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Nutrients Dec 2020Dysbiosis is implicated by many studies in the pathogenesis of Parkinson's disease (PD). Advances in sequencing technology and computing have resulted in confounding... (Review)
Review
Dysbiosis is implicated by many studies in the pathogenesis of Parkinson's disease (PD). Advances in sequencing technology and computing have resulted in confounding data regarding pathogenic bacterial profiles in conditions such as PD. Changes in the microbiome with reductions in short-chain fatty acid (SCFA)-producing bacteria and increases in endotoxin-producing bacteria likely contribute to the pathogenesis of PD. GPR109A, a G-protein coupled receptor found on the surface of the intestinal epithelium and immune cells, plays a key role in controlling intestinal permeability and the inflammatory cascade. The absence of GPR109A receptors is associated with decreased concentration of tight junction proteins, leading to increased intestinal permeability and susceptibility to inflammation. In inflammatory states, butyrate acts via GPR109A to increase concentrations of tight junction proteins and improve intestinal permeability. Niacin deficiency is exacerbated in PD by dopaminergic medications. Niacin supplementation has been shown to shift macrophage polarization from pro-inflammatory to an anti-inflammatory profile. Niacin and butyrate, promising nutrients and unique ligands for the G protein-coupled receptor GPR109A, are reviewed in this paper in detail.
Topics: Animals; Butyrates; Dietary Supplements; Dysbiosis; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Niacin; Parkinson Disease; Permeability
PubMed: 33374784
DOI: 10.3390/nu13010028 -
Gut Oct 1987Evidence 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...
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.
Topics: Acetates; Acetic Acid; Animals; Butyrates; Butyric Acid; Fatty Acids; Female; Fermentation; Gastrointestinal Contents; Hepatic Veins; Humans; Hydrogen-Ion Concentration; Intestine, Large; Male; Portal Vein; Propionates; Swine
PubMed: 3678950
DOI: 10.1136/gut.28.10.1221 -
Frontiers in Endocrinology 2021Metagenomics studies have shown that type 2 diabetes (T2D) is associated with an altered gut microbiota. Whereas different microbiota patterns have been observed in... (Review)
Review
Metagenomics studies have shown that type 2 diabetes (T2D) is associated with an altered gut microbiota. Whereas different microbiota patterns have been observed in independent human cohorts, reduction of butyrate-producing bacteria has consistently been found in individuals with T2D, as well as in those with prediabetes. Butyrate is produced in the large intestine by microbial fermentations, particularly of dietary fiber, and serves as primary fuel for colonocytes. It also acts as histone deacetylase inhibitor and ligand to G-protein coupled receptors, affecting cellular signaling in target cells, such as enteroendocrine cells. Therefore, butyrate has become an attractive drug target for T2D, and treatment strategies have been devised to increase its intestinal levels, for example by supplementation of butyrate-producing bacteria and dietary fiber, or through fecal microbiota transplant (FMT). In this review, we provide an overview of current literature indicating that these strategies have yielded encouraging results and short-term benefits in humans, but long-term improvements of glycemic control have not been reported so far. Further studies are required to find effective approaches to restore butyrate-producing bacteria and butyrate levels in the human gut, and to investigate their impact on glucose regulation in T2D.
Topics: Animals; Bacteria; Butyrates; Diabetes Mellitus, Type 2; Feces; Gastrointestinal Microbiome; Humans
PubMed: 34737725
DOI: 10.3389/fendo.2021.761834 -
Gut Microbes 2022The bacteria-derived short-chain fatty acids (SCFAs) butyrate and propionate play important (distinct) roles in health and disease, and understanding the ecology of...
The bacteria-derived short-chain fatty acids (SCFAs) butyrate and propionate play important (distinct) roles in health and disease, and understanding the ecology of respective bacteria on a community-wide level is a top priority in microbiome research. Applying sequence data (metagenomics and 16S rRNA gene) to predict SCFAs production and , a clear split between butyrate- and propionate-forming bacteria was detected with only very few taxa exhibiting pathways for the production of both SCFAs. After growth of fecal communities from distinct donors (n = 8) on different substrates (n = 7), abundances of bacteria exhibiting pathways correlated with respective SCFA concentrations, in particular in the case of butyrate. For propionate, correlations were weaker, indicating that its production is less imprinted into the core metabolism compared with butyrate-forming bacteria. Longitudinal measurements (n = 5 time-points from 20 subjects) also revealed a correlation between abundances of pathway-carrying bacteria and concentrations of the two SCFAs. Additionally, lower bacterial cell concentrations, together with higher stool moisture, promoted overall bacterial activity (measured by flow cytometry and coverage patterns of metagenome-assembled genomes) that led to elevated SCFA concentrations with over-proportional levels of butyrate. Predictions on pathway abundances based on 16S rRNA gene data using our in-house database worked well, yielding similar results as metagenomic-based analyses. Our study indicates that stimulating growth of butyrate- and propionate-producing bacteria directly leads to more production of those compounds, which is governed by two functionally distinct bacterial groups facilitating the development of precision intervention strategies targeting either metabolite.
Topics: Humans; Gastrointestinal Microbiome; Butyrates; Propionates; RNA, Ribosomal, 16S; Fatty Acids, Volatile; Bacteria
PubMed: 36416760
DOI: 10.1080/19490976.2022.2149019 -
Microbiology Spectrum Feb 2023Insufficient sleep is a key factor in the occurrence of intestinal diseases. This study was performed to clarify how sleep deficiency mediates the intestinal microbiota,...
Insufficient sleep is a key factor in the occurrence of intestinal diseases. This study was performed to clarify how sleep deficiency mediates the intestinal microbiota, metabolite butyrate disturbance induces intestinal mucosal damage, and butyrate ameliorates it. A questionnaire was launched for sleep and intestinal health issues. Twenty-two healthy volunteers were interviewed, and the influence of insufficient sleep on the gut microbiota and metabolite composition was explored. Moreover, a 72-h sleep deprivation (SD) mouse model with or without butyrate supplementation was used to reveal the effect of butyrate on ameliorating small intestines damage caused by SD. The questionnaire survey of 534 college students showed that among 85.39% of the students who slept less than 7 h, 41.76% were suffering from various bowel disorders. High-throughput 16S rRNA pyrosequencing demonstrated that SD and sleep restriction (SR) resulted in downregulation of and butyrate abundance in the feces of college students. Furthermore, we observed that butyrate supplementation markedly reversed sleep-deprivation-induced small intestinal mucosal injury in mice. Meanwhile, butyrate supplementation inverted the SD-caused inflammation response and oxidative stress and the decline of phospho-glycogen synthase kinase 3β (p-GSK-3β), β-catenin, Nrf2, and cyclin D1 and the increase in histone deacetylase 3 (HDAC3) and phospho-P65 (p-P65) proteins in the small intestines. Furthermore, , the ameliorative effects of butyrate were blocked by treatment with the HDAC3 agonist ITSA-1 and the Nrf2 antagonist ML385 and mimicked by treatment with the HDAC3 antagonist RGFP966 and p-P65 antagonist PDTC. Our study revealed that SD and SR downregulated butyrate production, further causing intestinal homeostasis dysfunction via the HDAC3-p-GSK-3β-β-catenin-Nrf2-NF-κB pathway. Radical inflammatory bowel disease (IBD) induced by sleep deficiency is a serious global public health threat. Butyrate, a member of the short-chain fatty acids, exerts multiple effects on it. However, existing research focuses on injury to the colon caused by insufficient sleep, while the changes in the small intestines are often overlooked. This study focused on revealing the influence of insufficient sleep on the intestinal microbiota and its metabolites and further revealed the ameliorative effect of butyrate on sleep deprivation (SD)-induced small intestinal mucosal damage in human and mice. Our studies suggest that butyrate can be used as a probiotic to restore SD-induced IBD and contribute to a better understanding of the mechanisms that govern the beneficial effects of butyrate.
Topics: Animals; Humans; Mice; beta Catenin; Butyrates; Glycogen Synthase Kinase 3 beta; Inflammatory Bowel Diseases; NF-E2-Related Factor 2; RNA, Ribosomal, 16S; Sleep Deprivation; Intestinal Mucosa
PubMed: 36541814
DOI: 10.1128/spectrum.02000-22 -
Obesity Reviews : An Official Journal... Oct 2022Evidence is increasing that disturbances in the gut microbiome may play a significant role in the etiology of obesity and type 2 diabetes. The short chain fatty acid... (Review)
Review
Evidence is increasing that disturbances in the gut microbiome may play a significant role in the etiology of obesity and type 2 diabetes. The short chain fatty acid butyrate, a major end product of the bacterial fermentation of indigestible carbohydrates, is reputed to have anti-inflammatory properties and positive effects on body weight control and insulin sensitivity. However, whether butyrate has therapeutic potential for the treatment and prevention of obesity and obesity-related complications remains to be elucidated. Overall, animal studies strongly indicate that butyrate administered via various routes (e.g., orally) positively affects adipose tissue metabolism and functioning, energy and substrate metabolism, systemic and tissue-specific inflammation, and insulin sensitivity and body weight control. A limited number of human studies demonstrated interindividual differences in clinical effectiveness suggesting that outcomes may depend on the metabolic, microbial, and lifestyle-related characteristics of the target population. Hence, despite abundant evidence from animal data, support of human data is urgently required for the implementation of evidence-based oral and gut-derived butyrate interventions. To increase the efficacy of butyrate-focused interventions, future research should investigate which factors impact treatment outcomes including baseline gut microbial activity and functionality, thereby optimizing targeted-interventions and identifying individuals that merit most from such interventions.
Topics: Animals; Butyrates; Diabetes Mellitus, Type 2; Fatty Acids, Volatile; Humans; Insulin Resistance; Obesity
PubMed: 35856338
DOI: 10.1111/obr.13498 -
Life Sciences Dec 2023Butyrate, a short-chain fatty acid (SCFA), has demonstrated significant efficacy in preventing colitis-associated inflammation. Acute pancreatitis is an acute...
Butyrate, a short-chain fatty acid (SCFA), has demonstrated significant efficacy in preventing colitis-associated inflammation. Acute pancreatitis is an acute gastrointestinal disorder characterized by increased systemic inflammation, bacterial translocation, and disrupted intestinal barrier. However, the effects and mechanisms of butyrate in attenuating acute pancreatitis remain unclear. In this study, we established two mouse models of acute pancreatitis induced by cerulein (Cer) and taurocholate (TA), which were further exacerbated by a ketogenic diet (KD). The results suggested that butyrate supplementation effectively reduced mortality rates, systemic inflammation, and intestinal barrier disruption caused by Cer- and TA-induced acute pancreatitis in mice fed a KD. Furthermore, we observed a significant reduction in gut microbiota diversity as well as overgrowth of Lachnospirales and Erysipelotrichales along with depletion of SCFAs in mice fed a KD, and these alterations were reversed by butyrate supplement. To evaluate the role of microbiota and butyrate supplement, we conducted germ-depletion trials by antibiotics. The results showed that while systemic inflammation was attenuated in mice with TA-induced pancreatitis following antibiotic treatment, the reduction in mortality remained inconclusive (p = 0.055). Importantly, the key differential change between antibiotic treatment and butyrate supplementation was found to be related to intestinal barrier dysfunction and repairment. These results suggest that butyrate plays a central role in mitigating acute pancreatitis through amelioration of intestinal barrier dysfunction.
Topics: Animals; Mice; Butyrates; Pancreatitis; Diet, Ketogenic; Acute Disease; Intestinal Diseases; Inflammation; Anti-Bacterial Agents; Mice, Inbred C57BL
PubMed: 37866809
DOI: 10.1016/j.lfs.2023.122188 -
Frontiers in Immunology 2023Atopic dermatitis (AD) is an inflammatory skin disease caused by the disruption of skin barrier, and is dominated by the type 2 immune responses. Patients with AD have a...
Atopic dermatitis (AD) is an inflammatory skin disease caused by the disruption of skin barrier, and is dominated by the type 2 immune responses. Patients with AD have a high risk of developing infection. Interleukin-33 (IL-33), an alarmin, has been implicated in the pathophysiology of AD development. Butyrate, a short chain fatty acid known to be produced from the fermentation of glycerol by the commensal skin bacterium, , has been reported to possess antimicrobial and anti-inflammatory properties that suppress inflammatory dermatoses. However, little is known about the effects of butyrate on dermal IL-33 expression and associated immune response in -aggravated skin inflammation in the context of AD. To decipher the underlying mechanism, we established an AD-like mouse model with epidermal barrier disruption by delipidizing the dorsal skin to induce AD-like pathophysiology, followed by the epicutaneous application of and butyrate. We discovered that infection exacerbated IL-33 release from keratinocytes and aggravated dermal leukocyte infiltration and IL-13 expression. Moreover, we showed that butyrate could attenuate -aggravated skin inflammation with decreased IL-33, IL-13, and leukocyte infiltration in the skin. Mechanistically, we demonstrated that butyrate suppressed IL-33 expression and ameliorated skin inflammation through histone deacetylase 3 (HDAC3) inhibition. Overall, our findings revealed the potential positive effect of butyrate in controlling inflammatory skin conditions in AD aggravated by infection.
Topics: Animals; Mice; Staphylococcus aureus; Interleukin-33; Butyrates; Interleukin-13; Dermatitis, Atopic; Staphylococcal Infections; Inflammation
PubMed: 37261337
DOI: 10.3389/fimmu.2023.1114699 -
The Journal of Allergy and Clinical... Feb 2023Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs)....
BACKGROUND
Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs). Rhinoviruses (RVs) induce upper respiratory tract illnesses and precipitate exacerbations of asthma and chronic obstructive pulmonary disease through poorly understood mechanisms. Local interactions between SCFAs and antiviral immune responses in the respiratory tract have not been previously investigated.
OBJECTIVE
We sought to investigate whether pulmonary metabolite manipulation through lung-delivered administration of SCFAs can modulate antiviral immunity to RV infection.
METHODS
We studied the effects of intranasal administration of the SCFAs acetate, butyrate, and propionate on basal expression of antiviral signatures, and of acetate in a mouse model of RV infection and in RV-infected lung epithelial cell lines. We additionally assessed the effects of acetate, butyrate, and propionate on RV infection in differentiated human primary bronchial epithelial cells.
RESULTS
Intranasal acetate administration induced basal upregulation of IFN-β, an effect not observed with other SCFAs. Butyrate induced RIG-I expression. Intranasal acetate treatment of mice increased interferon-stimulated gene and IFN-λ expression during RV infection and reduced lung virus loads at 8 hours postinfection. Acetate ameliorated virus-induced proinflammatory responses with attenuated pulmonary mucin and IL-6 expression observed at day 4 and 6 postinfection. This interferon-enhancing effect of acetate was confirmed in human bronchial and alveolar epithelial cell lines. In differentiated primary bronchial epithelial cells, butyrate treatment better modulated IFN-β and IFN-λ gene expression during RV infection.
CONCLUSIONS
SCFAs augment antiviral immunity and reduce virus load and proinflammatory responses during RV infection.
Topics: Humans; Mice; Animals; Antiviral Agents; Rhinovirus; Propionates; Picornaviridae Infections; Interferons; Bronchi; Enterovirus Infections; Epithelial Cells; Acetates; Butyrates
PubMed: 36216081
DOI: 10.1016/j.jaci.2022.09.026 -
Nutrients Jun 2023Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs),...
Butyrate Protects Barrier Integrity and Suppresses Immune Activation in a Caco-2/PBMC Co-Culture Model While HDAC Inhibition Mimics Butyrate in Restoring Cytokine-Induced Barrier Disruption.
Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs), especially butyrate, could be a potential treatment because of their combined anti-inflammatory and barrier- protective capacities, but more insight into their mechanism of action is needed. In the present study, non-activated, lipopolysaccharide-activated and αCD3/CD28-activated peripheral blood mononuclear cells (PBMCs) with and without intestinal epithelial cells (IEC) Caco-2 were used to study the effect of butyrate on barrier function, cytokine release and immune cell phenotype. A Caco-2 model was used to compare the capacities of butyrate, propionate and acetate and study their mechanism of action, while investigating the contribution of lipoxygenase (LOX), cyclooxygenase (COX) and histone deacetylase (HDAC) inhibition. Butyrate protected against inflammatory-induced barrier disruption while modulating inflammatory cytokine release by activated PBMCs (interleukin-1 beta↑, tumor necrosis factor alpha↓, interleukin-17a↓, interferon gamma↓, interleukin-10↓) and immune cell phenotype (regulatory T-cells↓, T helper 17 cells↓, T helper 1 cells↓) in the PBMC/Caco-2 co-culture model. Similar suppression of immune activation was shown in absence of IEC. Butyrate, propionate and acetate reduced inflammatory cytokine-induced IEC activation and, in particular, butyrate was capable of fully protecting against cytokine-induced epithelial permeability for a prolonged period. Different HDAC inhibitors could mimic this barrier-protective effect, showing HDAC might be involved in the mechanism of action of butyrate, whereas LOX and COX did not show involvement. These results show the importance of sufficient butyrate levels to maintain intestinal homeostasis.
Topics: Humans; Cytokines; Butyrates; Leukocytes, Mononuclear; Coculture Techniques; Histone Deacetylases; Caco-2 Cells; Propionates; Interleukins; Intestinal Mucosa
PubMed: 37375664
DOI: 10.3390/nu15122760