Short-chain Fatty Acids Supplementation Research Articles

Microbial and host factors contribute to bloodstream infection in a pediatric acute lymphocytic leukemia mouse model

BackgroundHematological malignancies are the most common cancers in the pediatric population, and T-cell acute lymphocytic leukemia (T-ALL) is the most common hematological malignancy in children. Bloodstream infection (BSI) is a commonly occurring complication in leukemia due to underlying conditions and therapy-induced neutropenia. Several studies identified the gut microbiome as a major source of BSI due to bacterial translocation. This study aimed to investigate changes in the intestinal and fecal microbiome, and their roles in the pathophysiology of BSI in a pediatric T-ALL mouse model using high-throughput shotgun metagenomics sequencing, and metabolomics. ResultsOur results show that BSI in ALL is characterized by an increase of a mucin degrading bacterium (Akkermansia muciniphila) and a decrease of butyrate producer Clostridia spp., along with a decrease in short-chain fatty acid (SCFA) concentrations and differential expression of tight junction proteins in the small intestine. Functional analysis of the small intestinal microbiome indicated a reduced capability of SCFA synthesis, while SCFA supplementation ameliorated the development of BSI in ALL. ConclusionsOur data indicates that changes in the microbiome, and the resulting changes in levels of SCFAs contribute significantly to the pathogenesis of bloodstream infection in ALL. Our study provides tailored preventive or therapeutic approaches to reduce BSI-associated mortality in ALL.

Mesoporous silica nanoparticle-encapsulated Bifidobacterium attenuates brain Aβ burden and improves olfactory dysfunction of APP/PS1 mice by nasal delivery

BackgroundDysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aβ burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment.MethodsWe investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice.ResultsMesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aβ burden but also improved olfactory sensitivity in APP/PS1 mice.ConclusionsThese findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease.

SCFAs Ameliorate Chronic Postsurgical Pain–Related Cognition Dysfunction via the ACSS2-HDAC2 Axis in Rats

Patients with chronic postsurgical pain (CPSP) frequently exhibit comorbid cognitive deficits. Recent observations have emphasized the critical effects of gut microbial metabolites, like short-chain fatty acids (SCFAs), in regulating cognitive function. However, the underlying mechanisms and effective interventions remain unclear. According to hierarchical clustering and 16S rRNA analysis, over two-thirds of the CPSP rats had cognitive impairment, and the CPSP rats with cognitive impairment had an aberrant composition of gut SCFA-producing bacteria. Then, using feces microbiota transplantation, researchers identified a causal relationship between cognitive-behavioral and microbic changes. Similarly, the number of genera that generated SCFAs was decreased in the feces from recipients of cognitive impairment microbiota. Moreover, treatment with the SCFAs alleviated the cognitive-behavioral deficits in the cognitively compromised pain rats. Finally, we observed that SCFA supplementation improved histone acetylation and abnormal synaptic transmission in the medial prefrontal cortex (mPFC), hippocampal CA1, and central amygdala (CeA) area via the ACSS2 (acetyl-CoA synthetase2)-HDAC2 (histone deacetylase 2) axis. These findings link pain-related cognition dysfunction, gut microbiota, and short-chain fatty acids, shedding fresh insight into the pathogenesis and therapy of pain-associated cognition dysfunction.

The effect of increasing intestinal short‐chain fatty acid concentration on gut permeability and liver injury in the context of liver disease: A systematic review

Background and AimThe gut barrier protects the liver through tight junctions, which are disrupted in liver disease either from dysbiosis, inflammation, or the effects of ingested compounds such as alcohol. Strengthening of the gut barrier may ameliorate liver injury of varying etiologies. Short chain fatty acids (SCFAs) have been shown to improve gut barrier function. This systematic review aims to synthesize all studies that have trialed SCFA supplementation as a therapy for liver disease.MethodsA systematic review assessing the impact of SCFA supplementation on liver injury and intestinal permeability was conducted. All forms of intervention that specifically increased intestinal SCFA concentration and measured both liver injury and permeability were eligible. Two independent reviewers assessed each study for outcomes, risk of bias, and quality using checklists relevant to the study's methodology.ResultsSeventeen studies were identified; two utilized a human model (15 murine). Fifty‐eight markers of liver injury were identified, with 26 different measures of permeability. Given the numerous designs, no meta‐analysis was possible. SCFA supplements included oral and enteral butyrate, probiotics, and prebiotics. Fourteen studies demonstrated improved permeability. All studies showed a significant amelioration of liver injury.ConclusionsShort chain fatty acid supplementation to reduce intestinal permeability represents a potential therapy in a variety of liver disease models. A large number of outcome measures were reported however not all are practical in human studies. Future work should evaluate methods to increase luminal SCFA concentrations and the effect of this on gut permeability and liver inflammation in people with liver disease.

Effects of different short-chain fatty acids (SCFA) on gene expression of proteins involved in barrier function in IPEC-J2

BackgroundGut microbial anaerobic fermentation produces short-chain fatty acids (SCFA), which are important substrates for energy metabolism and anabolic processes in mammals. SCFA can regulate the inflammatory response and increase the intestinal barrier integrity by enhancing the tight junction protein (TJp) functions, which prevent the passage of antigens through the paracellular space. The aim of this study was to evaluate the effect of in vitro supplementation with SCFA (acetate, propionate, butyrate, and lactate) at different concentrations on viability, nitric oxide (NO) release (oxidative stress parameter) in cell culture supernatants, and gene expression of TJp (occludin, zonula occludens-1, and claudin-4) and pro-inflammatory pathway-related mediators (β-defensin 1, TNF-α, and NF-κB) in intestinal porcine epithelial cell line J2 (IPEC-J2).ResultsThe SCFA tested showed significant effects on IPEC-J2, which proved to be dependent on the type and specific concentration of the fatty acid. Acetate stimulated cell viability and NO production in a dose-dependent manner (P < 0.05), and specifically, 5 mM acetate activated the barrier response through claudin-4, and immunity through β-defensin 1 (P < 0.05). The same effect on these parameters was shown by propionate supplementation, especially at 1 mM (P < 0.05). Contrarily, lactate and butyrate showed different effects compared to acetate and propionate, as they did not stimulate an increase of cell viability and regulated barrier integrity through zonula occludens-1 and occludin, especially at 30 mM and 0.5 mM, respectively (P < 0.05). Upon supplementation with SCFA, the increase of NO release at low levels proved not to have detrimental effects on IPEC-J2 proliferation/survival, and in the case of acetate and propionate, such levels were associated with beneficial effects. Furthermore, the results showed that SCFA supplementation induced β-defensin 1 (P < 0.05) that, in turn, may have been involved in the inhibition of TNF-α and NF-κB gene expression (P < 0.05).ConclusionsThe present study demonstrates that the supplementation with specific SCFA in IPEC-J2 can significantly modulate the process of barrier protection, and that particularly acetate and propionate sustain cell viability, low oxidative stress activity and intestinal barrier function.

The beneficial effect of SCFAs on the cardiovascular system during hypertension

Hypertension, which is associated with gut dysbiosis, is an independent and preventable risk factor for the development of cardiovascular diseases. The gut microbiota and its metabolites such as short‐chain fatty acids (SCFAs) play an important role in host physiology. SCFAs can regulate blood pressure in both rodent models and humans. However, the exact mechanism by which SCFA regulates hypertension is unknown. Our data showed that SCFAs can regulate miR‐204, a non‐coding RNA that is expressed in vessels. We recently showed that miR‐204, is reduced in vessels during hypertension. Additionally, miR‐204 targets inositol 1, 4, 5‐triphosphate receptor type1 (IP3R1) and therefore disrupt the calcium release into the cytosol leading to exacerbated vascular constriction. Thus, we hypothesize that SCFAs can regulate blood pressure and vascular constriction through miRNA‐204/IP3R1/Ca2+ axis. To test our hypothesis, we treated hypertensive mice with SCFAs cocktail (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) in drinking water for 21 days. Increased blood pressure from hypertensive mice was reduced after SCFAs intake. Aortas and mesenteric arteries from hypertensive mice display increased vasoconstriction in response to phenylephrine, U46619, and angiotensin II. Treatment with SCFAs reduced vasoconstriction in response to all agonists. During hypertension, aortas display low levels of miR‐204 expression which was recovered after SCFAs intake. Additionally, IP3R1 was significantly up‐regulated in hypertensive mice and decreased after SCFAs supplementation. Furthermore, our in vitro data showed that SCFAs can directly affect the vascular miRNA‐204/IP3R1/Ca2+ axis. Our results suggest that SCFAs can regulate Ca2+ homeostasis and vascular contraction through the miR‐204/IP3R1 axis. The outcome of this study will establish novel treatment strategies conferring the benefits of SCFA control while circumventing the potential risks of delivering live biologics.

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids

BackgroundChronic cerebral hypoperfusion (CCH) underlies secondary brain injury following certain metabolic disorders and central nervous system (CNS) diseases. Dysregulation of the microbiota-gut-brain axis can exacerbate various CNS disorders through aberrantly expressed metabolites such as short-chain fatty acids (SCFAs). Yet, its relationship with CCH remains to be demonstrated. And if so, it is of interest to explore whether restoring gut microbiota to maintain SCFA metabolism could protect against CCH.ResultsRats subjected to bilateral common carotid artery occlusion (BCCAO) as a model of CCH exhibited cognitive impairment, depressive-like behaviors, decreased gut motility, and compromised gut barrier functions. The 16S ribosomal RNA gene sequencing revealed an abnormal gut microbiota profile and decreased relative abundance of some representative SCFA producers, with the decreased hippocampal SCFAs as the further evidence. Using fecal microbiota transplantation (FMT), rats recolonized with a balanced gut microbiome acquired a higher level of hippocampal SCFAs, as well as decreased neuroinflammation when exposed to lipopolysaccharide. Healthy FMT promoted gut motility and gut barrier functions, and improved cognitive decline and depressive-like behaviors by inhibiting hippocampal neuronal apoptosis in BCCAO rats. Long-term SCFA supplementation further confirmed its neuroprotective effect in terms of relieving inflammatory response and hippocampal neuronal apoptosis following BCCAO.ConclusionOur results demonstrate that modulating the gut microbiome via FMT can ameliorate BCCAO-induced gut dysbiosis, cognitive decline, and depressive-like behaviors, possibly by enhancing the relative abundance of SCFA-producing floras and subsequently increasing SCFA levels.9q_eednNVPt41Vawjie4QyVideo abstract

Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters

ABSTRACT Mounting evidence suggests that the gut-to-lung axis is critical during respiratory viral infections. We herein hypothesized that disruption of gut homeostasis during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may associate with early disease outcomes. To address this question, we took advantage of the Syrian hamster model. Our data confirmed that this model recapitulates some hallmark features of the human disease in the lungs. We further showed that SARS-CoV-2 infection associated with mild intestinal inflammation, relative alteration in intestinal barrier property and liver inflammation and altered lipid metabolism. These changes occurred concomitantly with an alteration of the gut microbiota composition over the course of infection, notably characterized by a higher relative abundance of deleterious bacterial taxa such as Enterobacteriaceae and Desulfovibrionaceae. Conversely, several members of the Ruminococcaceae and Lachnospiraceae families, including bacteria known to produce the fermentative products short-chain fatty acids (SCFAs), had a reduced relative proportion compared to non-infected controls. Accordingly, infection led to a transient decrease in systemic SCFA amounts. SCFA supplementation during infection had no effect on clinical and inflammatory parameters. Lastly, a strong correlation between some gut microbiota taxa and clinical and inflammation indices of SARS-CoV-2 infection severity was evidenced. Collectively, alteration of the gut microbiota correlates with disease severity in hamsters making this experimental model valuable for the design of interventional, gut microbiota-targeted, approaches for the control of COVID-19. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; SCFAs, short-chain fatty acids; dpi, day post-infection; RT-PCR, reverse transcription polymerase chain reaction; IL, interleukin. ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2.

Impact of short-chain fatty acid supplementation on gut inflammation and microbiota composition in a murine colitis model

Short-chain fatty acids (SCFAs) play a pivotal role in maintaining intestinal homeostasis. We aimed to investigate the effects of SCFA supplementation on gut inflammation and microbiota composition in a murine colitis model. Mice were fed with sodium butyrate or a mixture of SCFAs in the drinking water for 2 weeks, followed by 2% dextran sulfate sodium (DSS) for 7 d. After euthanasia, mouse colons were extracted to examine histological findings. Flow cytometry of the mouse colon tissues was performed to assess T cell differentiation. Changes in gut microbiota were assessed by high-throughput sequencing of the mouse feces. There were no significant differences in weight change, colonic length, or histologic inflammation score between the DSS, butyrate, and SCFA mix groups. However, flow cytometry revealed that both the expression of CD4+Foxp3+ regulatory T cells and of IL-17-producing T cells were increased in the butyrate and SCFA mix groups. Microbial compositions of the butyrate and SCFA mix groups were significantly different from those of the control and DSS groups in principal coordinate analysis. Relative abundances of the phyla Verrucomicrobia and Proteobacteria, species Akkermansia muciniphila and Escherichia fergusonii were increased in the butyrate and SCFA mix groups. Genera Roseburia and Lactobacillus showed a negative correlation with the degree of colitis, whereas genera Escherichia and Mucispirillum showed a positive correlation. SCFA supplementation did not result in a significant reduction in colon inflammation, but it promoted both regulatory T cell and IL-17-producing T cell expression, and increased both protective and aggressive gut microbiota.

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

BackgroundCognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis.ResultsIn this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment.ConclusionsThis study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.2_wgC4CVAKtYwCNZbg5Y4xVideo

Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition.

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype.

Mannan oligosaccharide attenuates cognitive and behavioral disorders in the 5xFAD Alzheimer's disease mouse model via regulating the gut microbiota-brain axis

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive deficits and psychiatric symptoms. The gut microbiota-brain axis plays a pivotal role during AD development, which could target nutritional intervention. The prebiotic mannan oligosaccharide (MOS) has been reported to reshape the gut microbiome and enhanced the formation of the neuroprotective metabolites short-chain fatty acids (SCFAs). Here, we found that an 8-week treatment of MOS (0.12%, w/v in the drinking water) significantly improved cognitive function and spatial memory, accompanied by attenuated the anxiety- and obsessive-like behaviors in the 5xFAD transgenic AD mice model. MOS substantially reduced the Aβ accumulation in the cortex, hippocampus, and amygdala of the brain. Importantly, MOS treatment significantly balanced the brain redox status and suppressed the neuroinflammatory responses. Moreover, MOS also alleviated the HPA-axis disorders by decreasing the levels of hormones corticosterone (CORT) and corticotropin-releasing hormone (CRH) and upregulated the norepinephrine (NE) expressions. Notably, the gut barrier integrity damage and the LPS leak were prevented by the MOS treatment. MOS re-constructed the gut microbiota composition, including increasing the relative abundance of Lactobacillus and reducing the relative abundance of Helicobacter. MOS enhanced the butyrate formation and related microbes levels. The correlation analysis indicated that the reshaped gut microbiome and enhanced butyrate formation are highly associated with behavioral alteration and brain oxidative status. SCFAs supplementation experiment also attenuated the behavioral disorders and Aβ accumulation in the AD mice brain, accompanied by balanced HPA-axis and redox status. In conclusion, the present study indicated that MOS significantly attenuates the cognitive and mental deficits in the 5xFAD mice, which could be partly explained by the reshaped microbiome and enhanced SCFAs formation in the gut. MOS, as a prebiotics, can be translated into a novel microbiota-targeted approach for managing metabolic and neurodegenerative diseases.

The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes

Intestinal Foxp3+ regulatory T cell (Treg) subsets are crucial players in tolerance to microbiota-derived and food-borne antigens, and compelling evidence suggests that the intestinal microbiota modulates their generation, functional specialization, and maintenance. Selected bacterial species and microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), have been reported to promote Treg homeostasis in the intestinal lamina propria. Furthermore, gut-draining mesenteric lymph nodes (mLNs) are particularly efficient sites for the generation of peripherally induced Tregs (pTregs). Despite this knowledge, the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated. Here, using an adoptive transfer-based pTreg induction system, we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs. Even mice housed under germ-free (GF) conditions displayed equivalent pTreg induction within mLNs. Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape. Overall, our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.

Maternal γδ T Cells Shape Offspring Pulmonary Type-2 Immunity in a Microbiota-Dependent Manner

Immune development is greatly influenced by vertically transferred cues. However, beyond B cells, little is known about the role of other subsets of the maternal immune system in regulating offspring immunity. We found that mice born from γδT cell-deficient (TCRδ-/-) dams display, early after birth, a pulmonary milieu selectively enriched in type-2 cytokines such as IL-33, IL-4, IL-5, and IL-13, and type-2-polarized immune cells, when compared to the progeny of γδT cell-sufficient dams. In addition, upon helminth infection, mice born from TCRδ-/- dams sustained an increased type-2 inflammatory response. Critically, this was independent of the genotype of the pups. The intestinal microbiota in the offspring of TCRδ-/- and TCRδ+/- dams harbored distinct bacterial communities acquired during birth and fostering, which were accompanied by changes in intestinal short-chain fatty acids (SCFA) profiles. Importantly, antibiotic treatment abrogated the differences in the pulmonary milieu, and exogenous SCFA supplementation suppressed first-breath- and infection-induced inflammation.

The Effects of Short-Chain Fatty Acids on Rat Colonic Hypermotility Induced by Water Avoidance Stress.

PurposeShort-chain fatty acids (SCFAs) have been reported to play an important role in regulating gastrointestinal motility. The aim of this study is to investigate the possible role of SCFAs in water avoidance stress-induced colonic hypermotility.MethodsA rat IBS model was established by water avoidance stress (WAS). Intestinal motility was assessed by fecal pellets expulsion. The fecal SCFA level was detected using gas chromatography-mass spectrometry (GC-MS). Western blotting was performed to assess the expression of SCFAs receptors. To determine the role of SCFAs in gut dysmotility, the rats of the WAS+SCFAS and SCFAs group were administrated with oral SCFAs. The colonic contractile activity was recorded with a RM6240 multichannel physiological signal system.Key ResultsWAS induced gastrointestinal hypermotility and increased defecation in rats. After repeated stress, the fecal SCFAs decreased significantly and the proportion of acetic acid, propionic acid, and butyric acid had changed from Control 2.6:1:1.5 to WAS 2:1:2.3. Protein levels of SCFAs receptors in the colon were promoted by WAS. In addition, oral SCFAs partly inhibited the colonic spontaneous motility both for SCFAs and WAS+SCFAs group in vivo. Meanwhile, we observed acetate had no effect on the contractile amplitudes of muscle strips, but it could slow down contractile frequency in a dose-dependent manner (1–100 mM). Propionate significantly inhibited the motor activity of colonic strips (1–30 mM). Butyrate inhibited the contractile amplitude of CM strips in a dose-dependent manner (1–30 mM), but for LM, it exhibited a stimulating effect at low concentrations of butyrate 1 mM–10 mM and was suppressed at high concentrations of 30 mM butyrate. Total SCFAs increased the contractile amplitude at low concentration (5–50 mM) and inhibited it at high concentration (50–150 mM). All SCFAs slowed down the frequency of colonic activity.ConclusionThe stress-induced colonic hypermotility by WAS could be ameliorated through oral SCFA supplementation. SCFAs may have potential clinical therapeutic use in modulating gut motility.

Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.

Bugs, breathing and blood pressure: microbiota-gut-brain axis signalling in cardiorespiratory control in health and disease.

There is clear evidence of physiological effects of the gut microbiota on whole-body function in health and disease. Microbiota-gut-brain axis signalling is recognised as a key player in behavioural disorders such as depression and anxiety. Recent evidence suggests that the gut microbiota affects neurocontrol networks responsible for homeostatic functions that are essential for life. We consider the evidence suggesting the potential for the gut microbiota to shape cardiorespiratory homeostasis. In various animal models of disease, there is an association between cardiorespiratory morbidity and perturbed gut microbiota, with strong evidence in support of a role of the gut microbiota in the control of blood pressure. Interventions that target the gut microbiota or manipulate the gut-brain axis, such as short-chain fatty acid supplementation, prevent hypertension in models of obstructive sleep apnoea. Emerging evidence points to a role for the microbiota-gut-brain axis in the control of breathing and ventilatory responsiveness, relevant to cardiorespiratory disease. There is also evidence for an association between the gut microbiota and disease severity in people with asthma and cystic fibrosis. There are many gaps in the knowledge base and an urgent need to better understand the mechanisms by which gut health and dysbiosis contribute to cardiorespiratory control. Nevertheless, there is a growing consensus that manipulation of the gut microbiota could prove an efficacious adjunctive strategy in the treatment of common cardiorespiratory diseases, which are the leading causes of morbidity and mortality.

Short chain fatty acids regulate T cell metabolism to promote IL-22 production and gut immunity

Abstract Interleukin-22 (IL-22) is critical in gut immunity. Both innate lymphocyte cells (ILCs) and CD4+ T cells produce IL-22. ILCs provide a rapid source of IL-22 that is essential for early protection of epithelial barrier function upon enteric infection and inflammatory insult, while T cells become the dominant source of IL-22 in the intestinal lamina propria during chronic intestinal inflammation. Microbiota is central in IL-22 production in the intestines, however, the factors that regulate IL-22 production in T cells and ILCs in the intestines, and the mechanisms involved remain unclear. We found that microbiota-derived short-chain fatty acids (SCFAs) promoted IL-22 production in T cells and ILCs through their inhibition of HDAC activity but not GPR43. Additionally, SCFAs upregulated IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor (HIF)1α expression, which were differentially regulated by mTOR and Stat3 pathways. Furthermore, HIF1α directly bind to the il22 promoter, and SCFAs increased HIF1α binding to the il22 promoter through histone modification. SCFAs enhanced oxygen consumption and glycolysis, which mediated SCFA-induced IL-22 production. Hypixic condition enhanced the SCFAs induction of IL-22, and glucose facilitated SCFAs induction of IL-22 production in a dose-dependent manner. SCFA supplementation protected intestines from Citrobacter Rodentium infection and dextran sodium sulfate (DSS) insult, which was mediated by enhanced IL-22. SCFAs promoted T cell IL-22 production from patients with Crohn’s disease through inducing AHR and HIF1α. These findings establish the roles of SCFAs in inducing IL-22 production in T cells and ILCs to maintain the intestinal homeostasis.

Altered Gut Microbiome Linked to Short Chain Fatty Acids Production in a Rat Model of Superimposed Preeclampsia

Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity. It affects 2–8% of all pregnancies, and its pathophysiology is not fully understood. Recent studies in preeclamptic patients have suggested a role for the gut microbiome (GM) in the disease. In addition, emerging evidence from both human and animal studies have reported that short‐chain fatty acids (SCFAs) and other gut‐derived metabolites such as lactate may modulate blood pressure (BP). We have characterized the Dahl salt‐sensitive (Dahl S) rat as a spontaneous rodent model of superimposed PE. The goal of our study was to determine if SCFAs production is impaired in PE. We hypothesized that preexisting chronic hypertension impairs maternal GM remodeling and maladaptation in SCFAs metabolism contributing to the development of superimposed PE. Female Sprague Dawley (SD) and Dahl S rats were maintained in conventional caging in the same room and on the same diet (Teklad 7034, 0.3% NaCl). Half of the rats of each strain were mated to have pregnant and virgin groups (n=7–9/group). Fecal samples were collected at baseline (BL), gestation day 20 (GD20) and one‐week postpartum (PP) to assess gut microbiome via 16S rRNA gene sequencing. Alpha diversity (Shannon index), beta diversity (Bray‐Curtis index), and linear discriminant analysis effect size (LEfSe) were determined from the sequenced data to assess microbial differences. PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states) was used to predict functional potential. At BL, Dahl S rats had higher alpha diversity (P&lt;0.0001) and distinctly clustered beta diversity (p&lt;0.001) compared to SD rats. Dahl S had higher Proteobacteria abundance (665,980 vs 51,240, p&lt;0.05), a marker of dysbiosis. In response to pregnancy, we observed significant differences among groups in both alpha and beta diversity during late pregnancy. Also, Proteobacteria abundance in the SD rats rose from 0.56% (BL) to 13.46% (GD20) before subsiding to 7.36% (PP) suggesting that these changes may be a normal adaptation to pregnancy. The Dahl S, however, showed no change in proteobacteria: 5.29% (BL) to 6.35% (GD20) and 7.8% (PP). We found Dahl S groups to have significantly lower abundance of genera such as Odoribacter and Roseburia which are known to produce butyrate, a SCFA associated with lowering BP, compared to the SD rats. On the other hand, Dahl S rats were significantly enriched in lactate producing genera including Turibacter and Streptococcus. Increased lactate producers have been previously associated with increased BP. In addition, when comparing each pregnant group to its virgin counterpart of the same strain, we found that Dahl S rats had differentially regulated butanoate (33 hits, p=0.01 vs. 32 hits, p=0.43) and propanoate (31 hits, p=0.01 vs. 29 hits, p=0.57) metabolic pathways but not in SD groups. Altogether, these data suggest that superimposed PE may be associated with impaired pregnancy‐specific GM changes and dysregulation in SCFAs production. Future studies will assess the therapeutic potential of beneficial SCFAs supplementation for the treatment of PE in this model.Support or Funding InformationR01HL134711 ( J. M. Sasser) &amp; funds to UMMC Molecular and Genomics Facility

SUN-040 MANIPULATING THE GUT MICROBIOME BY DIETARY FIBRE TO PREVENT FOLIC ACID INDUCED KIDNEY DISEASE

Gut dysbiosis has been associated with inflammation and mortality in chronic kidney disease. Bacterial fermentation of dietary fibre produces short-chain fatty acids (SCFAs) that regulate inflammation and immunity. Here we evaluated the effect of dietary fibre or SCFA supplementation on development of AKI and subsequent fibrosis in a murine model of folic acid nephropathy (FAN). FAN was induced in C57BL/6 (WT) and GRP43-/- mice by intraperitoneal folic acid injection. Mice were fed a high fibre (HF) diet, normal chow (NF), or supplemented with oral SCFAs (150mM sodium acetate (SA), 150mM propionate (SP), or 100mM butyrate (SB) in drinking water). Diets and SCFA treatment commenced 2 weeks prior to injection and continued throughout the duration of all experiments. Samples were collected on day 2 and 28 after FAN induction. Gut microbiota composition was assessed by 16S rRNA sequencing of faecal DNA. Metabolic profiling of serum and faeces was performed using 1H NMR spectroscopy. HF diet protected against FAN, with improvement of renal function and histological parameters versus NF diet, as evidenced by lower serum creatinine (day2: 5.7±3.0 vs 69.3±54.2; day28: 6.6±2.2 vs 12.3±4.4, P<0.0001), reduced tubular injury (P<0.05) and less cellular infiltration at days 2 and 28. FAN caused intestinal dysbiosis, while gut microbiota balance was restored by HF diet with increased relative abundance of phylum Actinobacteria at the expense of Firmicutes, and expansion of SCFA producing Bifidobacterium (p<0.0001) and Prevotella (p<0.0005) genera compared to FAN controls on NF diet. This change in microbial ecology correlated with a significant increase in faecal SCFAs (p<0.0005) and serum acetate (1.00±0.18vs0.53±0.15, p<0.0001) relative to NF fed controls. Supplementation with SCFAs in FAN achieved similar degrees of protection from loss of renal function (P<0.0001) and histological injury at days 2 and 28, and interstitial fibrosis at day 28. mRNA expression of the innate immune receptor (TLR2), proinflammatory cytokines (IL-6, TNFα) and chemokine (MIP2) at day 2 and 28, and fibrotic genes (TGFb, MMP2 & MMP9 ) at day 28 were downregulated in HF diet and SCFA mice compared with NF diet. SA supplementation was equally effective in GPR43+/+ and GPR43-/- FAN mice. Kidney tissue histone deacetylase (HDAC) activity was inhibited in HF FAN mice (P<0.01) at day 2, with significantly reduced mRNA expression of HDAC4 (P<0.005) and HDAC10 (P<0.01) compared to NF FAN mice. HF diet prevented development of folic acid induced acute and chronic kidney injury through enrichment of SCFA producing gut bacteria and increased SCFA production that inhibited HDAC activity. The protective effects of dietary modulation of the gut microbiota identify this as a simple, potentially translatable therapy for AKI and CKD.