermore, acetic acid, propionic acid, butyric acid, valeric acid, and total SCFA were significantly increased in the centenarian group (p < 0.05) and were also positively associated with the dietary fiber intake (p < 0.01). It was age-accompanied and diet-associated remodeling of phospholipid, amino acid, and SCFA metabolism that expressed the unique metabolic signatures related to exceptional longevity. This metabolic remodeling is suggestive of cognitive benefits, better antioxidant capacity, the attenuation of local inflammation, and health-span-promoting processes, which play a critical and positive role in shaping healthy aging.
... 32 SCFAs produced by certain bacterial strains are involved in increasing insulin sensitivity and intestinal barrier integrity, in addition to mediating the activation of intestinal gluconeogenesis (mainly butyrate and propionate), thereby ensuring energy homeostasis and better regulation of glucose metabolism. 33- 35 Reduction of strains that produce SCFAs is associated with T2DM, while its increase was observed in metformin-treated T2DM patients. ...
... Gul et al. [24] reported that aspartame may inhibit alkaline phosphatase activity in the intestine to promote glucose intolerance. Palmnäs et al. indicated that aspartame significantly increased fasting blood glucose and propionate production in the colon in male SD mice [22], and propionate is a gluconeogenesis substance in the liver [25]. In the postabsorptive state, EGP metabolized levels were identical in the liver and kidney [26]. ...
Article
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Frequent consumption of diet drinks was associated with oocyte dysmorphism, decreased embryo quality, and an adverse effect on pregnancy rate. We investigated the harmful effects of aspartame and potential mechanisms through which it increases infertility risk through clinical observations and in vivo and in vitro studies. Methods: We established a cohort of 840 pregnant women and retrospectively determined their time to conceive. We assessed the estrus cycle, the anti-Mullerian hormone level, ovarian oxidative stress, and ovarian mitochondrial function in an animal study. We also evaluated mitochondria function, mitochondrial biogenesis, and progesterone release with in vitro studies. Aspartame consumption was associated with increased infertility risk in the younger women (Odds ratio: 1.79, 95% confidence interval: 1.00, 3.22). The results of the in vivo study revealed that aspartame disrupted the estrus cycle and reduced the anti-Mullerian hormone level. Aspartame treatment also suppressed antioxidative activities and resulted in higher oxidative stress in the ovaries and granulosa cells. This phenomenon is caused by an aspartame-induced decline in mitochondrial function (maximal respiration, spare respiratory capacity, and ATP production capacity) and triggered mitochondrial biogenesis (assessed by examining the energy depletion signaling-related factors sirtuin-1, phosphorylated adenosine monophosphate-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator-1α, and nuclear respiratory factor 1 expression levels). Aspartame may alter fertility by reserving fewer follicles in the ovary and disrupting steroidogenesis in granulosa cells. Hence, women preparing for pregnancy are suggested to reduce aspartame consumption and avoid oxidative stressors of the ovaries.
... One class of metabolites, called short-chain fatty acids (SC-FAs), play multiple roles, including the regulation of energy derived from food, reducing inflammation, preventing pathogen invasion and maintaining barrier integrity. These also act as ligands to G-protein coupled receptors (GPCRs), which upon activation can lead to a variety of metabolic effects, including the stimulation of the secretion of insulin, glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), which in turn, act to increase satiety and increase transit time [368][369][370][371]. Butyrate, a SCFA, also leads to AMPK activation and accompanying beneficial effects discussed above. ...
Article
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Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on ‘what to eat’ or ‘how much to eat’ to reduce the obesity burden, but increasingly evidence indicates that ‘when to eat’ is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
... 'Should we propose a specific diet for the patients, such as high fibre intake and modification of the quality of protein?' The properties provided by fibres (increased SCFA production; increased microbiota-produced succinate, which is a major intermediary in the citric acid cycle and involved in improvement of glucose homeostasis and intestinal function [14]; reduced proteolytic bacteria; improved constipation) could strongly influence the engraftment of an FMT in the gut uraemic environment as recently demonstrated in obesity [15]. A high-sulphur amino acid-containing diet increases bacterial production of hydrogen sulphide (H 2 S) in CKD, and H 2 S can directly reduce the activity of tryptophanase activity and improve kidney function [16]. ...
... Butyric acid has anticancer properties besides being the energy supplier of colonocytes. The anticancer properties of butyrate are due to its capacity to induce programmed cell death of colon cancer cells and gene expressional changes due to its inhibitory activities on histone deacetylases (De Vadder et al. 2014). Propionic acid, besides serving as an energy source, is involved in the gluconeogenesis process in liver. ...
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Hidden hunger is a worldwide problem that is characterized by insufficient intake of micronutrients, which are necessary for optimal human health. Biofortification of food crops is an effective and efficient strategy to alleviate human nutrient deficiencies. It has the ability to increase the nutrient content in the edible parts of the plants. This potent agronomic tool is employed to increase the accumulation of nutrients such as mineral elements, amino acids, and vitamins among others. The main factors that determine the success of biofortification are plant-/crop-dependent, such as the genotypes’ nutrient accumulation mechanisms, and others, namely environmental conditions, and consumer or public acceptance. In general, two complementary approaches of plant biofortification, the agronomic and the biotechnological tools, are adopted. In the agronomic approach, the nutrients accumulation is enhanced through the application of fertilizers and biostimulants or the management of cultivation conditions. Alternatively, in the latter, crops with higher nutrient concentration or bioavailability are developed using breeding (including molecular) or genetic engineering techniques. Indeed, novel gene or genome editing tools are gaining prominence in the generation of biofortified crops. Application of these strategies has enabled enhancement of biosynthetic pathway of organic nutrients or decreased the concentration of antinutrients or increased nutrient transport to the edible parts. Thus, plant transporters are crucial targets for attaining optimal nutrient movement to and within the plant. Also, it is pertinent to continue to deepen our knowledge about the mechanisms of nutrients accumulation in the plant and their bioavailability for humans and animals and identifying ways and means to modify them to obtain plants with higher nutritional quality.
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With very little research exploring intestinal effects of red beetroot consumption, the present pilot study investigated gut microbial changes following red beetroot consumption, via a 14-day intervention trial in healthy adults. Compared to baseline, the study demonstrates transient changes in abundance of some taxa e.g., Romboutsia and Christensenella, after different days of intervention (p<0.05). Enrichment of Akkermansia muciniphila and decrease of Bacteroides fragilis (p<0.05) were observed after 3 days of juice consumption, followed by restoration in abundance after 14 days. With native betacyanins and catabolites detected in stool after juice consumption, betacyanins were found to correlate positively with Bifidobacterium and Coprococcus, and inversely with Ruminococcus (p<0.1), potentiating a significant rise in (iso)butyric acid content (172.7±30.9 µmol/g stool). Study findings indicate the potential of red beetroot to influence gut microbial populations and catabolites associated with these changes, emphasizing the potential benefit of red beetroot on intestinal as well as systemic health.
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Studies in human microbiota dysbiosis have shown that short-chain fatty acids (SCFAs) like propionate, acetate, and particularly butyrate, positively affect energy homeostasis, behavior, and inflammation. This positive effect can be demonstrated in the reduction of butyrate-producing bacteria observed in the gut microbiota of individuals with type 2 diabetes (T2DM) and other energy-associated metabolic alterations. Butyrate is the major end product of dietary fiber bacterial fermentation in the large intestine and serves as the primary energy source for colonocytes. In addition, it plays a key role in reducing glycemia and improving body weight control and insulin sensitivity. The major mechanisms involved in butyrate regulation include key signaling pathways such as AMPK, p38, HDAC inhibition, and cAMP production/signaling. Treatment strategies using butyrate aim to increase its intestine levels, bioavailability, and improvement in delivery either through direct supplementation or by increasing dietary fiber in the diet, which ultimately generates a higher production of butyrate in the gut. In the final part of this review, we present a summary of the most relevant studies currently being carried out in humans.
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Levels of its utilization suggest that the host glycosaminoglycan heparin is an important carbohydrate in the human gut microbiota. However, the interaction between heparin and the gut microbiota is not well understood. In this study, an in vitro fermentation system combined with microbiome and metabolome technologies was used to study the interaction between heparin and the gut microbiota. Interestingly, we found that heparin can be used by the gut microbiota, which produce large amounts of short chain fatty acids leading to a decrease in pH. In addition, the addition of heparin increased the relative abundance of Bacteroides and Bifidobacterium and decreased the relative abundance of Escherichia-Shigella. Correlation analysis of the microbiome and metabolome revealed that the catabolism of heparin was accompanied by the biosynthesis of bile acids and tryptophan metabolism. Overall, this study provides new evidence on the role of heparin as a stable carbon source for the gut microbiota and forms a strong basis for the use of heparin to condition the gut microbiota.
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The small intestine displays marked anatomical and functional plasticity that includes adaptive alterations in adult gut morphology, enteroendocrine cell profile and their hormone secretion, as well as nutrient utilization and storage. In this Perspective, we examine how shifts in dietary and environmental conditions bring about changes in gut size, and describe how the intestine adapts to changes in internal state, bowel resection and gastric bypass surgery. We highlight the critical importance of these intestinal remodelling processes in maintaining energy balance of the organism, and in protecting the metabolism of other organs. The intestinal resizing is supported by changes in the microbiota composition, and by activation of carbohydrate and fatty acid metabolism, which govern the intestinal stem cell proliferation, intestinal cell fate, as well as survivability of differentiated epithelial cells. The discovery that intestinal remodelling is part of the normal physiological adaptation to various triggers, and the potential for harnessing the reversible gut plasticity, in our view, holds extraordinary promise for developing therapeutic approaches against metabolic and inflammatory diseases. The authors of this Perspective discuss the remarkable plasticity of the intestine in response to dietary and physiological changes, and highlight the importance of intestinal remodelling and metabolism in maintaining energy balance of the organism.
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Food bioactive components have garnered greater attention due to their effect in the prevention and therapeutic value against diseases. In this context, bioavailability of food bioactives refers to their prevalence in body fluids and accessibility for the tissues so that beneficial effects are harnessed. Hence, the metabolic processes that a food undergoes inside human system have greater implications for its bioavailability. The ultimate aim of the research is to identify factors responsible for improving the bioavailability of food so as to enhance the utility of food-derived components in according multiple health benefits. This chapter deliberates upon the metabolic processes of food-derived bioactive components, and factors affecting their bioavailability. Also, the role of gut microbiome in the process of food metabolism, the concept of food-derived modulations in host epigenetics, disease progression, and wellness are discussed. Finally, the effect of food on host epigenetic-based gene regulation, referred to as nutrigenomics, is also discussed.
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Hemicelluloses, a major component of plant cell walls, are a non-cellulosic heteropolysaccharide composed of several distinct sugars that is second in abundance to cellulose, which are one of the most abundant and cheapest renewable resources on earth. Hemicelluloses structure is complex and its chemical structure varies greatly among the different plant species. In addition to its wide use in production of feed and other chemical materials, hemicelluloses are known for its remarkable biological activities that remain largely underutilised to date. Therefore, comprehensive investigations of hemicelluloses structural and biological properties would be helpful for achieving rational utilisation and high-value conversion of this underutilised substance into agents with enhanced health benefits for incorporation in drugs and health foods. In this review, details of diverse research initiatives that have enhanced our understanding of hemicelluloses properties are summarised, including hemicelluloses sources, extraction and purification methods, structural characteristics and biological activities. Furthermore, hemicelluloses structure-activity relationships and new directions for future hemicelluloses research studies are discussed.
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Short chain fatty acids (SCFAs), crucial intestinal bacterial metabolites, have been widely accepted as potential diagnostic markers in neonatal medicine. Nevertheless, it is still a great challenge to accurately quantify SCFAs in newborn fecal samples due to the huge variation of water content, limited commercial isotope-labeled internal standards and poor sensitivity. In this study, Na2CO3 solution (50 μg/mL) was applied to convert the free SCFAs to SCFA sodium salts, which could prevent the loss of violate SCFAs during lyophilization process. Furthermore, N-methylbenzylamine-d0/d3 was applied as the chemical derivatization regent to enhance the sensitivity and accuracy. Based on this method, the SCFA contents in meconium and neonatal fecal samples were analyzed to illustrate the change of SCFAs during the gut microbiome development. Chemical derivatization based on N-methylbenzylamine-d0/d3 could not only significantly promote the sensitivity (323-1280 folds compared to free SCFAs) by promoting the ionization efficiency, but also provide one-to-one isotope internal standards. Moreover, 7 SCFAs, including acetic acid (2), n-butyric acid (4), isobutyric acid (5), 2-hydroxybutyric acid (11), 2-hydroxy-3-methylbutyric acid (13), 3-hydroxybutyric acid (14), 2-hydroxy-2-methylbutyric acid (17) were found to be significantly increased in neonatal fecal samples compared to the meconium fecal samples. All these results proved that this method could be applied for SCFA analysis in newborn fecal samples with perfect accuracy and sensitivity.
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Consumption of live microorganisms “Probiotics” for health benefits and well-being is increasing worldwide. Their use as a therapeutic approach to confer health benefits has fascinated humans for centuries; however, its conceptuality gradually evolved with methodological advancement, thereby improving our understanding of probiotics-host interaction. However, the emerging concern regarding safety aspects of live microbial is enhancing the interest in non-viable or microbial cell extracts, as they could reduce the risks of microbial translocation and infection. Due to technical limitations in the production and formulation of traditionally used probiotics, the scientific community has been focusing on discovering new microbes to be used as probiotics. In many scientific studies, probiotics have been shown as potential tools to treat metabolic disorders such as obesity, type-2 diabetes, non-alcoholic fatty liver disease, digestive disorders (e.g., acute and antibiotic-associated diarrhea), and allergic disorders (e.g., eczema) in infants. However, the mechanistic insight of strain-specific probiotic action is still unknown. In the present review, we analyzed the scientific state-of-the-art regarding the mechanisms of probiotic action, its physiological and immuno-modulation on the host, and new direction regarding the development of next-generation probiotics. We discuss the use of recently discovered genetic tools and their applications for engineering the probiotic bacteria for various applications including food, biomedical applications, and other health benefits. Finally, the review addresses the future development of biological techniques in combination with clinical and preclinical studies to explain the molecular mechanism of action, and discover an ideal multifunctional probiotic bacterium.
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Pain-sensing neurons detect environmental insults and tissue injury, driving avoidance behavior and the local release of neuropeptides. Two related papers in this issue of Cell report that gut-innervating pain neurons sense bacterial presence to both shape the constituents of the gut microbiome and protect against excessive inflammation.
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Despite milestones in preventive measures and treatment, cardiovascular disease (CVD) remains associated with a high burden of morbidity and mortality. The protracted nature of the development and progression of CVD motivates the identification of early and complementary targets that might explain and alleviate any residual risk in treated patients. The gut microbiota has emerged as a sentinel between our inner milieu and outer environment and relays a modified risk associated with these factors to the host. Accordingly, numerous mechanistic studies in animal models support a causal role of the gut microbiome in CVD via specific microbial or shared microbiota-host metabolites and have identified converging mammalian targets for these signals. Similarly, large-scale cohort studies have repeatedly reported perturbations of the gut microbial community in CVD, supporting the translational potential of targeting this ecological niche, but the move from bench to bedside has not been smooth. In this Review, we provide an overview of the current evidence on the interconnectedness of the gut microbiome and CVD against the noisy backdrop of highly prevalent confounders in advanced CVD, such as increased metabolic burden and polypharmacy. We further aim to conceptualize the molecular mechanisms at the centre of these associations and identify actionable gut microbiome-based targets, while contextualizing the current knowledge within the clinical scenario and emphasizing the limitations of the field that need to be overcome.
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Background The available evidence about the possible effects of synbiotics on glycemic indices is not conclusive. In this regard, an umbrella meta-analysis was conducted with the aim of providing a better estimate of the overall effects of synbiotic supplementation on glycemic indices. Methods The following international databases were systematically searched until January 2022: PubMed, Scopus, EMBASE, Web of Science, and Google Scholar. Results A meta-analysis of 13 studies revealed a significant decreases in fasting blood sugar (FBS) (ES = -0.40, 95 % CI: −0.64, −0.15; p = 0.002, I² = 69.2 %, p < 0.001), HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) (ES = -0.55; 95 % CI: −0.79, −0.30, p < 0.001, I² = 48.4 %, p = 0.042), and insulin (ES = -1.58; 95 % CI:-2.50, −0.67; p < 0.001, I² = 95.0 %, p < 0.001) following synbiotic supplementation. Conclusion The current umbrella of meta-analyses suggests that synbiotic supplementation can improve FBS, HOMA-IR, and insulin levels. Overall, synbiotics can be recommended as an adjunctive anti-hyperglycemic agent.
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Background: Resistant starch may modulate insulin sensitivity, although the precise mechanism of this action is unknown. Objective: We studied the effects of resistant starch on insulin sensitivity and tissue metabolism. Design: We used a 4-wk supplementation period with 30 g resistant starch/d, compared with placebo, in 10 healthy subjects and assessed the results by using arteriovenous difference methods. Results: When assessed by euglycemic-hyperinsulinemic clamp, insulin sensitivity was higher after resistant starch supplementation than after placebo treatment (9.7 and 8.5 × 10⁻² mg glucose · kg⁻¹ · min⁻¹ · (mU insulin/L)⁻¹, respectively; P = 0.03); insulin sensitivity during the meal tolerance test (MTT) was 33% higher (P = 0.05). Forearm muscle glucose clearance during the MTT was also higher after resistant starch supplementation (P = 0.03) despite lower insulin concentrations (P = 0.02); glucose clearance adjusted for insulin was 44% higher. Subcutaneous abdominal adipose tissue nonesterified fatty acid (NEFA; P = 0.02) and glycerol (P = 0.05) release were lower with resistant starch supplementation, although systemic NEFA concentrations were not significantly altered. Short-chain fatty acid concentrations (acetate and propionate) were higher during the MTT (P = 0.05 and 0.01, respectively), as was acetate uptake by adipose tissue (P = 0.03). Fasting plasma ghrelin concentrations were higher with resistant starch supplementation (2769 compared with 2062 pg/mL; P = 0.03), although postprandial suppression (40–44%) did not differ significantly. Measurements of gene expression in adipose tissue and muscle were uninformative, which suggests effects at a metabolic level. The resistant starch supplement was well tolerated. Conclusion: These results suggest that dietary supplementation with resistant starch has the potential to improve insulin sensitivity. Further studies in insulin-resistant persons are needed.
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Gluconeogenesis is induced in both the liver and intestine by increased cAMP levels. However, hepatic and intestinal glucose production can have opposite effects on glucose homeostasis. Glucose release into the portal vein by the intestine increases glucose uptake and reduces food intake. In contrast, glucose production by the liver contributes to hyperglycemia in type II diabetes. Glucose-6-phosphatase (Glc6Pase) is the key enzyme of gluconeogenesis in both the liver and intestine. Here we specify the cAMP/protein kinase A regulation of the Glc6Pase gene in the intestine compared with the liver. Similarly to the liver, the molecular mechanism of cAMP/protein kinase A regulation involves cAMP-response element-binding protein, HNF4alpha, CAAT/enhancer-binding protein, and HNF1. In contrast to the situation in the liver, we find that different isoforms of CAAT/enhancer-binding protein and HNF1 contribute to the specific regulation of the Glc6Pase gene in the intestine. Moreover, we show that cAMP-response element binding modulator specifically contributes to the regulation of the Glc6Pase gene in the intestine but not in the liver. These results allow us to identify intestine-specific regulators of the Glc6Pase gene and to improve the understanding of the differences in the regulation of gluconeogenesis in the intestine compared with the liver.
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Portal vein glucose sensors detect variations in glycemia to induce a nervous signal that influences food intake and glucose homeostasis. Previous experiments using high infusions of glucose suggested a metabolic sensing involving glucose transporter 2 (GLUT2). Here we evaluated the afferent route for the signal and candidate molecules for detecting low glucose fluxes. Common hepatic branch vagotomy did not abolish the anorectic effect of portal glucose, indicating dorsal transmission. GLUT2-null mice reduced their food intake in response to portal glucose signal initiated by protein-enriched diet. A similar response of Trpm5-null mice and portal infusions of sweeteners also excluded sugar taste receptors. Conversely, infusions of alpha-methylglucose, but not 3-O-methylglucose, decreased food intake, while phlorizin prevented the effect of glucose. This suggested sensing through SGLT3, which was expressed in the portal area. From these results we propose a finely tuned dual mechanism for portal glucose sensing that responds to different physiological conditions.
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The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, gastric inhibitory peptide, and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorter FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca(2+) in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.
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The interplay between dietary nutrients, gut microbiota and mammalian host tissues of the gastrointestinal tract is recognised as highly relevant for host health. Combined transcriptome, metabonome and microbial profiling tools were employed to analyse the dynamic responses of germfree mouse colonic mucosa to colonisation by normal mouse microbiota (conventionalisation) at different time-points during 16 days. The colonising microbiota showed a shift from early (days 1 and 2) to later colonisers (days 8 and 16). The dynamic changes in the microbial community were rapidly reflected by the urine metabolic profiles (day 1) and at later stages (day 4 onward) by the colon mucosa transcriptome and metabolic profiles. Correlations of host transcriptomes, metabolite patterns and microbiota composition revealed associations between Bacilli and Proteobacteria, and differential expression of host genes involved in energy and anabolic metabolism. Differential gene expression correlated with scyllo- and myo-inositol, glutamine, glycine and alanine levels in colonic tissues during the time span of conventionalisation. Our combined time-resolved analyses may help to expand the understanding of host-microbe molecular interactions during the microbial establishment.The ISME Journal advance online publication, 22 November 2012; doi:10.1038/ismej.2012.142.
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Background: Metabolites released by the gut microbiota may influence host metabolism and immunity. We have tested the hypothesis that inulin-type fructans (ITF), by promoting microbial production of short-chain fatty acids (SCFA), influence cancer cell proliferation outside the gut. Methods: Mice transplanted with Bcr-Abl-transfected BaF3 cells, received ITF in their drinking water. Gut microbiota was analysed by 16S rDNA polymerase chain reaction (PCR)–denaturing gradient gel electrophoresis (DGGE) and qPCR. Serum Short-chain fatty acids were quantified by UHPLC-MS. Cell proliferation was evaluated in vivo, by molecular biology and histology, and in vitro. Results: Inulin-type fructans treatment reduces hepatic BaF3 cell infiltration, lessens inflammation and increases portal propionate concentration. In vitro, propionate reduces BaF3 cell growth through a cAMP level-dependent pathway. Furthermore, the activation of free fatty acid receptor 2 (FFA2), a Gi/Gq-protein-coupled receptor also known as GPR43 and that binds propionate, lessens the proliferation of BaF3 and other human cancer cell lines. Conclusion: We show for the first time that the fermentation of nutrients such as ITF into propionate can counteract malignant cell proliferation in the liver tissue. Our results support the interest of FFA2 activation as a new strategy for cancer therapeutics. This study highlights the importance of research focusing on gut microbes–host interactions for managing systemic and severe diseases such as leukaemia.
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The microbial communities that colonize different regions of the human gut influence many aspects of health. In the healthy state, they contribute nutrients and energy to the host via the fermentation of nondigestible dietary components in the large intestine, and a balance is maintained with the host's metabolism and immune system. Negative consequences, however, can include acting as sources of inflammation and infection, involvement in gastrointestinal diseases, and possible contributions to diabetes mellitus and obesity. Major progress has been made in defining some of the dominant members of the microbial community in the healthy large intestine, and in identifying their roles in gut metabolism. Furthermore, it has become clear that diet can have a major influence on microbial community composition both in the short and long term, which should open up new possibilities for health manipulation via diet. Achieving better definition of those dominant commensal bacteria, community profiles and system characteristics that produce stable gut communities beneficial to health is important. The extent of interindividual variation in microbiota composition within the population has also become apparent, and probably influences individual responses to drug administration and dietary manipulation. This Review considers the complex interplay between the gut microbiota, diet and health.
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Objective: Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region. Design: Germ-free mice aged 8-10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, (1)H NMR metabonomics and microbiota phylogenetic profiling analyses were used. Results: The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4-30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus. Conclusion: This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.
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Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.
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Interest in how the gut microbiome can influence the metabolic state of the host has recently heightened. One postulated link is bacterial fermentation of "indigestible" prebiotics to short-chain fatty acids (SCFAs), which in turn modulate the release of gut hormones controlling insulin release and appetite. We show here that SCFAs trigger secretion of the incretin hormone glucagon-like peptide (GLP)-1 from mixed colonic cultures in vitro. Quantitative PCR revealed enriched expression of the SCFA receptors ffar2 (grp43) and ffar3 (gpr41) in GLP-1-secreting L cells, and consistent with the reported coupling of GPR43 to Gq signaling pathways, SCFAs raised cytosolic Ca2+ in L cells in primary culture. Mice lacking ffar2 or ffar3 exhibited reduced SCFA-triggered GLP-1 secretion in vitro and in vivo and a parallel impairment of glucose tolerance. These results highlight SCFAs and their receptors as potential targets for the treatment of diabetes.