Action Of Short-chain Fatty Acids Research Articles

A comprehensive map of microbial biomarkers along the gastrointestinal tract for celiac disease patients.

Dysbiosis of the microbiome has been related to Celiac disease (CeD) progress, an autoimmune disease characterized by gluten intolerance developed in genetically susceptible individuals under certain environmental factors. The microbiome contributes to CeD pathophysiology, modulating the immune response by the action of short-chain fatty acids (SCFA), affecting gut barrier integrity allowing the entrance of gluten-derived proteins, and degrading immunogenic peptides of gluten through endoprolyl peptidase enzymes. Despite the evidence suggesting the implication of gut microbiome over CeD pathogenesis, there is no consensus about the specific microbial changes observed in this pathology. Here, we compiled the largest dataset of 16S prokaryotic ribosomal RNA gene high-throughput sequencing for consensus profiling. We present for the first time an integrative analysis of metataxonomic data from patients with CeD, including samples from different body sites (saliva, pharynx, duodenum, and stool). We found the presence of coordinated changes through the gastrointestinal tract (GIT) characterized by an increase in Actinobacteria species in the upper GIT (pharynx and duodenum) and an increase in Proteobacteria in the lower GIT (duodenum and stool), as well as site-specific changes evidencing a dysbiosis in patients with CeD’ microbiota. Moreover, we described the effect of adherence to a gluten-free diet (GFD) evidenced by an increase in beneficial bacteria and a decrease in some Betaproteobacteriales but not fully restoring CeD-related dysbiosis. Finally, we built a Random Forest model to classify patients based on the lower GIT composition achieving good performance.

Microbiota intestinal y modulación del tejido adiposo en la patogénesis de la obesidad

The investigations carried out during the last century related to the description of the Gut Microbiota (GM) suggest a concrete relationship between its composition and the health of the host. Its deregulation called intestinal dysbiosis has been associated with different types of gastrointestinal, metabolic, oncological and even psychiatric diseases. Numerous reports that have described the condition of dysbiosis in obesity stand out, both in animal and human models of different age groups and regions of the world. In turn, the composition of the microbiome has also been associated with the different comorbidities of obesity, postulating that MI has an influence on adipose tissue (AT) dysfunction, understanding that it corresponds to the main modulator of the pathogenesis of obesity. However, it is not yet possible to establish a plausible mechanistic explanation. Currently, the use of multi-omics technologies, together with the evaluation of physiological variables, could provide us with a better understanding of the question raised. In view of this, this review aims to review the latest advances in understanding the influence of the intestinal microbiota on AT and its contribution to the mechanisms related to the pathogenesis of obesity. Among the main mechanisms identified, the evidence reports physiological links between the composition of GM and the modulation of inflammation, intestinal permeability and adipogenesis. The pathways involved derive from the influence of intestinal dysbiosis on the action of short-chain fatty acids, claudins, macrophages, oligosaccharides, among others. The mechanisms involved, mainly studied in animal models, should be considered for evaluation in future longitudinal and experimental studies in humans in order to obtain a better understanding of the implication of each mechanism in the global pathogenesis of obesity.

The role of short-chain fatty acids in inflammatory bowel diseases and colorectal cancer

Short-chain fatty acids (SCFAs) produced in the human colon are the major products of bacterial fermentation and are believed that they have a protective effect in case of gastrointestinal diseases. SCFAs, such as acetate, propionate, and butyrate are significant metabolites in intestinal homeostasis, and have been shown to be beneficial in inflammatory bowel diseases and colorectal cancer. SCFA are responsible for maintaining proper intestinal barrier and they take part in relevant immune functions. Action of SCFAs is dependent on the activation of protein receptors for receptor activation (GPCR) such as GPR41, GPR43 and GPR109A. In this review, we discuss the effects of SCFA on the intestinal mucosa in terms of inflammatory diseases and colorectal cancer.

Gut microbial-derived short-chain fatty acids and bone: a potential role in fracture healing.

Bone healing complications such as delayed healing or non-union affect 5-10 % of patients with a long-bone fracture and lead to reduced quality of life and increased health-care costs. The gut microbiota and the metabolites they produce, mainly short-chain fatty acids (SCFAs), have been shown to impact nearly all organs of the human body including bone. SCFAs show broad activity in positively influencing bone healing outcomes either by acting directly on cell types involved in fracture healing, such as osteoblasts, osteoclasts, chondrocytes and fibroblasts, or indirectly, by shaping an appropriate anti-inflammatory and immune regulatory response. Due to the ability of SCFAs to influence osteoblast and osteoclast differentiation, SCFAs may also affect the integration of orthopaedic implants in bone. In addition, SCFA-derivatives have already been used in a variety of tissue engineering constructs to reduce inflammation and induce bone tissue production. The present review summarises the current knowledge on the role of the gut microbiota, in particular through the action of SCFAs, in the individual stages of bone healing and provides insights into how SCFAs may be utilised in a manner beneficial for fracture healing and surgical reconstruction.

Sodium butyrate attenuated neuronal apoptosis via GPR41/Gβγ/PI3K/Akt pathway after MCAO in rats

Sodium butyrate, a short-chain fatty acid, is predominantly produced by gut microbiota fermentation of dietary fiber and serves as an important neuromodulator in the central nervous system. Recent experimental evidence has suggested that sodium butyrate may be an endogenous ligand for two orphan G protein-coupled receptors, GPR41 and GP43, which regulate apoptosis and inflammation in ischemia-related pathologies, including stroke. In the present study, we evaluated the potential efficacy and mechanism of action of short-chain fatty acids in a rat model of middle cerebral artery occlusion (MCAO). Fatty acids were intranasally administered 1 h post MCAO. Short-chain fatty acids, especially sodium butyrate, reduced infarct volume and improved neurological function at 24 and 72 h after MCAO. At 24 h, the effects of MCAO, increased apoptosis, were ameliorated after treatment with sodium butyrate, which increased the expressions of GPR41, PI3K and phosphorylated Akt. To confirm these mechanistic links and characterize the GPR active subunit, PC12 cells were subjected to oxygen–glucose deprivation and reoxygenation, and pharmacological and siRNA interventions were used to reverse efficacy. Taken together, intranasal administration of sodium butyrate activated PI3K/Akt via GPR41/Gβγ and attenuated neuronal apoptosis after MCAO.

Identification and characterization of the free fatty acid receptor 2 (FFA2) and a novel functional FFA2-like receptor (FFA2L) for short-chain fatty acids in pigs: Evidence for the existence of a duplicated FFA2 gene (FFA2L) in some mammalian species

Free fatty acid receptor 2 (FFA2, also called GPR43) is reported to play a critical role in mediating the actions of short-chain fatty acids (SCFAs) in humans and mice. However, little is known about the structure, functionality, and tissue expression of FFA2 in other mammalian species, including pigs. In the present study, the full-length cDNAs of FFA2 (pFFA2) and a novel FFA2-like gene (named pFFA2L) were cloned from pig intestines by reverse transcription PCR. Both cloned pFFA2 and pFFA2L are predicted to encode 2 receptors of remarkable structural similarity and share high amino acid sequence identities with FFA2 from other mammalian species. Interestingly, the novel FFA2L could also be identified in 9 other mammalian species, suggesting that FFA2L was likely duplicated from FFA2 in the last common ancestor of these species. With the use of a pGL4-SRE-luciferase reporter assay, we demonstrated that pFFA2 expressed in human embryonic kidney 293 cells could be activated by acetate, propionate, and butyrate equipotently, whereas pFFA2L could be activated only by acetate and propionate, indicating that both pFFA2 and pFFA2L are functional receptors for SCFAs with nonidentical pharmacologic properties. Reverse transcription PCR found that pFFA2 mRNA was widely expressed in nearly all tissues examined, including adipose tissue and gastrointestinal (GI) tract, whereas pFFA2L expression was mainly restricted to the GI tract. Taken together, our findings raise a novel concept that the actions of SCFAs are likely mediated by 2 FFA2s (FFA2 and FFA2L) in target tissues of some mammalian species, such as the GI tract of pigs.

Epigenome targeting by probiotic metabolites

BackgroundThe intestinal microbiota plays an important role in immune development and homeostasis. A disturbed microbiota during early infancy is associated with an increased risk of developing inflammatory and allergic diseases later in life. The mechanisms underlying these effects are poorly understood but are likely to involve alterations in microbial production of fermentation-derived metabolites, which have potent immune modulating properties and are required for maintenance of healthy mucosal immune responses. Probiotics are beneficial bacteria that have the capacity to alter the composition of bacterial species in the intestine that can in turn influence the production of fermentation-derived metabolites. Principal among these metabolites are the short-chain fatty acids butyrate and acetate that have potent anti-inflammatory activities important in regulating immune function at the intestinal mucosal surface. Therefore strategies aimed at restoring the microbiota profile may be effective in the prevention or treatment of allergic and inflammatory diseases.Presentation of the hypothesisProbiotic bacteria have diverse effects including altering microbiota composition, regulating epithelial cell barrier function and modulating of immune responses. The precise molecular mechanisms mediating these probiotic effects are not well understood. Short-chain fatty acids such as butyrate are a class of histone deacetylase inhibitors important in the epigenetic control of host cell responses. It is hypothesized that the biological function of probiotics may be a result of epigenetic modifications that may explain the wide range of effects observed. Studies delineating the effects of probiotics on short-chain fatty acid production and the epigenetic actions of short-chain fatty acids will assist in understanding the association between microbiota and allergic or autoimmune disorders.Testing the hypothesisWe propose that treatment with specific probiotic bacteria under in vivo conditions would offer the ideal conditions to examine the microbiological, immunological and epigenetic mechanisms of action. Advances in epigenetic technology now allow investigators to better understand the complex biological properties of probiotics and their metabolites.Implications of the hypothesisDetermining the precise mechanisms of probiotic action will lead to more specific and efficacious therapeutic strategies in the prevention or treatment of chronic inflammatory conditions.

Neural reflex pathways in the contractile and secretory actions of short-chain fatty acids in the rat intestine

Neural reflex pathways in the contractile and secretory actions of short-chain fatty acids in the rat intestine

Butyrate Induces Intestinal Sodium Absorption via Sp3-Mediated Transcriptional Up-Regulation of Epithelial Sodium Channels

The epithelial sodium channel (ENaC) is the rate-limiting factor for colonic electrogenic sodium absorption. This study aimed to investigate ENaC regulation by butyrate, a short-chain fatty acid (SCFA) produced by intestinal bacteria. ENaC was examined in HT-29/B6 cells and glucocorticoid receptor(GR)-transfected HT-29/B6 cells (HT-29/B6-GR) by reverse-transcription polymerase chain reaction, real-time polymerase chain reaction, and confocal microscopy. ENaC promoters were investigated by deletion/mutation analysis, electrophoretic mobility shift assays, and quantitative chromatin immunoprecipitation. Sodium transport of HT-29/B6-GR cells and rat distal colon was quantified in Ussing chambers. Butyrate up-regulated beta- and gamma-ENaC mRNA expression in HT-29/B6 cells and induced transcription from beta- and gamma-ENaC promoter constructs. The gamma-ENaC promoter could also be induced by the SCFA propionate but not by acetate. Deletion/mutation assays revealed that activation of the gamma-ENaC promoter depended on 2 GC boxes, which were shown to bind Sp1 and Sp3 in vitro. Although both transcription factors increased butyrate-mediated gamma-ENaC transcription upon overexpression, chromatin immunoprecipitation revealed that only Sp3 binds to the gamma-ENaC promoter in vivo and that Sp3 binding is enhanced by butyrate. Transcriptional ENaC induction by butyrate led to synthesis of gamma-ENaC subunits, but correct targeting of ENaC channels to the apical cell membrane was dependent on corticosteroid hormones. Finally, butyrate substantially increased electrogenic sodium absorption via ENaC in the presence of corticosteroid hormones in HT-29/B6-GR cells and in rat distal colon. Concerted action of SCFA and corticosteroid hormones is required for induction of ENaC and maintenance of intestinal electrogenic sodium absorption.

A ação dos ácidos graxos de cadeia curta na cicatrização de anastomoses colônicas: estudo experimental em ratos

Os ácidos graxos de cadeia curta (AGCC) derivam da fermentação das fibras ingeridas na dieta e atuam como substrato das células da mucosa colônica. O presente estudo tem como objetivo avaliar a ação dos AGCC na cicatrização do cólon. Utilizaram-se 16 ratos fêmea divididos em 2 grupos de 8 animais. No grupo controle (HC) os animais foram submetidos à cirurgia de Hartmann e infusão pós-operatória de solução salina isotônica via retal por 7 dias. No grupo experimento (HA) a solução salina foi substituída por solução isosmolar contendo AGCC. Nos animais do grupo controle, a pressão média de ruptura do segmento distal do cólon foi de 128,37 mmHg, sendo este valor de 137,25 mmHg no grupo experimento (p=0,5693). A avaliação histológica em hematoxilina-eosina foi semelhante nos dois grupos estudados. A densitometria do colágeno demonstrou concentração significativamente maior de colágeno maduro (tipo I) no grupo experimento, quando comparado com o grupo controle (p=0,0094). O colágeno total também foi mais encontrado no grupo experimento, comparado-se com o grupo controle (p=0,0371). Conclui-se que os ratos submetidos à infusão intraluminal de AGCC têm maior concentração de colágeno maduro e total na linha de sutura do coto retal, quando comparados com o grupo controle.

Short-chain fatty acids improve clinical, pathologic, and microbiologic features of experimental shigellosis.

Because of the metabolic and antibacterial actions of short-chain fatty acids (SCFA), their roles in modifying the clinicopathologic features of shigellosis were evaluated in a rabbit model of shigellosis. Acute colitis was induced in adult rabbits by intracolonic administration of Shigella flexneri 2a. After 24 h, rabbits were given 6-h colonic infusions of SCFA (acetate, propionate, n-butyrate; 60:30:40 mM) or SCFA-free solution (control); groups of rabbits were killed in batches of 2 or 3 animals at 24, 48, 72, and 96 h after treatment, for histologic and bacteriologic assessment. SCFA significantly reduced fecal blood and mucus and improved clinical symptoms. Histologically, SCFA significantly (P<.01) reduced mucosal congestion, cellular infiltration, and necrotic changes. SCFA also significantly (P<.05) reduced the number of shigellae in the colon. No such improvements occurred in the control group. SCFA may be useful agents in improving clinicopathologic features of shigellosis and should be clinically evaluated.

Effect of short - chain fatty acids on electrical activity of the small intestinal mucosa of rat.

Abstract Intravenous administration of short-chain fatty acid (SCFA), such as propionate, butyrate, valerate and caproate, caused a transient increase in transmural potential difference (p.d.) across the small intestine of rat in vivo . There was a sigmoid relationship between the change in the p.d. and the logarithm of the dose of SCFA. The median effective dose of propionate, n-butyrate, n-valerate and n-caproate, which was calculated from the each dose-response curve obtained from the terminal ileum, 1.31, 1.43, 0.83 and 0.81 μmole, respectively. Repeated administrations of the same dose of propionate evoked progressively smaller response. The dose-response curve of propionate was shifted to the left by neostigmine and to the right by atropine, suggesting that the action of SCFA may be mediated by acetylcholine, which was released from a nerve ending.