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Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits
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.
... Fat is the least appetite suppressant among macronutrients [33]. The appetite suppressant effect of proteins has recently been shown through μ-opioid receptors, leading to intestinal gluconeogenesis [37] [38]. It seems that when these receptors are overworked, they become insensitive; hence the need to find the best way to inhibit them "moderately," to maintain their beneficial effect in the long term on the control of food intake. ...
... Treatment containing 30 g protein/2 g soluble fiber had the best-prolonged effect on satiety (about 4 hours) compared to the control [39]. This study showed that formulations containing vegetable [37]. Acetate reduces acute food intake by acting directly on the central nervous system. ...
... The prolonged interaction with the intestinal mucosa will, therefore, promote the secretion of intestinal peptides involved in appetite regulation. The fiber in Pb fruit pulp helps increase satiety through fermentation by the gut microbiota to form short-chain fatty acids, including acetate, propionate, and butyrate[37] [41] [42][43]. Pb pulp is rich in succinate, which is a substrate for intestinal gluconeogenesis[20] ...
... Dietary interventions that increase fibre intake enhance short-chain fatty acid (SCFA) production, such as acetate, propionate, and butyrate. SCFAs serve as an energy source for colon cells that improves metabolic pathways [21][22][23][24][25]. ...
... SCFAs' influence in gluconeogenesis, promotes improved glucose tolerance and reduced fat accumulation, thereby increasing bile acid metabolism, which is critical for fat digestion, and positively impacting lipid metabolism [22,23]. These metabolites regulate fat storage and energy expenditure by favouring the growth of beneficial bacteria [23]. ...
... SCFAs' influence in gluconeogenesis, promotes improved glucose tolerance and reduced fat accumulation, thereby increasing bile acid metabolism, which is critical for fat digestion, and positively impacting lipid metabolism [22,23]. These metabolites regulate fat storage and energy expenditure by favouring the growth of beneficial bacteria [23]. Additionally, SCFAs modulate the production of hormones involved in appetite regulation, such as peptide YY (PYY) and GLP-1, which contribute to enhanced satiety and energy balance [25]. ...
Introduction: Obesity management strategies such as caloric restriction, very-low-calorie diets (VLCDs), and meal replacements can lead to moderate short-term weight loss. However, many patients face significant challenges in maintaining these results. Personalized interventions, including behavioral counseling and physical activity, have been shown to improve long-term adherence and success. Current clinical guidelines emphasize the pivotal role of dietitians in enhancing patient outcomes through nutritional therapy. When combined with pharmacotherapy and bariatric surgery, the focus shifts from mere weight loss to broader health improvements. Methods: This review explores the evolving role of dietitians in obesity management, advocating for a shift from a weight-centric approach to a more holistic model that prioritizes overall health gains. Key areas of interest include dietetic interventions’ impact on metabolic health, cardiovascular function, gut microbiome balance, inflammation, and psychological well-being. Results: Dietetic interventions have been shown to provide significant health improvements beyond weight loss. These include enhanced metabolic and cardiovascular health, better gut microbiome balance, reduced inflammation, improved sleep quality, mental well-being, and overall quality of life. By focusing on non-scale victories such as improved insulin sensitivity, lipid profiles, and mental health, dietitians play a crucial role in driving long-term success in obesity management. These outcomes highlight the need to shift the focus from short-term weight loss to a more comprehensive view of health gains. Conclusions: The role of dietitians in obesity management is expanding to encompass a more comprehensive and individualized approach. Moving beyond a focus on weight reduction, this paradigm promotes long-term, patient-centered strategies that address the multifactorial nature of obesity. By combining dietary changes with regular physical activity and behavioral support, dietitians can contribute to sustained health improvements, treating obesity as a chronic, complex disease.
... [12] A possible explanation for the increase may be the publication of 2 literatures in Cell and Nature communications in 2014. [13,14] Before 2014, researches were mainly about SCFAs and gastrointestinal disease, only a few studies revealed that SCFAs might be associated with some CNS diseases. [4,5] The underlying mechanism of SCFAs mainly concentrated on indirect regulation via the release of the gut hormones, peptide-YY and glucagon-like peptide1, by activating SCFAs' receptors FFAR3 and FFAR2. ...
... In Filipe report, butyrate activated intestinal gluconeogenesis gene expression via an increase in cAMP (not via FFAR2) and propionate directly acted as an agonist of FFAR3 in the periportal afferent neural system to induce intestinal gluconeogenesis via a gut-brain neural circuit. [13] These 2 studies provided novel insights into the mechanism to explain how did SCFAs affect brain functions. [13,14] Based on these potential mechanism, renewed interest in SCFAs has emerged (Fig. 1). ...
... [13] These 2 studies provided novel insights into the mechanism to explain how did SCFAs affect brain functions. [13,14] Based on these potential mechanism, renewed interest in SCFAs has emerged (Fig. 1). According to the prediction curve (Fig. 1), more literatures are expected to be published in the next couple of years. ...
Background
The interest on short chain fatty acids (SCFAs) regulating the progress of neurological diseases has gained significant attention in recent years. This bibliometric analysis aimed to provide insights into the current state and future trends of global research on SCFAs in neurological research.
Methods
To analysis the general trend of publications, the scientific output in this field from 1995 to 2024 was first retrieved from the Web of Science Core Collection, Scopus, and PubMed with SCFAs-related and neurological diseases related terms as the subjects. Based on above publication analysis, rapid development stage was marked as 2016 to 2024 and 878 relevant original articles in rapid development stage was retrieved with the time limit from 2016 to 2024. Key bibliometric indicators were calculated and evaluated using CiteSpace with these 878 articles.
Results
SCFAs are related to the occurrence and development of neurological diseases. China and the USA have contributed in a significant way to foster a better understanding on SCFAs in neurological diseases. The hot theme of research have gradually shifted from neurodegenerative diseases to psychical diseases. In the aspect of mechanism research, the current hotspot is inflammation. SCFAs are able to modulate oxidative stress and microglia maturation, morphology and function to intervene in the development of neurological diseases and thus SCFAs interventions are promising to treat neurological diseases. 2016 to 2024 is the fast-developing stage in this field. In this stage the publications dramatically increased and were of high quality.
Conclusion
SCFAs in neurological research will continue to be an active area in the near future. Future trends might be correlation analysis and neurotherapeutics of SCFAs on patients with psychical diseases and deeper mechanism research is still needed.
... Influencers abundant in control (alternatively, scarce in T2D) include E. rectale and Streptococcus salivarius. E. rectale is a wellknown producer of butyrate, which has been demonstrated to be capable of improving T2Dassociated features [35][36][37] . S. salivarius was found to have overall negative metabolic influences toward many microbial entities scarce in control, with competition for the consumption of sugars and B vitamins. ...
... Butyrate and propionate have been shown to exert multiple beneficial effects on host physiology [38][39][40][41] . Some of these effects, which may contribute to protection from T2D, include intestinal glucose production (IGN, which helps prevent deregulation of glucose homeostasis and weight-gain) 35 , increase of energy expenditure 36 , and anti-inflammatory effects 8,42 . In regards to lactate, it is noteworthy that certain strains of lactic acid bacteria have been reported to show anti-diabetic activities, possibly through a suppression of glucose absorption from the intestine 43 . ...
A system-level framework of complex microbe-microbe and host-microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ~570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently-produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut.
... GPCRs sense dietary metabolites, and their activation suppresses cAMP-dependent signaling and activates alternative pathways including mTOR. In the intestine, via GPR-41cAMP, propionate promotes gluconeogenesis, thereby controlling glucose homeostasis [24]. Through GPR-43, propionate also stimulates the production of gut hormones that reduce food intake and thus disfavor diet-induced obesity [25]. ...
... Finally, SCFAs modify the host epigenome (DNA methylation and histone modification) [28,29]. Specifically, propionic acid functions as an inhibitor of histone deacetylases In the intestine, via GPR-41cAMP, propionate promotes gluconeogenesis, thereby controlling glucose homeostasis [24]. Through GPR-43, propionate also stimulates the production of gut hormones that reduce food intake and thus disfavor diet-induced obesity [25]. ...
Accumulating evidence suggests that multiple sclerosis (MS) is an environmentally influenced disorder with contributions from life-time exposure to factors including Epstein–Barr virus infection or shifts in microbiome, diet and lifestyle. One suggested factor is a deficiency in propionic acid, a short-chain fatty acid produced by gut bacteria that may contribute to the disease pathology both in animal models and in human cases of MS. Propionate appears to exert beneficial effects on the immune, peripheral and central nervous systems of people with MS (pwMS), showing immunoregulatory, neuroprotective and neurogenerative effects. These functions are crucial, given that MS is characterized by immune-mediated damage of myelin in the central nervous system. Accordingly, propionate supplementation or a modulated increase in its levels through the microbiome and diet may help counteract the pro-inflammatory state in MS by directly regulating immune system and/or by decreasing permeability of gut barrier and blood–brain barrier. This could potentially improve outcomes when used with immune-modulating therapy. However, while its broad effects are promising, further large clinical trials are necessary to evaluate its efficacy and safety in pwMS and clarify its role as a complementary therapeutic strategy. This review provides a comprehensive analysis of the evidence, challenges and limitations concerning propionic acid supplementation in MS.
... These results indicate that LA can promote SCFA production in the intestine. Acetate synthesized from acetyl-CoA during glycolysis can enzymatically convert into butyrate via butyryl-CoA: acetyl-CoA transferase [53], and acetates are essential for several biological activities, including lipid metabolism, energy homeostasis, and appetite modulation via regulating gut-brain neural circuits [54]. Furthermore, acetate produced by Bifidobacteria can protect from infection against Escherichia coli O157:H7 and modulate the permeability of intestinal epithelial cells in mice [55]; acetate also exhibits protective effects against inflammation by regulating the levels of TJ-related proteins in porcine intestinal epithelial cells [56]. ...
... This resulted in a decrease in the relative abundance of pathogens and a shift in the overall composition of the intestinal microbial community. This suggests that LA could increase the abundance of intestinal SCFA-producing bacteria, resulting in anti-inflammatory effects and improving intestinal health [54]. ...
Background
Preventing post-weaning diarrhea (PWD) in weaned piglets is a crucial challenge in the swine production industry. The stress of weaning, dietary shifts from maternal milk to solid feed, and environmental changes lead to decreased microbial diversity, increased pathogen abundance, and compromised intestinal integrity. We have previously identified Lactiplantibacillus argentoratensis AGMB00912 (LA) in healthy porcine feces, which demonstrated antimicrobial activity against pathogens and enhanced short-chain fatty acid production. This research aimed to evaluate the efficacy of LA strain supplementation as a strategy to inhibit PWD and enhance overall growth performance in weaned piglets.
Results
LA supplementation in weaned piglets significantly increased body weight gain, average daily gain, and average daily feed intake. It also alleviated diarrhea symptoms (diarrhea score and incidence). Notably, LA was found to enrich beneficial microbial populations (Lactobacillus, Anaerobutyricum, Roseburia, Lachnospiraceae, and Blautia) while reducing the abundance of harmful bacteria (Helicobacter and Campylobacter). This not only reduces the direct impact of pathogens but also improves the overall gut microbiota structure, thus enhancing the resilience of weaned piglets. LA treatment also promotes the growth of the small intestinal epithelial structure, strengthens gut barrier integrity, and increases short-chain fatty acid levels in the gut.
Conclusions
The study findings demonstrate the promising potential of LA in preventing PWD. Supplementation with the LA strain offers a promising feed additive for improving intestinal health and growth in piglets during the weaning transition, with the potential to significantly reduce the incidence and severity of PWD.
... However, recurring and chronic inflammation of either intestinal or cerebral origin can block such auto-regulatory feedback-loops, thus potentiating the release of pro-inflammatory signals and respective receptor activities, leading to increased GIT permeability and pro-inflammatory activity. 15 It is postulated that in response to this inflammatory environment microbiota adjust their physiology to survive, and that these adjustments might be linked to further aggravations of brain injury. 16 Here, we report on a metagenomic analysis of extremely premature infant gut microbiota, linking species-resolved taxonomy and respective metabolic potentials to the pathology of perinatal white matter injury, as diagnosed via cranial magnetic resonance imaging at term-equivalent age. ...
... This could provide a competitive advantage over other microbiota lacking the potential for nitrate reduction and lead to overgrowth of pathobionts, which could furthermore prohibit reestablishment of noninflammatory metabolic states of colonocytes, 60 thus underlying further aggravations of severe brain damage. 15 Therefore, nitrite or nitrate reductases serve as promising target enzymes for the development of alternative antimicrobials with the potential to reduce inflammation and alleviate aggravations of brain damage in premature infants. A common feature shared by N-compound utilizing terminal reductases is the incorporation of an essential molybdenum cofactor into their active sites, and therefore a suppression in nitrate respiration upon molybdenum deficiency. ...
Severe brain damage is common among premature infants, and the gut microbiota has been implicated in its pathology. Although the order of colonizing bacteria is well described, the mechanisms underlying aberrant assembly of the gut microbiota remain elusive. Here, we employed long-read nanopore sequencing to assess abundances of microbial species and their functional genomic potential in stool samples from a cohort of 30 extremely premature infants. We identify several key microbial traits significantly associated with severe brain damage, such as the genomic potential for nitrate respiration and iron scavenging. Members of the Enterobacteriaceae were prevalent across the cohort and displayed a versatile metabolic potential, including pathogenic and nonpathogenic traits. Predominance of Enterobacter hormaechei and Klebsiella pneumoniae were associated with an overall loss of genomic functional redundancy as well as poor neurophysiological outcome. These findings reveal microbial traits that may be involved in exacerbating brain injury in extremely premature infants and provide suitable targets for therapeutic interventions.
... Of these SCFAs, propionate, in particular, is reported to centrally control intestinal gluconeogenesis, a process that confers metabolic benefits, including reduced endogenous glucose production, independent of insulin. 30 Furthermore, like acetate, elevated plasma propionate levels promote hypothalamic anorexigenic neuronal activation by inducing leptin release from adipocytes through FFARsdependent mechanism. Butyrate, on the other hand, is reported to be the most potent stimulant of anorexigenic peptides and the most potent suppressor of food intake. ...
Obesity currently represents a major societal and health problem worldwide. Its prevalence has reached epidemic levels, and trends continue to increase; This, in turn, reflects the need for more effective preventive measures. Dietary composition is one of the main factors that modulate the structure and function of the gut microbiota. Therefore, abnormal dietary patterns or unhealthy diets can alter gut microbiota-diet interactions and alter nutrient availability and/or microbial ligands that transmit information from the gut to the brain in response to nutrient intake, thereby disrupting energy homeostasis. Accordingly, this review aims to examine how dietary composition modulates the gut microbiota and thus the potential effects of these biological products on energy homeostasis through gut-brain based mechanisms. It also assesses the knowledge gaps and advances needed to clinically implement microbiome-based strategies to improve gut-brain axis function and therefore combat obesity.
... Research indicates that acetate affects host energy metabolism by reducing fat degrade and the number of pro-inflammatory cytokines, as well as by increasing energy expenditure and fat oxidation [33]. Propionate serves as a substrate for hepatic gluconeogenesis, participates in the body's metabolic processes [34], and improves energy homeostasis through intestinal gluconeogenesis by converting to glucose [35,36]. Studies have shown that VFA content in pig digesta is positively correlated with dietary fiber levels [37], consistent with the results observed in this study. ...
This study aimed to explore the effects of dietary fiber level and breed on the growth performance, nutrient utilization, intestinal morphology, slaughter performance, and meat quality of finishing pigs using fermented corn straw (FCS) as the fiber source. The experiment employed a 2 × 4 factorial design, selecting 96 Songliao Black (SLB) and Duroc × Landrace × Yorkshire (DLY) crossbred finishing pigs (a total of 192 pigs, with an initial body weight of 60.52 ± 4.59 kg) randomly assigned by breed to four dietary treatment groups (A: 2.92% crude fiber; B: 4.82% crude fiber; C: 6.86% crude fiber; D: 9.01% crude fiber). The results showed that DLY finishing pigs had higher final weight (FW), average daily gain (ADG), and average daily feed intake (ADFI) in both finishing stages 1 and 2 compared to SLB pigs (p < 0.05), while the ratio of feed to weight gain (F/G) showed no significant differences (p > 0.05). Compared to the basal diet, increasing the dietary fiber level to 4.82% improved FW and ADG in both SLB and DLY finishing pigs (p < 0.05) and reduced F/G (p < 0.05). Additionally, SLB finishing pigs had lower ether extract (EE) digestibility but higher crude fiber (CF) and acid detergent fiber (ADF) digestibility than DLY (p < 0.05). Dietary fiber level and breed exhibited an interaction effect on dry matter (DM) and crude protein (CP) digestibility in finishing pigs (p < 0.05). At a dietary fiber level of 4.82%, villus height, crypt depth in the jejunum, and cecal volatile fatty acid (VFA) concentrations were increased in both SLB and DLY finishing pigs (p < 0.05). Dietary fiber level and breed showed an interaction effect on cecal VFA production in finishing pigs (finishing stage 1; p < 0.05). The dietary fiber level of 4.82% increased loin eye area (LA) (p < 0.05) and decreased backfat thickness (BT) (p < 0.05) in both SLB and DLY finishing pigs. Dietary fiber level and breed had an interaction effect on LA in finishing pigs (p < 0.05). SLB pigs had higher muscle redness (a*), shear force, and contents of crude protein (CP), EE, saturated fatty acid (SFA), and polyunsaturated fatty acids (PUFA) than DLY (p < 0.05). Increasing the dietary fiber level improved pH24h and reduced drip loss and shear force in both SLB and DLY finishing pigs (p < 0.05). Dietary fiber level and breed showed an interaction effect on pig meat color and drip loss (p < 0.05). In conclusion, FCS is a beneficial source of dietary fiber for SLB and DLY pigs. Its proper addition can enhance the growth performance, carcass traits, and meat quality in fattening pigs.
... For instance, they elevate anti-inflammatory Treg cell levels, lower metabolic endotoxemia, and decrease the expression of pro-inflammatory adipocytokines and chemokines (Al-Lahham et al., 2012). Research also indicates that SCFAs regulate gut hormones such as glucagon-like peptide-1, leptin, and peptide YY, which help maintain energy balance and prevent metabolic diseases such as obesity, dysregulated glucose and lipid metabolism, and NAFLD (De Vadder et al., 2014). Secondly, the succinates produced by Prevotella (Kovatcheva-Datchary et al., 2015), as intermediates in the tricarboxylic acid cycle, not only regulate intestinal gluconeogenesis to maintain host glucose homeostasis but also influence the host's energy metabolism, aiding in the prevention of insulin resistance and associated metabolic diseases (De Vadder et al., 2016). ...
Background
Liver disease is among the top ten causes of death globally. With studies suggesting a link between gut microbiota (GM) and liver disease.
Method
We selected summary statistics data from the largest available whole-genome association study (n = 13,266) of GM by the MiBioGen consortium as the exposure, and obtained liver disease-related data from IEU Open GWAS and The NHGRI-EBI GWAS Catalog. A two-sample Mendelian Randomization (MR) analysis employing various methods, to establish the causal relationship between GM and five liver diseases. Meanwhile, single-cell RNA sequencing data were used to examine Prevotella-related genes expression under healthy and disease liver.
Results
The IVW analysis indicate a causal relationship between GM and liver diseases, with Prevotella exhibiting a protective effect in all five liver diseases: Alcoholic liver disease (OR:0.81,95% confidence interval:0.66-1.00,P IVW = 0.0494); Cirrhosis (OR: 0.85,95% confidence interval: 0.73-0.99,P IVW = 0.0397); Hepatic failure, not elsewhere classified (OR:0.60,95% confidence interval:0.37-0.95,P IVW = 0.0305); Benign neoplasm:Liver (OR:0.39,95% confidence interval:0.2-0.75,P IVW = 0.0046); Malignant neoplasm of liver, primary (OR:0.41, 95% confidence interval:0.18-0.93,P IVW = 0.0334). The single-cell results suggest differential expression of Prevotella-related genes between liver disease patients and healthy individuals.
Conclusion
Our MR results show a causal relationship between the GM and liver disease. Prevotella displays a notable protective effect. This finding may enhance the precision of GM-based therapies and offer new insights for clinical research.
... 21 In addition, SCFAs have also been associated with effects such as regulating liver mitochondrial function and maintaining energy homeostasis in the body. 34,35 Though the primary source of SCFAs is carbohydrates, 36 amino acids such as valine, leucine, and isoleucine from protein breakdown can also be converted into isobutyrate, isovalerate, and 2-methylbutyrate, called branched-chain SCFs; these products account for about 5% of the total SCFA production. [37][38][39][40] Numerous studies have been conducted to show that butyric acid or sodium butyrate has a vital role to play in improving liver health. ...
Background
Short‐chain fatty acids have been reported to have anti‐inflammatory and antioxidant functions; whether isobutyrate, a short‐chain fatty acid, is protective against liver injury in a dextran sodium sulfate (DSS)‐induced colitis and its molecular mechanism is unknown. In this study, DSS was used to induce a liver injury from a colitis model in piglets, which was expected to prevent and alleviate DSS‐induced liver injury by feeding sodium isobutyrate in advance.
Results
The results showed that sodium isobutyrate could restore DSS‐induced histopathological changes in the liver, inhibit the activation of the toll‐like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa‐B signaling pathway, and then reduce the DSS‐induced release of pro‐inflammatory cytokines tumor necrosis factor‐α, interleukin 1β, and interleukin 6, reducing inflammatory response. Moreover, we found that sodium isobutyrate could play an antioxidant and apoptosis‐reducing role by maintaining reduced mitochondrial function.
Conclusion
In conclusion, sodium isobutyrate has a preventive and protective effect on liver injury in a DSS‐induced colitis. There is a potential application prospect for it in treating ulcerative‐colitis‐induced liver injuries. © 2024 Society of Chemical Industry.
... These metabolites mainly include short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine oxide (TMAO), and compounds containing hydrogen, carbon, and sulfur. SCFAs, in particular, have been linked to obesity development (De Vadder et al., 2014). SCFAs are saturated fatty acids with one to six carbon atoms, also known as volatile fatty acids. ...
Background
Individuals with obesity often experience elevated blood lipid levels, leading to a chronic low-grade inflammatory state, exacerbating liver oxidative stress, and increasing the risk of various metabolic diseases. Recent evidence suggests that intestinal microbiota and short-chain fatty acids (SCFAs) play crucial roles in the development and progression of obesity. While the mechanisms by which Lingguizhugan decoction (LGZGD) intervenes in obesity by improving lipid metabolism, enhancing insulin sensitivity, and reducing inflammatory responses are well-documented, its potential in intestinal microbiota and SCFAs remains unclear. This study aims to explore the impact of LGZGD on high-fat diet (HFD) induced obesity in rats and its regulatory effects on intestinal microbiota and SCFAs, providing new insights for obesity prevention and treatment.
Methods
Fifty-one male SD rats were randomly divided into groups, with six in the normal control group (NC) receiving a ddH2O treatment and a standard diet. The remaining 45 rats were fed a high-fat diet (HFD) using D12451 feed. After 10 weeks, the rats on the HFD gained 20% more weight than the NC group, confirming the successful modeling of obesity. These rats were then randomly divided into the following groups: ddH2O high-fat diet model group (MC), 20 mg/kg/day Orlistat positive control group (Orlistat), 1.62 g/kg/day low-dose LGZGD group (LGZGL), and 3.24 g/kg/day high-dose LGZGD group (LGZGH) for 8 weeks. We evaluated changes in body weight, serum total cholesterol (TC), total triacylglycerol (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) levels. Fat and liver tissues were collected for pathological analysis. Intestinal contents were aseptically collected for 16S rRNA gene sequencing and gas chromatography–mass spectrometry (GC–MS) to assess gut microbiota and SCFA levels.
Results
LGZGD reduces body weight, TC, TG, LDL, and HDL levels, significantly reducing hepatic steatosis. Besides, it restored the richness and diversity of gut microbiota, which was reduced by HFD, altering the overall structure. Specifically, LGZGD significantly promoted the growth of Muribaculaceae and Dubosiella while inhibiting the growth of Christensenellaceae_R_7_group and UCG_005. It also restricts the production of caproic acid. Correlation analysis indicated positive correlations: Muribaculaceae with Butyric acid and Isovaleric acid; UCG_005 with TC, LDL, and HDL; and Christensenellaceae_R_7_group with TC and LDL.
Conclusion
LGZGD increased the abundance of beneficial gut microbiota in HFD-induced obese rats, improved gut microbiota dysbiosis, and inhibited the increase in caproic acid content. These results suggest that LGZGD can mitigate HFD-induced obesity, and its active components warrant further investigation.
... Acetate impacts host energy and substrate metabolism by reducing fat breakdown, decreasing the number of pro-inflammatory cytokines, and increasing energy expenditure and fat oxidation, thereby influencing appetite [33]. Propionate serves as a substrate for hepatic gluconeogenesis, participating in the body's metabolic processes [34,35], and it improves energy homeostasis by being converted into glucose through intestinal gluconeogenesis [36]. Studies have shown a positive effect between the VFA content in pig chyme and the dietary fiber level [37], which is consistent with the results of this study. ...
This study aimed to investigate the effects of dietary fiber (DF) levels and copper concentrations on the production performance and cecal microbial diversity of finishing pigs. A 2 × 2 factorial experimental design was used, with different levels of dietary fiber (low [23% DF]: L and high [30% DF]: H) and copper concentrations (normal [25 mg/kg]: N and supplemented [45 mg/kg]: S) resulting in four diets (LN, LS, HN, and HS). Forty-eight hybrid barrows (Duroc × Landrace × Yorkshire), with an initial body weight of 76 kg ± 1.5 kg, were randomly assigned to four groups: LN, LS, HN, and HS, with 12 replicates per group and one pig per replicate. There was a 7-day adaptation period followed by a 56-day feeding trial, after which all pigs were slaughtered for sampling. Results indicated that in finishing pigs, the low dietary fiber group exhibited a higher final weight, a higher average daily gain, and a lower feed-to-gain ratio compared to the high fiber group (p < 0.05). The LS group showed higher digestibility of dry matter, crude protein, crude fiber, ash, neutral detergent fiber, and DF than the HN and HS groups (p < 0.05). Blood total protein levels were higher in the high fiber group, whereas blood Cu levels were higher in the supplemented copper group (p < 0.05). High dietary fiber increased the activities of colonic carboxymethylcellulase and β-glucanase (p < 0.05). Concentrations of acetic acid, propionic acid, and total volatile fatty acids were elevated in the high fiber group (p < 0.05). Microbial α-diversity indices (observed species, Chao 1, and Shannon indices) increased with fiber but decreased with copper supplementation (p < 0.05). The Firmicutes/Bacteroidetes ratio increased with fiber levels, with a higher relative abundance of Lactobacillus in the LS group. In conclusion, appropriate copper supplementation in diets can mitigate the negative effects of high fiber levels on finishing pig production performance by enhancing nutrient digestibility, fiber-degrading enzyme activity, regulating the microbial community, and its metabolic products.
... Anaerobic bacteria in the cecum and proximal colon ferment nondigestible carbohydrates, yielding SCFAs as metabolites. SCFAs play roles in regulating intestinal immune homeostasis, serving as energy sources for colonic epithelial cells, and inducing intestinal gluconeogenesis [205]. Moreover, SCFAs exert metabolic benefits by affecting energy expenditure and insulin sensitivity through G protein-coupled receptors (GPCRs) [206,207]. ...
Recent studies have shown a growing interest in the complex relationship between the human gut microbiota, metabolism, and overall health. This review aims to explore the gut microbiota–host association, focusing on its implications for precision nutrition and personalized medicine. The objective is to highlight how gut microbiota modulate metabolic and immune functions, contributing to disease susceptibility and wellbeing. The review synthesizes recent research findings, analyzing key studies on the influence of gut microbiota on lipid and carbohydrate metabolism, intestinal health, neurobehavioral regulation, and endocrine signaling. Data were drawn from both experimental and clinical trials examining microbiota–host interactions relevant to precision nutrition. Our findings highlight the essential role of gut microbiota-derived metabolites in regulating host metabolism, including lipid and glucose pathways. These metabolites have been found to influence immune responses and gut barrier integrity. Additionally, the microbiota impacts broader physiological processes, including neuroendocrine regulation, which could be crucial for dietary interventions. Therefore, understanding the molecular mechanisms of dietary–microbiota–host interactions is pivotal for advancing personalized nutrition strategies. Tailored dietary recommendations based on individual gut microbiota compositions hold promise for improving health outcomes, potentially revolutionizing future healthcare approaches across diverse populations.
... Correspondingly, playing a significant role in satiety signaling due to its interaction with gut receptors, notably G proteincoupled receptors GPR 41 and GPR 43, also known as fatty acid receptors FFAR2 and FFAR3. This interaction may, initiate intestinal IGN (Brown et al., 2003;De Vadder et al., 2014;Karaki et al., 2008). Intestinal gluconeogenesis converts propionate to glucose, which reduces hepatic glucose production, obesity, and thus directly promotes energy homeostasis. ...
The microbiota, intensely intertwined with mammalian physiology, significantly impacts health, productivity, and reproductive functions. The normal microbiota interacts with the host through the following key mechanisms: acting as a protective barrier against pathogens, maintain mucosal barrier integrity, assisting in nutrient metabolism, and modulating of the immune response. Therefore, supporting growth and development of host, and providing protection against pathogens and toxic substances. The microbiota significantly influences brain development and behavior, as demonstrated by comprehensive findings from controlled laboratory experiments and human clinical studies. The prospects suggested that gut microbiome influence neurodevelopmental processes, modulate stress responses, and affect cognitive function through the gut-brain axis. Microbiota in the gastrointestinal tract of farm animals break down and ferment the ingested feed into nutrients, utilize to produce meat and milk. Among the beneficial by-products of gut microbiota, short-chain fatty acids (SCFAs) are particularly noteworthy for their substantial role in disease prevention and the promotion of various productive aspects in mammals. The microbiota plays a pivotal role in the reproductive hormonal systems of mammals, boosting reproductive performance in both sexes and fostering the maternal–infant connection, thereby becoming a crucial factor in sustaining mammalian existence. The microbiota is a critical factor influencing reproductive success and production traits in mammals. A well-balanced microbiome improves nutrient absorption and metabolic efficiency, leading to better growth rates, increased milk production, and enhanced overall health. Additionally, it regulates key reproductive hormones like estrogen and progesterone, which are essential for successful conception and pregnancy. Understanding the role of gut microbiota offers valuable insights for optimizing breeding and improving production outcomes, contributing to advancements in agriculture and veterinary medicine. This study emphasizes the critical ecological roles of mammalian microbiota, highlighting their essential contributions to health, productivity, and reproductive success. By integrating human and veterinary perspectives, it demonstrates how microbial communities enhance immune function, metabolic processes, and hormonal regulation across species, offering insights that benefit both clinical and agricultural advancements.
... For example, acetic acid and propionic acid stimulate the production and secretion of GLP-1 through the activation of GPR43 in the intestinal tract, promoting insulin release and inhibiting glucagon secretion (108). Butyrate independently induces the expression of key intestinal gluconeogenesis genes, such as phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC), via histone acetylation and activation of the cAMP response element-binding protein (CREB) (109). Additionally, SCFAs protect the gut from infection and inflammationinduced damage through GPR41-mediated promotion of interleukin-22 (IL-22) production by innate lymphoid cells (ILCs) (110). ...
The human gut harbors a complex and diverse microbiota essential for maintaining health. Diet is the most significant modifiable factor influencing gut microbiota composition and function, particularly through bioactive compounds like polyphenols, dietary fibers, and carotenoids found in vegetables, fruits, seafood, coffee, and green tea. These compounds regulate the gut microbiota by promoting beneficial bacteria and suppressing harmful ones, leading to the production of key microbiota-derived metabolites such as short-chain fatty acids, bile acid derivatives, and tryptophan metabolites. These metabolites are crucial for gut homeostasis, influencing gut barrier function, immune responses, energy metabolism, anti-inflammatory processes, lipid digestion, and modulation of gut inflammation. This review outlines the regulatory impact of typical bioactive compounds on the gut microbiota and explores the connection between specific microbiota-derived metabolites and overall health. We discuss how dietary interventions can affect disease development and progression through mechanisms involving these metabolites. We examine the roles of bioactive compounds and their metabolites in the prevention and treatment of diseases including inflammatory bowel disease, colorectal cancer, cardiovascular diseases, obesity, and type 2 diabetes mellitus. This study provides new insights into disease prevention and underscores the potential of dietary modulation of the gut microbiota as a strategy for improving health.
... Notably, oral supplementation with B. wexlerae led to a remarkable suppression of obesity and abnormal glucose metabolism in diet-induced obese mice (27), which underscores the pivotal role of Blautia in mitigating obesity by modulating the gut microbiota composition and enhancing the production of SCFAs via interactions with commensal bacteria, such as Butyricicoccus. SCFAs synthesized by gut bacteria contribute to 10% of the daily energy requirements (28) and serve as regulatory molecules that are beneficial for host energy homeostasis (29). Furthermore, butyrate generated by butyrate-producing bacteria, such as Feacalibacterium prausnitzii, may also exert anti-obesity effects by stimulating GLP-1 secretion from colon L cells via fatty acid receptor (FFAR2)-mediated signaling and mitigating insulin resistance (30, 31). ...
Objective
Barley, abundant in β-glucan, a soluble dietary fiber, holds promise in obesity prevention. Given the microbial metabolism of dietary fiber in the gastrointestinal tract, we investigated the role of gut microbiota in non-obese individuals consuming high levels of barley.
Methods
Our study enrolled 185 participants from “The cohort study on barley and the intestinal environment (UMIN000033479).” Comprehensive physical examinations, including blood tests, were conducted, along with separate assessments of gut microbiome profiling and dietary intake. Participants were categorized into high and low barley consumption groups based on the median intake, with non-obese individuals in the high intake group identified as barley responders while participants with obesity were designated as non-responders. We compared the relative abundance of intestinal bacteria between these groups and used multivariate analysis to assess the association between intestinal bacteria and barley responders while controlling for confounding factors.
Results and discussion
Among the fermented food choices, responders exhibited notably higher consumption of natto (fermented soybeans) than non-responders. Moreover, after adjusting for confounders, Butyricicoccus and Subdoligranulum were found to be significantly more prevalent in the intestines of responders. Given natto’s inclusion of Bacillus subtilis, a glycolytic bacterium, and the butyrate-producing capabilities of Butyricicoccus and Subdoligranulum, it is hypothesized that fiber degradation and butyrate production are likely to be enhanced within the digestive tract of barley responders.
... Such alterations in gut microbiota composition contribute to enhanced production of shortchain fatty acids such as acetate, butyrate and propionate via the fermentation of dietary fibres 47,50,51 . Shortchain fatty acids have pivotal roles in metabolic regulation by promoting lipolysis, modu lating adipokine secretion, inhibiting inflammation and enhancing gut hormone production (including GLP1 and PYY) 52 . This cascade of events highlights the intricate interplay between AMPK signalling and the gut-brain axis to maintain the neural, hormonal and immune pathways involved in preserving metabolic homeostasis. ...
Metformin is an effective oral hypoglycaemic agent used in the treatment of type 2 diabetes mellitus; however, its use in pregnancy for the treatment of gestational diabetes mellitus (GDM) remains controversial owing to concerns around safety and efficacy. This comprehensive review outlines the physiological metabolic functions of metformin and synthesizes existing literature and key knowledge gaps pertaining to the use of metformin in pregnancy across various end points in women with GDM. On the basis of current evidence, metformin reduces gestational weight gain, neonatal hypoglycaemia and macrosomia and increases insulin sensitivity. However, considerable heterogeneity between existing studies and the grouping of aggregate and often inharmonious data within meta-analyses has led to disparate findings regarding the efficacy of metformin in treating hyperglycaemia in GDM. Innovative analytical approaches with stratification by individual-level characteristics (for example, obesity, ethnicity, GDM severity and so on) and treatment regimens (diagnostic criteria, treatment timing and follow-up duration) are needed to establish efficacy across a range of end points and to identify which, if any, subgroups might benefit from metformin treatment during pregnancy.
... This activity generates a state of hypoxia, which helps to preserve the oxygen intestinal balance and prevent any imbalances in the microbiota. Propionate is transported to the liver, regulating gluconeogenesis and satiety through interaction with intestinal fatty acid receptors [9]. Acetate, the most present among SCFAs, represents an essential metabolite for bacteria proliferation, spreading into peripheral tissues and participating in cholesterol metabolism and lipogenesis [10]. ...
Introduction: Microbiota, composed of micro-organisms like bacteria, viruses, and non-pathogenic fungi, plays a crucial role in digestion, vitamin production, and protection against dangerous microbes. Several factors, including age, diet, alcohol consumption, stress, environmental microorganisms, and therapies (particularly antibiotics), as well as birth and nursing, could modify the microbiota. Recent research has highlighted its alteration and involvement in a various disease, including metabolic syndrome and acne. This systematic review aimed to identify common biomarkers and microbiota alterations shared between metabolic syndrome and acne, and to explore how the potential prebiotic activities of polyphenols may promote intestinal eubiosis. Materials and methods: A comprehensive search in PubMed and EMBASE resulted in 4142 articles, from which nine studies were selected based on specific criteria after removing duplicates and reviewing abstracts and full texts. All studies correlated the microbiota alteration in both pathologies and the activity of polyphenols in metabolic syndrome. Results: This review suggests that acne may be influenced by some of the same microorganisms involved in metabolic syndrome. While the literature highlights the effectiveness of polyphenols in treating metabolic syndrome, no studies have yet demonstrated their specific impact on acne. Conclusions: The research points to the potential benefits of polyphenols in modulating the microbiota, which could be relevant for individuals with metabolic syndrome. However, due to the limited data available, it was not possible to establish a direct correlation between metabolic syndrome and acne.
... Dietary fibre can exert a beneficial effect on host physiology by modulating gut microbiota composition and influencing both metabolism and inflammation (20). Certain species of colonic microbiota can ferment dietary fibre to produce SCFA which in turn lower insulin resistance though multiple mechanisms (21)(22)(23). SCFAs can also act as histone deacetylase (HDAC) inhibitors. HDAC inhibition can supress pro-inflammatory macrophage responses, regulate cytokine expression in T cells and generate regulatory T cells thus exerting an anti-inflammatory effect (24,25). ...
The increased global prevalence of type II diabetes mellitus (T2DM) is associated with consumption of low fibre “Western diets”. Characteristic metabolic parameters of these individuals include insulin resistance, high fasting and postprandial glucose, as well as low-grade systemic inflammation. Gut microbiota composition is altered significantly in these cohorts suggesting a causative link between diet, microbiota and disease. Dietary fibre consumption has been shown to alleviate these changes and improve glucose parameters in individuals with metabolic disease. We previously reported that yeast β -glucan (yeast beta-1,3/1,6-D-glucan; Wellmune) supplementation ameliorated hyperinsulinemia and insulin resistance in a murine model. Here we conducted a randomised, placebo-controlled, two-armed dietary fibre phase I exploratory intervention study in patients with T2DM. The primary outcome measure was alteration to microbiota composition while the secondary outcome measures included markers of glycaemic control, inflammation as well as metabolomics. Patients were supplemented with 2.5g/day of maltodextrin (placebo) or yeast β -1,3/1,6-D-glucan (treatment). Yeast β -glucan (Wellmune) lowered insulin resistance (HOMA-IR) compared to the placebo maltodextrin after 8 weeks of consumption. TNFα was significantly lower after 4 weeks of β -glucan supplementation. Significantly higher faecal concentrations of several bile acids were detected in the treatment group when compared to the placebo after 8 weeks. These included tauroursodeoxycholic acid (TUDCA) which was previously shown to improve glucose control and lower insulin resistance. Interestingly, the hypoglycaemic and anti-inflammatory effect of yeast β -glucan was independent of any changes in faecal microbiota composition or short-chain fatty acid (SCFA) levels. Our findings highlight the potential of yeast β -glucan to lower insulin resistance in patients with T2DM.
... Skin test reaction associated with production of Th1 cytokines including IFNγ that play crucial role in protective immunity against cryptococcal infections, these idea was in consistent with Wormley et al. (2007), who, found that vaccination with C neoformans can stimulated significant increasing in the levels of Th1-type proinflammatory cytokines and chemokines in the lung, associated with decreases in the levels of cytokines that are mediators of Th2-type anti-inflammatory activities and protective immunity against a lethal pulmonary infection with wild-type C. neoformans Immunized animals treated with antibiotics: The current finding showed that immunized animals with antibiotic showed intense lesions compared to immunized animals at 4 weeks post infection. These results indicated that application high dose of antibiotic can influence on the vaccine activity associated with defect in immune responses through its effect on the intestinal microbiota, which play role in development immunity of the hosts (O'Hara & Shanahan 2007;De Vadder et al. 2014;Tilg et al. 2020). Also, Ivanov & Honda (2012) showed that the Intestinal microbiota play a pivotal role in the protective of a healthy immune system of host. ...
This study aimed to investigate the effect of immune stimulation by sonicated fungal antigens of Cryptococcus adeliensis using chitosan nanoparticles in rats treated with high doses of antibiotics. For this purpose, sixty rats of both sexes were divided randomly into six groups (10 animals, both males and females, in each group), as following: (G1) immunized with 0.5ml whole sonicated fungal Ag (0.83mg/ml protein concentration) /SC, 2 dose / 2 weeks interval. 2 nd group (G2) immunized with 0.5ml whole fungal Ag as G1 and treated daily with high doses of antibiotic for six weeks (gentamicin 0.5mg/mL). 3 rd group (G3) immunized I\P, with whole fungal Ag mixed with chitosan nanoparticles (1:1) 0.5 ml, 2 dose / 2 weeks intervals and treated with antibiotic as 2 nd group, and (G4) was served as control positive group and (G5) was treated with antibiotic as 2 nd group, and sixth group (G6) was served as negative control inoculated with normal saline 0.3ml. At 27 and 30 days post-immunization, skin test was done in 1 st , 2 nd , 3 rd , and 5th groups and blood samples were collected to measure the serum level of antibody titers, after those animals of G1, G2, G3, G4, and G5 were inoculated SC, with 0.3ml, containing 1x10 8 of the fungal cell, and the sixth group was injected with 0.3ml normal saline I/P. At 4 weeks post-infection. All animals were sacrificed and pieces of tissues were removed from the liver, lung, kidney, and brain for histopathological examination. The result revealed a high mean of skin thickness and high serum antibody titers in immunized animals but in 2 nd group, the antibiotic treatment led to depressing values of skin test (ns) and serum of antibody titers (ns). Chitosan nanoparticles can improve values of skin test (***) and serum of antibody titers (***) in the 3 rd group. The histopathological result showed severe pathological lesions in examined organs of the positive control group and severe lesions in these organs in animals treated with antibiotics post-infection. In addition, the current result showed mild to moderate lesions in examined organs of immunized animals with moderate lesions in immunized animal's treatment with antibiotics post-infection. The immunized animals with mixed fungal antigens and chitosan nanoparticles and treatment with antibiotics express mild to no clear lesions in examined organs post-infection. As a conclusion, the prolonged high doses of antibiotics lead to depressing immune response in immunized animal,s while immunized animals with fungal antigens mixed with chitosan nanoparticles can improve the immune response.
... SCFAs alleviate gut inflammation and improve intestinal permeability. Studies have shown that SCFAs, specifically butyrate, can reduce the production of IL-6, MCP-1, and TNF-α and inhibit the NF-κB signaling pathway [109] Furthermore, butyric acid and propionic acid can improve glucose homeostasis by activating intestinal gluconeogenesis through the cAMP-dependent pathway and thus reducing hepatic glucose production [110]. Acetic acid improves lipid metabolism by inhibiting liver lipid accumulation through the upregulation of the peroxisome proliferator-activated receptor α (PPARα) gene and several fatty acid oxidation-related proteins [111]. ...
Liver diseases cause millions of deaths globally. Current treatments are often limited in effectiveness and availability, driving the search for alternatives. Herbal preparations offer potential hepatoprotective properties. Disrupted gut microbiota is linked to liver disorders. This scoping review aims to explore the effects of herbal preparations on hepatoprotective mechanisms, particularly in the context of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatic steatosis, with a focus on gut microbiota modulation. A systematic search was performed using predetermined keywords in four electronic databases (PubMed, Scopus, EMBASE, and Web of Science). A total of 55 studies were included for descriptive analysis, covering study characteristics such as disease model, dietary model, animal model, intervention details, comparators, and study outcomes. The findings of this review suggest that the hepatoprotective effects of herbal preparations are closely related to their interactions with the gut microbiota. The hepatoprotective mechanisms of herbal preparations are shown through their effects on the gut microbiota composition, intestinal barrier, and microbial metabolites, which resulted in decreased serum levels of liver enzymes and lipids, improved liver pathology, inhibition of hepatic fatty acid accumulation, suppression of inflammation and oxidative stress, reduced insulin resistance, and altered bile acid metabolism.
... Adaptive GM changes feature increased diversity, with abundant short-chain fatty acid (SCFA)-producing bacterial orders like Clostridiales and taxa such as Roseburia [13,14]. These microbial populations contribute to metabolic homeostasis by producing SCFAs and enhancing immune regulation [15][16][17] and endurance exercise performance [18]. Improved endurance and strength may result from this synergy, modulating oxidative stress and inflammatory responses, enhancing metabolism, and optimizing energy expenditure during intense exercise [19]. ...
Purpose: This study aimed to characterize the association between microbial dynamics and excessive exercise. Methods: Swabbed fecal samples, body composition (percent body fat), and swimming logs were collected (n = 94) from a single individual over 107 days as he swam across the Pacific Ocean. The V4 region of the 16S rRNA gene was sequenced, generating 6.2 million amplicon sequence variants. Multivariate analysis was used to analyze the microbial community structure, and machine learning (random forest) was used to model the microbial dynamics over time using R statistical programming. Results: Our findings show a significant reduction in percent fat mass (Pearson; p < 0.01, R = −0.89) and daily swim distance (Spearman; p < 0.01, R = −0.30). Furthermore, the microbial community structure became increasingly similar over time (PERMANOVA; p < 0.01, R = −0.27). Decision-based modeling (random forest) revealed the genera Alistipes, Anaerostipes, Bifidobacterium, Butyricimonas, Lachnospira, Lachnobacterium, and Ruminococcus as important microbial biomarkers of excessive exercise for explaining variations observed throughout the swim (OOB; R = 0.893). Conclusions: We show that microbial community structure and composition accurately classify outcomes of excessive exercise in relation to body composition, blood pressure, and daily swim distance. More importantly, microbial dynamics reveal the microbial taxa significantly associated with increased exercise volume, highlighting specific microbes responsive to excessive swimming.
... After being absorbed by the colon, SCFAs enter the bloodstream, but after entering the liver through the portal vein, they are metabolized by liver cells, 31 and ultimately about 5% of SCFAs are excreted from the body. 32 The functions of the different SCFAs vary, with butyric acid providing energy for the growth of intestinal cells 33 propionic acid being mainly absorbed and utilized by the liver as a substrate for gluconeogenesis and participating in host metabolism, 34 and most acetic acid entering the peripheral circulation. ...
Di (2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor and commonly used as a plasticizer. Exposure to DEHP and its active metabolite mono-2-ethylhexyl phthalate (MEHP) can lead to adverse health consequences; however, the toxic mechanism is remains unclear. In this research, male and female rats were exposed to DEHP and MEHP by oral gavage for 60 consecutive days. Pathological analysis revealed that DEHP and MEHP exposure could affect liver, heart, kidney, and testis tissues, as well as alter biochemical indicators. Metagenomics (16S rRNA gene sequencing) analysis indicated that DEHP and MEHP could reduce the diversity and alter the composition of the gut microbiota. Toxic exposure also affected the levels of short chain fatty acids (SCFAs), with noticeable variations between genders. Metabolomic analysis revealed that DEHP and MEHP could influence bile acids, amino acids, hormones, and lipids. These results demonstrate that exposure to DEHP and MEHP can induce toxicity in rats via the gut-liver axis.
The gut–liver axis and its interactions are essential for host physiology. Thus, we examined the jejunal microbiota, fermentation parameters, digestive enzymes, morphology, and liver metabolic profiles in different growth development lambs to investigate the liver–gut axis’s role in their development. One hundred male Hu lambs of similar birth weight and age were raised under the same conditions until they reached 180 days of age. Subsequently, the eight lambs with the highest (HADG) and lowest (LADG) average daily weight gains were slaughtered for index assessment. The study indicates that the body weight, carcass weight, propanoic acid, butyric acid, propanoic acid ratio, butyric acid ratio, and digestive enzymes (beta-glucosidase, microcrystalline cellulase, xylanase, and carboxymethyl cellulase) were significantly higher in HDAG lambs than in LADG lambs (p < 0.05). Additionally, there were no significant differences in the jejunal microbiota’s structure and function among lambs at different growth development stages (p > 0.05). Overall, our analysis revealed that HADG lambs compared to LADG lambs exhibited an up-regulation of metabolites (such as spermine, cholic acid, succinic acid, betaine, etc.) that were positively correlated with the butyric acid ratio, propanoic acid ratio, propanoic acid, xylanase, microcrystalline cellulase, beta-glucosidase, amylase, carboxymethyl cellulase, carcass weight, and body weight, while these metabolites were negatively correlated with the kidney, acetic acid, acetic acid/ propanoic acid, and acetic acid ratio. Furthermore, there was a significant correlation between liver metabolism and jejunal microbiota. This study revealed significant differences in hepatic metabolites and jejunal fermentation among lambs at different growth stages, which may inform targeted regulation strategies to enhance lamb productivity.
In order to understand how our susceptibility to pathogens is increasing, we must first reflect on our own defences. Human beings are generally protected against enteric pathogens by the ‘innate’ and ‘adaptive’ arms of the immune system.
Lung cancer (LC) continues to pose the highest mortality and exhibits a common prevalence among all types of cancer. The genetic interaction between human eukaryotes and microbial cells plays a vital role in orchestrating every physiological activity of the host. The dynamic crosstalk between gut and lung microbiomes and the gut–lung axis communication network has been widely accepted as promising factors influencing LC progression. The advent of the 16s rDNA sequencing technique has opened new horizons for elucidating the lung microbiome and its potential pathophysiological role in LC and other infectious lung diseases using a molecular approach. Numerous studies have reported the direct involvement of the host microbiome in lung tumorigenesis processes and their impact on current treatment strategies such as radiotherapy, chemotherapy, or immunotherapy. The genetic and metabolomic cross‐interaction, microbiome‐dependent host immune modulation, and the close association between microbiota composition and treatment outcomes strongly suggest that designing microbiome‐based treatment strategies and investigating new molecules targeting the common holobiome could offer potential alternatives to develop effective therapeutic principles for LC treatment. This review aims to highlight the interaction between the host and microbiome in LC progression and the possibility of manipulating altered microbiome ecology as therapeutic targets.
The circadian clock gene system plays a pivotal role in coordinating the daily rhythms of most metabolic processes. It is synchronized with the light–dark cycle and the eating–fasting schedule. Notably, the interaction between meal timing and circadian clock genes (CGs) allows for optimizing metabolic processes at specific times of the day. Breakfast has a powerful resetting effect on the CG network. A misaligned meal pattern, such as skipping breakfast, can lead to a discordance between meal timing and the endogenous CGs, and is associated with obesity and T2D. Conversely, concentrating most calories and carbohydrates (CH) in the early hours of the day upregulates metabolic CG expression, thus promoting improved weight loss and glycemic control. Recently, it was revealed that microorganisms in the gastrointestinal tract, known as the gut microbiome (GM), and its derived metabolites display daily oscillation, and play a critical role in energy and glucose metabolism. The timing of meal intake coordinates the oscillation of GM and GM-derived metabolites, which in turn influences CG expression, playing a crucial role in the metabolic response to food intake. An imbalance in the gut microbiota (dysbiosis) can also reciprocally disrupt CG rhythms. Evidence suggests that misaligned meal timing may cause such disruptions and can lead to obesity and hyperglycemia. This manuscript focuses on the reciprocal interaction between meal timing, GM oscillation, and circadian CG rhythms. It will also review studies demonstrating how aligning meal timing with the circadian clock can reset and synchronize CG rhythms and GM oscillations. This synchronization can facilitate weight loss and improve glycemic control in obesity and those with T2D.
Intestinal microbiota and the brain axis affect each other and the functioning of the whole body. The brain continuously receives signals from intestinal microbiota and immune system. Gut dysbiosis aggravates patients’ health and may cause persistent hurtful effects. Probiotics serve to increase functional camaraderie of normal gut microorganisms and confer multiple behavioral and cognitive health benefits. Diverting gut microbes to produce brain-activating metabolites can lower the severity of age-related emotional, cognitive, and neurological problems. Dietary modifications, active health style, and the targeted strategies may perform as novel therapies to avert cognitive disorders and improve behavioral, physical, mental, and systemic health.
Aging is a natural process of becoming elder owing to cellular and biomolecular damages in the functioning of body organs over the time. Aging is characterized by gradual damage of functional and mental capacity, susceptibility to diseases, and ultimately the bereavement. Deterioration in normal functioning is the primary risk factor for pathologies, such as metabolic, cardiovascular, and neurological diseases and cancer. In addition, the diseased persons display a loss in composition and functioning of dwelling microbiota. Balanced diet, probiotics, fecal microbiota transplantation, and active lifestyle prevent oxidative stress, improve immune homeostasis, suppress metabolic diseases and inflammation, and slow the process of aging.
Over the past years, biological sciences have transformed strongly and shaped our understanding about the composition and role of the human microbiome in health and disease. Culture-independent technologies have unraveled the community structure and amazing role of the human microbiome. New generation sequencing technologies, synthetic biology, artificial intelligence, gene-editing, and in silico analysis of massive data have provided novel information on the role of the human microbiome in nutrition, health and behavior, development and immunity, and connection with noncommunicable diseases. System-level understanding is essential to evolve strategies to benefit humans from the genetic and metabolic repertoire of the human microbiome. New insights might translate the available microbiological information into diagnostic, therapeutic, and preventive developments in the context of personalized precision medicine.
Feline obesity puts many cats at risk for comorbidities such as hepatic lipidosis, diabetes mellitus, urinary tract diseases, and others. Restricted feeding of specially formulated diets may improve feline health and safely support weight loss while maintaining lean mass. The objective of this study was to determine the effects of restricted intake of weight control diets on weight loss, body composition, voluntary physical activity, serum metabolic and inflammatory markers, and fecal metabolites and microbiota of obese cats. Twenty-four obese adult domestic shorthair cats [body weight (BW) = 5.51 ± 0.92 kg; body condition score (BCS) = 8.44 ± 0.53] were used. A leading grocery brand diet was fed during a 4-wk baseline to identify intake needed to maintain BW. After baseline (wk 0), cats were allotted to one of two weight control diets (DRY or CAN) and fed to lose 1.5% BW per wk for 18 wk. At baseline and 6, 12, 18 wk after weight loss, dual-energy x-ray absorptiometry scans were performed, blood and fecal samples were collected, and voluntary physical activity was measured. Change from baseline data were analyzed statistically using the Mixed Models procedure of SAS, with P<0.05 being significant and P<0.10 being trends. BW was reduced by 1.54 ± 0.51% per wk. Restricted feeding of both diets led to BW (P<0.01) and fat mass loss (P<0.01), reduced BCS (P<0.01), reduced leptin (P<0.01) and insulin (P<0.01) concentrations, and increased superoxide dismutase (P<0.01) and active ghrelin (P<0.01) concentrations. Change from baseline fecal scores were reduced (P<0.01) with restricted feeding and weight loss, while total short-chain fatty acid, acetate, and propionate concentration reductions were greater (P<0.05) in cats fed CAN than those fed DRY. Fecal bacterial alpha diversity measures increased (P<0.01) with restricted feeding and weight loss. Fecal bacterial beta diversity was altered by time in all cats, with wk 0 being different (P<0.05) than wk 6, 12, and 18. Change from baseline relative abundances of 3 fecal bacterial phyla and over 30 fecal bacterial genera were impacted (P<0.05) or tended to be impacted (P<0.10) by dietary treatment. Our data demonstrate that restricted feeding of both weight control diets was an effective means for weight loss in obese adult domestic cats. Some changes were also impacted by diet, highlighting the importance of diet formulation and format, and nutrient composition in weight control diets.
Most of the short-chain fatty acids (SCFAs) are produced by Bifidobacterium, Lactobacillus, Lachnospiraceae, Blautia, Coprococcus, Roseburia, Facealibacterium and Oscillospira. Butyrate (C4H7O2⁻) supplies 70% of energy to intestinal epithelial cells (IECs), supports tight-junction protein formation, induces the production of inflammatory cytokines, and inhibits histone deacetylase (HDAC). Butyrate is also associated with the recovery of brain trauma, improvement of dementia, the alleviation of autoimmune encephalitis, and several intestinal disorders. Low levels of SCFAs are associated with hypertension, cardiovascular disease (CVD), strokes, obesity, and diabetes mellitus. Cis-palmitoleic acid (C16H30O2), a mono-unsaturated fatty acid (MUFA), increases insulin sensitivity and reduces the risk of developing CVD. Lipokine palmitoleic acid reduces the expression of pro-inflammatory cytokines IL-1β (pro-IL1β), tumor necrosis factor α (TNF-α), and isoleucine 6 (IL-6). Polyunsaturated fatty acids (PUFAs), such as omega-3 and omega-6, are supplied through the diet. The conversion of PUFAs by cyclooxygenases (COX) and lipoxygenases (LOX) leads to the production of anti-inflammatory prostaglandins and leukotrienes. Oxidation of linoleic acid (LA, C18H32O2), an omega-6 essential fatty acid, leads to the formation of 13-hydroperoxy octadecadienoic acid (13-HPODE, C18H32O4), which induces pro-inflammatory cytokines. Omega-3 PUFAs, such as eicosapentaenoic acid (EPA, C20H30O2) and docosahexaenoic acid (DHA, C22H32O2), lower triglyceride levels, lower the risk of developing some sort of cancers, Alzheimer’s disease and dementia. In this review, the importance of SCFAs, MUFAs, PUFAs, and saturated fatty acids (SFAs) on human health is discussed. The use of fatty acids in the treatment of diseases is investigated.
The microbiota-gut-brain axis involves complex bidirectional communication through neural, immune, and endocrine pathways. Microbial metabolites, such as short-chain fatty acids, influence gut motility and brain function by interacting with gut receptors and modulating hormone release. Additionally, microbial components such as lipopolysaccharides and cytokines can cross the gut epithelium and the blood–brain barrier, impacting immune responses and cognitive function. Ex vivo models, which preserve gut tissue and neural segments, offer insight into localized gut-brain communication by allowing for detailed study of nerve excitability in response to microbial signals, but they are limited in systemic complexity. Miniaturized in vitro models, including organ-on-chip platforms, enable precise control of the cellular environment and simulate complex microbiota-host interactions. These systems allow for the study of microbial metabolites, immune responses, and neuronal activity, providing valuable insights into gut-brain communication. Despite challenges such as replicating long-term biological processes and integrating immune and hormonal systems, advancements in bioengineered platforms are enhancing the physiological relevance of these models, offering new opportunities for understanding the mechanisms of the microbiota-gut-brain axis. This review aims to describe the ex vivo and miniaturized in vitro models which are used to mimic the in vivo conditions and facilitate more precise studies of gut brain communication.
The early-life gut microbiota (GM) is increasingly recognized for its contributions to human health and disease over time. Microbiota composition, influenced by factors like race, geography, lifestyle, and individual differences, is subject to change. The GM serves dual roles, defending against pathogens and shaping the host immune system. Disruptions in microbial composition can lead to immune dysregulation, impacting defense mechanisms. Additionally, GM aids digestion, releasing nutrients and influencing physiological systems like the liver, brain, and endocrine system through microbial metabolites. Dysbiosis disrupts intestinal homeostasis, contributing to age-related diseases. Recent studies are elucidating the bacterial species that characterize a healthy microbiota, defining what constitutes a ‘healthy’ colonic microbiota. The present review article focuses on the importance of microbiome composition for the development of homeostasis and the roles of GM during aging and the age-related diseases caused by the alteration in gut microbial communities. This article might also help the readers to find treatments targeting GM for the prevention of various diseases linked to it effectively.
Type 2 diabetes (T2D) is a major public health concern worldwide and there has been increasing attention on the role of natural dietary drugs in diabetes therapy. However, the effects of these drugs on gut microbial composition, functional potentials and metabolisms remain unclear. Here, we conducted integrated 16S rRNA sequencing and metabolomic analyses in T2D GK rats and healthy Wistar rats that exposed to four natural dietary drugs (highly porous activated carbon, wheatgrass, dandelion and corn stigma). Oral administration of activated carbon and dandelion decreased the body weight gain in both high-fat diet (HFD) GK rats and Wistar rats. Significantly lower level of blood glucose was observed in GK rats with activated carbon intervention. A group of beneficial bacteria and metabolites were promoted, and the endotoxin-producing bacteria were inhibited by dietary drugs, especially for the activated carbon diet. Oral administration of activated carbon resulted in metabolic changes and anti-inflammatory effects that decreased both high-fat diet-induced obesity and diabetes. The beneficial effects of increased positive responders are related to improved carbohydrate and amino acid metabolism, regulated inflammatory mediators, with simultaneous reduction of detrimental compounds such as lipopolysaccharide (LPS) synthesis and modification of the gut microbiome. These findings highlight the effectiveness of natural dietary drugs, with a particular emphasis on activated carbon, and establish a foundation for tailoring the use of these drugs in T2D therapy.
Importance
Our findings highlight the significant hypoglycemic effect of activated carbon, demonstrating its potential to remodel the gut microbiota, improve carbohydrate and amino acid metabolism, regulate inflammatory mediators, and reduce detrimental compounds such as lipopolysaccharide (LPS). These results suggest that dietary intervention with activated carbon could be a noninvasive and accessible method for improving diabetes management, providing novel insights into the role of natural dietary drugs in metabolic health and diabetes therapy.
Epidemiological investigation confirmed that the intake of dietary fiber (DF) is closely related to human health, and the most important factor affecting the physiological function of DF, besides its physicochemical properties, is the gut microbiota. This paper mainly summarizes the interaction between DF and gut microbiota, including the influence of DF on the colonization of gut microbiota based on its different physicochemical properties, and the physiological role of gut microbiota in destroying the complex molecular structure of DF by encoding carbohydrate-active enzymes, thus producing small molecular products that affect the metabolism of the host. Taking cardiovascular disease (Atherosclerosis and hypertension), liver disease, and immune diseases as examples, it is confirmed that some DF, such as fructo-oligosaccharide, galactooligosaccharide, xylo-oligosaccharide, and inulin, have prebiotic-like physiological effects. These effects are dependent on the metabolites produced by the gut microbiota. Therefore, this paper further explores how DF affects the gut microbiota’s production of substances such as short-chain fatty acids, bile acids, and tryptophan metabolites, and provides a preliminary explanation of the mechanisms associated with their impact on host health. Finally, based on the structural properties of DF and the large heterogeneity in the composition of the population gut microbiota, it may be a future trend to utilize DF and the gut microbiota to correlate host health for precision nutrition by combining the information from population disease databases.
Obesity has become a serious epidemic problem in the world, and probiotics and prebiotics have been used to treat obesity. The effectiveness of diet therapy such as Clostridium butyricum (CB) and inulin supplementation in obesity and whether they can cooperate to produce better effects are still unclear. And during this process, intestinal flora play an important role, while the bacteria involved and the metabolic mechanism need to be explored. In this study, we successfully established a mouse obesity model with a high-fat diet (HFD) and divided it into three experimental groups: 7% CB (CB7), 7% CB + 1% inulin (C7G1), and 10% CB + 1% inulin (C10G). Dietary supplementation with CB and inulin could improve the glucose tolerance and intestinal microbial composition of obese mice, among which the simultaneous supplementation with 7% CB and 1% inulin (C7G1) has the most significant effect on obese mice fed with a HFD. It could significantly reduce the amount of total cholesterol, triglyceride, and low-density lipoprotein, improve abnormal glucose tolerance, and reduce abnormal blood glucose in obese mice. The intestinal flora of obese mice changed significantly, among which Lachnospiraceae_unclassified, Porphyromonaceae_unclassified, Olsenella, Bacteria_unclassified and Clostridiales_unclassified decreased due to the HFD, while Megamonas and Clostridium XIVa increased. After the supplementation with CB and inulin, the enrichment of three kinds of beneficial bacteria, Parabacteroides, Bacteroides, and Ruminococcaceae unclassified increased. The high-fat diet could upregulate the expression of FGF21, and the Clostridium butyricum and inulin supplemented diet could decrease the upregulation.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The gut microbiota has profound effects on host physiology but local host-microbial interactions in the gut are only poorly characterised and are likely to vary from the sparsely colonised duodenum to the densely colonised colon. Microorganisms are recognised by pattern recognition receptors such as Toll-like receptors, which signal through the adaptor molecule MyD88.
To identify host responses induced by gut microbiota along the length of the gut and whether these required MyD88, transcriptional profiles of duodenum, jejunum, ileum and colon were compared from germ-free and conventionally raised wild-type and Myd88-/- mice. The gut microbial ecology was assessed by 454-based pyrosequencing and viruses were analysed by PCR.
The gut microbiota modulated the expression of a large set of genes in the small intestine and fewer genes in the colon but surprisingly few microbiota-regulated genes required MyD88 signalling. However, MyD88 was essential for microbiota-induced colonic expression of the antimicrobial genes Reg3β and Reg3γ in the epithelium, and Myd88 deficiency was associated with both a shift in bacterial diversity and a greater proportion of segmented filamentous bacteria in the small intestine. In addition, conventionally raised Myd88-/- mice had increased expression of antiviral genes in the colon, which correlated with norovirus infection in the colonic epithelium.
This study provides a detailed description of tissue-specific host transcriptional responses to the normal gut microbiota along the length of the gut and demonstrates that the absence of MyD88 alters gut microbial ecology.
Since the pioneering work of Claude Bernard, the scientific community has considered the liver to be the major source of endogenous glucose production in all postabsorptive situations. Nevertheless, the kidneys and intestine can also produce glucose in blood, particularly during fasting and under protein feeding. The aim of this study was to better define the importance of the three gluconeogenic organs in glucose homeostasis.
We investigated blood glucose regulation during fasting in a mouse model of inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc(-/-) mice), encoding a mandatory enzyme for glucose production. Furthermore, we characterized molecular mechanisms underlying expression changes of gluconeogenic genes (G6pc, Pck1, and glutaminase) in both the kidneys and intestine.
We show that the absence of hepatic glucose release had no major effect on the control of fasting plasma glucose concentration. Instead, compensatory induction of gluconeogenesis occurred in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis. Moreover, the extrahepatic action of glucagon took place in wild-type mice.
Our study provides a definitive quantitative estimate of the capacity of extrahepatic gluconeogenesis to sustain fasting endogenous glucose production under the control of glucagon, regardless of the contribution of the liver. Thus, the current dogma relating to the respective role of the liver and of extrahepatic gluconeogenic organs in glucose homeostasis requires re-examination.
The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane receptor for short-chain fatty acids (SCFAs) that is implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency for FFA2 and can hence be considered as highly potent given its size. Propionate, however, does not discriminate between FFA2 and the closely related receptor FFA3 (GPR41). To identify FFA2-selective ligands and understand the molecular basis for FFA2 selectivity, a targeted library of small carboxylic acids was examined using holistic, label-free dynamic mass redistribution technology for primary screening and the receptor-proximal G protein [(35)S]guanosine 5'-(3-O-thio)triphosphate activation, inositol phosphate, and cAMP accumulation assays for hit confirmation. Structure-activity relationship analysis allowed formulation of a general rule to predict selectivity for small carboxylic acids at the orthosteric binding site where ligands with substituted sp(3)-hybridized α-carbons preferentially activate FFA3, whereas ligands with sp(2)- or sp-hybridized α-carbons prefer FFA2. The orthosteric binding mode was verified by site-directed mutagenesis: replacement of orthosteric site arginine residues by alanine in FFA2 prevented ligand binding, and molecular modeling predicted the detailed mode of binding. Based on this, selective mutation of three residues to their non-conserved counterparts in FFA3 was sufficient to transfer FFA3 selectivity to FFA2. Thus, selective activation of FFA2 via the orthosteric site is achievable with rather small ligands, a finding with significant implications for the rational design of therapeutic compounds selectively targeting the SCFA receptors.
The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.
Diet and nutritional status are among the most important modifiable determinants of human health. The nutritional value of food is influenced in part by a person's gut microbial community (microbiota) and its component genes (microbiome). Unraveling the interrelations among diet, the structure and operations of the gut microbiota, and nutrient and energy harvest is confounded by variations in human environmental exposures, microbial ecology, and genotype. To help overcome these problems, we created a well-defined, representative animal model of the human gut ecosystem by transplanting fresh or frozen adult human fecal microbial communities into germ-free C57BL/6J mice. Culture-independent metagenomic analysis of the temporal, spatial, and intergenerational patterns of bacterial colonization showed that these humanized mice were stably and heritably colonized and reproduced much of the bacterial diversity of the donor's microbiota. Switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar "Western" diet shifted the structure of the microbiota within a single day, changed the representation of metabolic pathways in the microbiome, and altered microbiome gene expression. Reciprocal transplants involving various combinations of donor and recipient diets revealed that colonization history influences the initial structure of the microbial community but that these effects can be rapidly altered by diet. Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation. Humanized gnotobiotic mice will be useful for conducting proof-of-principle "clinical trials" that test the effects of environmental and genetic factors on the gut microbiota and host physiology. Nearly full-length 16S rRNA gene sequences are deposited in GenBank under the accession numbers GQ491120 to GQ493997.
Several different protocols are used for fecal DNA extraction, which is an integral step in all phylogenetic and metagenomic approaches to characterize the highly diverse intestinal ecosystem. We compared four widely used methods, and found their DNA yields to vary up to 35-fold. Bacterial, archaeal and human DNA was quantified by real-time PCR, and a compositional analysis of different extracts was carried out using the Human Intestinal Tract Chip, a 16S rRNA gene-based phylogenetic microarray. The overall microbiota composition was highly similar between the methods in contrast to the profound differences between the subjects (Pearson correlations >0.899 and 0.735, respectively). A detailed comparative analysis of mechanical and enzymatic methods showed that despite their overall similarity, the mechanical cell disruption by repeated bead beating showed the highest bacterial diversity and resulted in significantly improved DNA extraction efficiency of archaea and some bacteria, including Clostridium cluster IV. By applying the mechanical disruption method a high prevalence (67%) of methanogenic archaea was detected in healthy subjects (n=24), exceeding the typical values reported previously. The assessment of performance differences between different methodologies serves as a concrete step towards the comparison and reliable meta-analysis of the results obtained in different laboratories.
We examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet.
In dietary-obese C57BL/6J mice, sodium butyrate was administrated through diet supplementation at 5% wt/wt in the high-fat diet. Insulin sensitivity was examined with insulin tolerance testing and homeostasis model assessment for insulin resistance. Energy metabolism was monitored in a metabolic chamber. Mitochondrial function was investigated in brown adipocytes and skeletal muscle in the mice.
On the high-fat diet, supplementation of butyrate prevented development of insulin resistance and obesity in C57BL/6 mice. Fasting blood glucose, fasting insulin, and insulin tolerance were all preserved in the treated mice. Body fat content was maintained at 10% without a reduction in food intake. Adaptive thermogenesis and fatty acid oxidation were enhanced. An increase in mitochondrial function and biogenesis was observed in skeletal muscle and brown fat. The type I fiber was enriched in skeletal muscle. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression was elevated at mRNA and protein levels. AMP kinase and p38 activities were elevated. In the obese mice, supplementation of butyrate led to an increase in insulin sensitivity and a reduction in adiposity.
Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse. The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.
The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).
The distal human intestine harbors trillions of microbes that allow us to extract calories from otherwise indigestible dietary polysaccharides. The products of polysaccharide fermentation include short-chain fatty acids that are ligands for Gpr41, a G protein-coupled receptor expressed by a subset of enteroendocrine cells in the gut epithelium. To examine the contribution of Gpr41 to energy balance, we compared Gpr41−/− and Gpr41+/+ mice that were either conventionally-raised with a complete gut microbiota or were reared germ-free and then cocolonized as young adults with two prominent members of the human distal gut microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic archaeon, Methanobrevibacter smithii. Both conventionally-raised and gnotobiotic Gpr41−/− mice colonized with the model fermentative community are significantly leaner and weigh less than their WT (+/+) littermates, despite similar levels of chow consumption. These differences are not evident when germ-free WT and germ-free Gpr41 knockout animals are compared. Functional genomic, biochemical, and physiologic studies of germ-free and cocolonized Gpr41−/− and +/+ littermates disclosed that Gpr41-deficiency is associated with reduced expression of PYY, an enteroendocrine cell-derived hormone that normally inhibits gut motility, increased intestinal transit rate, and reduced harvest of energy (short-chain fatty acids) from the diet. These results reveal that Gpr41 is a regulator of host energy balance through effects that are dependent upon the gut microbiota.
• host-microbial interactions
• energy balance
• enteroendocrine cells
• nutrient sensing
• polysaccharide fermentation
The aim of this study was to assess in rats the effect of protein feeding on the: 1) distribution of endogenous glucose production (EGP) among gluconeogenic organs, and 2) repercussion on the insulin sensitivity of glucose metabolism. We used gene expression analyses, a combination of glucose tracer dilution and arteriovenous balance to quantify specific organ release, and hyperinsulinemic euglycemic clamps to assess EGP and glucose uptake. Protein feeding promoted a dramatic induction of the main regulatory gluconeogenic genes (glucose-6 phosphatase and phosphoenolpyruvate carboxykinase) in the kidney, but not in the liver. As a consequence, the kidney glucose release was markedly increased, compared with rats fed a normal starch diet. Protein feeding ameliorated the suppression of EGP by insulin and the sparing of glycogen storage in the liver but had no effect on glucose uptake. Combined with the previously reported induction of gluconeogenesis in the small intestine, the present work strongly suggests that a redistribution of glucose production among gluconeogenic organs might occur upon protein feeding. This phenomenon is in keeping with the improvement of insulin sensitivity of EGP, most likely involving the hepatic site. These data shed a new light on the improvement of glucose tolerance, previously observed upon increasing the amount of protein in the diet, in type 2 diabetic patients.
Protein feeding increases kidney gluconeogenesis without increasing global endogenous glucose production, and improves insulin suppression of the latter, likely at the hepatic site.
Caco-2 cells develop morphologic characteristics of normal enterocytes when grown on plastic dishes or nitrocellulose filters. The purpose of this study was to determine whether Caco-2 cells undergo similar differentiation when grown on Transwell polycarbonate membranes, and to study the suitability of Caco-2 monolayers as an intestinal epithelial transport model system. Transepithelial electrical resistance values after confluence were 173.5 omega.cm2 and remained unchanged through day 17. Permeabilities to the water-soluble fluid-phase markers that do not permeate the membrane, Lucifer yellow CH, [14C]inulin, [14C]polyethylene glycol, and [3H] dextran were less than 0.25% of the administered amount per hour after day 10. Qualitative evaluation of uptake and permeability to horseradish peroxidase confirmed the similarity in uptake and barrier properties between this cell system and the small intestinal epithelial layer. We conclude that Caco-2 cells grown on collagen-coated polycarbonate membranes should represent a valuable transport model system for the small intestinal epithelium.
Evidence for the occurrence of microbial breakdown of carbohydrate in the human colon has been sought by measuring short chain fatty acid (SCFA) concentrations in the contents of all regions of the large intestine and in portal, hepatic and peripheral venous blood obtained at autopsy of sudden death victims within four hours of death. Total SCFA concentration (mmol/kg) was low in the terminal ileum at 13 +/- 6 but high in all regions of the colon ranging from 131 +/- 9 in the caecum to 80 +/- 11 in the descending colon. The presence of branched chain fatty acids was also noted. A significant trend from high to low concentrations was found on passing distally from caecum to descending colon. pH also changed with region from 5.6 +/- 0.2 in the caecum to 6.6 +/- 0.1 in the descending colon. pH and SCFA concentrations were inversely related. Total SCFA (mumol/l) in blood was, portal 375 +/- 70, hepatic 148 +/- 42 and peripheral 79 +/- 22. In all samples acetate was the principal anion but molar ratios of the three principal SCFA changed on going from colonic contents to portal blood to hepatic vein indicating greater uptake of butyrate by the colonic epithelium and propionate by the liver. These data indicate that substantial carbohydrate, and possibly protein, fermentation is occurring in the human large intestine, principally in the caecum and ascending colon and that the large bowel may have a greater role to play in digestion than has previously been ascribed to it.
At variance with the current view that only liver and kidney are gluconeogenic organs, because both are the only tissues to express glucose-6-phosphatase (Glc6Pase), we have recently demonstrated that the Glc6Pase gene is expressed in the small intestine in rats and humans and that it is induced in insulinopenic states such as fasting and diabetes. We used a combination of arteriovenous balance and isotopic techniques, reverse transcription-polymerase chain reaction, Northern blot analysis, and enzymatic activity assays. We report that rat small intestine can release neosynthesized glucose in mesenteric blood in insulinopenia, contributing 20-25% of total endogenous glucose production. Like liver glucose production, small intestine glucose production is acutely suppressed by insulin infusion. In the small intestine, glutamine and, to a much lesser extent, glycerol are the precursors of glucose, whereas alanine and lactate are the main precursors in liver. Accounting for these metabolic fluxes: 1) the phosphoenolpyruvate carboxykinase gene (required for the utilization of glutamine) is strongly induced at the mRNA and enzyme levels in insulinopenia; 2) the glycerokinase gene is expressed, but not induced; 3) the pyruvate carboxylase gene (required for the utilization of alanine and lactate) is repressed by 80% at the enzyme level in insulinopenia. These studies identify small intestine as a new insulin-sensitive tissue and a third gluconeogenic organ, possibly involved in the pathophysiology of diabetes.
Diets rich in insoluble-fibre are linked to a reduced risk of both diabetes and cardiovascular disease; however, the mechanism of action remains unclear. The aim of this study was to assess whether acute changes in the insoluble-fibre (resistant starch) content of the diet would have effects on postprandial carbohydrate and lipid handling.
Ten healthy subjects consumed two identical, low-residue diets on separate occasions for 24 h (33% fat; <2 g dietary fibre). Of the diets one was supplemented with 60 g resistant starch (Novelose 260). On the following morning a fibre-free meal tolerance test (MTT) was carried out (59 g carbohydrate; 21 g fat; 2.1 kJ) and postprandial insulin sensitivity (SI(ORAL)) assessed using a minimal model approach.
Prior resistant starch consumption led to lower postprandial plasma glucose (p=0.037) and insulin (p=0.038) with a higher insulin sensitivity(44+/-7.5 vs 26+/-3.5 x 10(-4) dl kg(-1) min(-1) per micro Uml(-1); p=0.028) and C-peptide-to-insulin molar ratio (18.7+/-6.5 vs 9.7+/-0.69; p=0.017). There was no effect of resistant starch consumption on plasma triacylglycerol although non-esterified fatty acid and 3-hydroxybutyrate levels were suppressed 5 h after the meal tolerance test.
Prior acute consumption of a high-dose of resistant starch enhanced carbohydrate handling in the postprandial period the following day potentially due to the increased rate of colonic fermentation.
10.1128/AEM.71.12.8228-8235.2005
Evidence for the occurrence of microbial breakdown of carbohydrate in the human colon has been sought by measuring short chain fatty acid (SCFA) concentrations in the contents of all regions of the large intestine and in portal, hepatic and peripheral venous blood obtained at autopsy of sudden death victims within four hours of death. Total SCFA concentration (mmol/kg) was low in the terminal ileum at 13 +/- 6 but high in all regions of the colon ranging from 131 +/- 9 in the caecum to 80 +/- 11 in the descending colon. The presence of branched chain fatty acids was also noted. A significant trend from high to low concentrations was found on passing distally from caecum to descending colon. pH also changed with region from 5.6 +/- 0.2 in the caecum to 6.6 +/- 0.1 in the descending colon. pH and SCFA concentrations were inversely related. Total SCFA (mumol/l) in blood was, portal 375 +/- 70, hepatic 148 +/- 42 and peripheral 79 +/- 22. In all samples acetate was the principal anion but molar ratios of the three principal SCFA changed on going from colonic contents to portal blood to hepatic vein indicating greater uptake of butyrate by the colonic epithelium and propionate by the liver. These data indicate that substantial carbohydrate, and possibly protein, fermentation is occurring in the human large intestine, principally in the caecum and ascending colon and that the large bowel may have a greater role to play in digestion than has previously been ascribed to it.
Type 2 diabetes (T2D) is a result of complex gene-environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.
The neural sensing of nutrients during food digestion plays a key role in the regulation of hunger. Recent data have emphasized that the extrinsic gastrointestinal nervous system is preponderant in this phenomenon and in its translation to the control of food intake by the central nervous system (CNS). Nutrient sensing by the extrinsic gastrointestinal nervous system may account for the satiation induced by food lipids, the satiety initiated by food protein, and for the rapid benefits of gastric bypass surgeries on both glucose and energy homeostasis. Thus, this recent knowledge provides novel examples of the mechanisms that control food intake and body weight, and this might pave the way for future approaches to the prevention and/or treatment of obesity.