Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Gut microbial metabolites SCFAs and chronic kidney disease.

The global incidence of Chronic Kidney Disease (CKD) is steadily escalating, with discernible linkage to the intricate terrain of intestinal microecology. The intestinal microbiota orchestrates a dynamic equilibrium in the organism, metabolizing dietary-derived compounds, a process which profoundly impacts human health. Among these compounds, short-chain fatty acids (SCFAs), which result from microbial metabolic processes, play a versatile role in influencing host energy homeostasis, immune function, and intermicrobial signaling, etc. SCFAs emerge as pivotal risk factors influencing CKD's development and prognosis. This paper review elucidates the impact of gut microbial metabolites, specifically SCFAs, on CKD, highlighting their role in modulating host inflammatory responses, oxidative stress, cellular autophagy, the immune milieu, and signaling cascades. An in-depth comprehension of the interplay between SCFAs and kidney disease pathogenesis may pave the way for their utilization as biomarkers for CKD progression and prognosis or as novel adjunctive therapeutic strategies.

The Role of Gut Microbiome-Derived Short-Chain Fatty Acid Butyrate in Hepatobiliary Diseases.

The short-chain fatty acid butyrate, produced from fermentable carbohydrates by gut microbiota in the colon, has multiple beneficial effects on human health. At the intestinal level, butyrate regulates metabolism, helps in the transepithelial transport of fluids, inhibits inflammation, and induces the epithelial defense barrier. The liver receives a large amount of short-chain fatty acids via the blood flowing from the gut via the portal vein. Butyrate helps prevent nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, inflammation, cancer, and liver injuries. It ameliorates metabolic diseases, including insulin resistance and obesity, and plays a direct role in preventing fatty liver diseases. Butyrate has different mechanisms of action, including strong regulatory effects on the expression of many genes by inhibiting the histone deacetylases and modulating cellular metabolism. The present review highlights the wide range of beneficial therapeutic and unfavorable adverse effects of butyrate, with a high potential for clinically important uses in several liver diseases.

Effects of short-chain fatty acids on blood glucose and lipid levels in mouse models of diabetes mellitus: A systematic review and network meta-analysis.

Short-chain fatty acids (SCFAs), the main metabolites of gut microbiota, have been associated with lower blood glucose and lipid levels in diabetic mice. However, a comprehensive summary and comparison of the effects of different SCFA interventions on blood glucose and lipid levels in diabetic mice is currently unavailable. This study aims to compare and rank the effects of different types of SCFAs on blood glucose and lipid levels by collecting relevant animal research. A systematic search through PubMed, Embase, Cochrane Library, and Web of Science database was conducted to identify relevant studies from inception to March 17, 2023. Both pairwise meta-analysis and Bayesian network meta-analysis were used for statistical analyses. In total, 18 relevant studies involving 5 interventions were included after screening 3793 citations and 53 full-text articles. Notably, butyrate therapy (mean difference [MD] = -4.52, 95% confidence interval [-6.29, -2.75]), acetate therapy (MD = -3.12, 95% confidence interval [-5.79, -0.46]), and propionate therapy (MD = -2.96, 95% confidence interval [-5.66, -0.26]) significantly reduced the fasting blood glucose levels compared to the control group; butyrate therapy was probably the most effective intervention, with a surface under the cumulative ranking curve (SUCRA) value of 85.5%. Additionally, acetate plus propionate therapy was probably the most effective intervention for reducing total cholesterol (SUCRA = 85.8%) or triglyceride levels (SUCRA = 88.1%). These findings underscore the potential therapeutic implications of SCFAs for addressing metabolic disorders, particularly in type 2 diabetes mellitus.

Sodium butyrate ameliorates diabetic retinopathy in mice via the regulation of gut microbiota and related short-chain fatty acids.

BACKGROUND: Diabetic retinopathy (DR) development is associated with disturbances in the gut microbiota and related metabolites. Butyric acid is one of the short-chain fatty acids (SCFAs), which has been found to possess a potential antidiabetic effect. However, whether butyrate has a role in DR remains elusive. This study aimed to investigate the effect and mechanism of sodium butyrate supplementation on DR. METHODS: C57BL/6J mice were divided into three groups: Control group, diabetic group, and diabetic with butyrate supplementation group. Type 1 diabetic mouse model was induced by streptozotocin. Sodium butyrate was administered by gavage to the experimental group daily for 12 weeks. Optic coherence tomography, hematoxylin-eosin, and immunostaining of whole-mount retina were used to value the changes in retinal structure. Electroretinography was performed to assess the retinal visual function. The tight junction proteins in intestinal tissue were evaluated using immunohistochemistry. 16S rRNA sequencing and LC-MS/MS were performed to determine the alteration and correlation of the gut microbiota and systemic SCFAs. RESULTS: Butyrate decreased blood glucose, food, and water consumption. Meanwhile, it alleviated retinal thinning and activated microglial cells but improved electroretinography visual function. Additionally, butyrate effectively enhanced the expression of ZO-1 and Occludin proteins in the small intestine. Crucially, only butyric acid, 4-methylvaleric acid, and caproic acid were significantly decreased in the plasma of diabetic mice and improved after butyrate supplementation. The deeper correlation analysis revealed nine genera strongly positively or negatively correlated with the above three SCFAs. Of note, all three positively correlated genera, including norank_f_Muribaculaceae, Ileibacterium, and Dubosiella, were significantly decreased in the diabetic mice with or without butyrate treatment. Interestingly, among the six negatively correlated genera, Escherichia-Shigella and Enterococcus were increased, while Lactobacillus, Bifidobacterium, Lachnospiraceae_NK4A136_group, and unclassified_f_Lachnospiraceae were decreased after butyrate supplementation. CONCLUSION: Together, these findings demonstrate the microbiota regulating and diabetic therapeutic effects of butyrate, which can be used as a potential food supplement alternative to DR medicine.

The Bridge Between Ischemic Stroke and Gut Microbes: Short-Chain Fatty Acids.

Short-chain fatty acids (SCFAs) are monocarboxylates produced by the gut microbiota (GM) and result from the interaction between diet and GM. An increasing number of studies about the microbiota-gut-brain axis (MGBA) indicated that SCFAs may be a crucial mediator in the MGBA, but their roles have not been fully clarified. In addition, there are few studies directly exploring the role of SCFAs as a potential regulator of microbial targeted interventions in ischemic stroke, especially for clinical studies. This review summarizes the recent studies concerning the relationship between ischemic stroke and GM and outlines the role of SCFAs as a bridge between them. The potential mechanisms by which SCFAs affect ischemic stroke are described. Finally, the beneficial effects of SFCAs-mediated therapeutic measures such as diet, dietary supplements (e.g., probiotics and prebiotics), fecal microbiota transplantation, and drugs on ischemic brain injury are also discussed.

Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Nutrient sensing mechanism of short-chain fatty acids in mastitis control.

Bovine mastitis is a disease that is widespread in dairy cows worldwide, and its impact is significant due to economic losses at all levels of the dairy value chain. For a long time, antibiotics have been the main tool for curing mastitis, however the cure rate is not very high, and sometime side effects may occur. Therefore, an in-depth understanding of mastitis and effective solutions are urgently needed to resolve the problem that in what way to prevent and treat mastitis in order to protect the profitability of dairy farms. The importance of diet in the regulation of health are not novel. Dietary control of the intestinal flora provides a promising approach to prevent or treat certain deadly diseases. Ample amount of studies has been conducted on the role of short-chain fatty acids (SCFAs) in the maintenance of health. SCFAs are the type of dietary substance that has the ability to restore blood-milk barrier permeability, inhibit the development of mammary inflammation, and are also effective epigenomic modifiers with histone deacetylases inhibitory activity. To date, the detailed mechanism of action of SCFAs in treating mastitis is unclear, but preliminary evidences are emerging. To assess the effectiveness of this recommendation, we examined the overall mammary gland health knowledge related to SCFAs by scrutinizing their potential role and evaluating its compatibility with the immunobiology of mammary gland inflammation. We then considered preliminary in vivo and in vitro experiments and analyzed the literature on the subject. Here, we outline the production of SCFAs and its protective effect on the mammary gland, with particular emphasis on their relevance to mastitis. In addition, we also discussed the therapeutic potential of SCFAs for mammary gland inflammation. Expectantly, this theory will provide new perception for the treatment of mastitis and other infectious diseases.

Regulatory role of short-chain fatty acids in inflammatory bowel disease.

Inflammatory bowel disease (IBD) comprises a group of chronic inflammatory disorders of the gastrointestinal tract. Accumulating evidence shows that the development of IBD is always accompanied by the dysbiosis of the gut microbiota (GM), causing a decrease in prebiotic levels and an increase in harmful metabolite levels. This leads to persistent immune response and inflammation in the intestine, greatly impairing the physiological function of the gastrointestinal tract. Short-chain fatty acids (SCFAs) are produced by probiotic gut bacteria from a fiber-rich diet that cannot be digested directly. SCFAs with significant anti-inflammatory functions regulate immune function and prevent an excessive immune response, thereby delaying the clinical progression of IBD. In this review, we summarize the generation of SCFAs and their potential therapeutic effects on IBD. Furthermore, we suggest that SCFAs may modulate innate immune recognition and cytokine production to intervene in the progression of IBD. Additional randomized controlled trials and prospective cohort studies should also investigate the clinical impact of SCFA. Video Abstract.

Influence of dietary supplementation of short-chain fatty acid sodium propionate in people living with HIV (PLHIV).

BACKGROUND: Non-AIDS-associated chronic diseases in HIV+ patients have been on the rise since the advent of antiretroviral therapy. Especially cardiovascular diseases and disruption in the gastrointestinal tract have limited health-related quality of life (QoL). Several of those complications have been associated with chronic systemic inflammation. Short-chain fatty acids (SCFA), with propionate as one of the major compounds, have been described as an important link between gut microbiota and the immune system, defining the pro- and the anti-inflammatory milieu through direct and indirect regulation of T-cell homeostasis. The effects of dietary supplementation of sodium propionate (SP) in people living with HIV (PLHIV) have not yet been investigated prior to this study. OBJECTIVES: To investigate the impact of SP uptake among PLHIV and its relevance to improve QoL, the study aimed to investigate metabolic, immunological, microbiome and patient-reported QoL-related changes post-SP supplementation with follow-up. METHODS: A prospective, non-randomized, controlled, monocentric interventional study was conducted in WIR, Center for Sexual Health and Medicine, in Bochum, Germany. 32 HIV+ patients with unaltered ART-regimen in the last three months were included. Participants were given SP for a duration of 12 weeks in the form of daily oral supplementation and were additionally followed-up for another 12 weeks. RESULTS: The supplementation of SP was well tolerated. We found an improvement in lipid profiles and long-term blood glucose levels. A decrease in pro-inflammatory cytokines and a depletion of effector T cells was observed. Regulatory T cells and IL-10 decreased. Furthermore, changes in taxonomic composition of the microbiome during follow-up were observed and improvement of items of self-reported life-quality assessment. CONCLUSION: Taken together, the beneficial impact of SP in PLHIV reflects its potential in improving metabolic parameters and modulating pro-inflammatory immune responses. Thus, possibly reducing the risk of cardiovascular disorders and facilitating long-term improvement of the gut flora.

Rutin-activated adipose tissue thermogenesis is correlated with increased intestinal short-chain fatty acid levels.

The activation of thermogenic programs in brown adipose tissue (BAT) and white adipose tissue (WAT) provides a promising approach to increasing energy expenditure during obesity and diabetes treatment. Although evidence has been found that rutin activates BAT against obesity and type 2 diabetes mellitus (T2DM), its potential mechanism is not completely understood. In this study, we focused on the potential modulating effect of rutin on short-chain fatty acids (SCFAs) and the thermogenesis of BAT and WAT, aiming to elucidate the molecular mechanism of rutin in the treatment of obesity and T2DM. The results showed that rutin could significantly reduce the body weight and fasting blood glucose, inhibit fat accumulation, relieve hepatic steatosis and ameliorate the disorder of glycolipid metabolism in db/db mice. Moreover, rutin also increased the expression of uncoupling protein 1 (Ucp1) and other thermogenic genes and proteins in BAT and inguinal WAT (IWAT), indicating that rutin activated BAT and induced browning of IWAT. Importantly, rutin markedly enhanced the concentration of SCFAs (acetate, propionate and butyrate) and SCFA-producing enzymes (acetate kinase (ACK), methylmalonyl-CoA decarboxylase (MMD) and butyryl-CoA (BUT)) in feces of db/db mice. In addition, rutin significantly increased the mRNA expression of monocarboxylate transporter 1 (Mct1), catabolic enzyme acyl-CoA medium-chain synthetase 3 (Acsm3), carnitine palmitoyl transferase 1α (Cpt-1α) and Cpt-1ß genes in BAT and IWAT of db/db mice, which is conducive to inducing adipocyte thermogenesis. In summary, our findings revealed that rutin played a variety of regulatory roles in improving glucose and lipid metabolism disorders, reducing hepatic steatosis, inducing browning of IWAT and activating BAT, which has potential therapeutic significance for the treatment of obesity and T2DM. Mechanistically, rutin activates the thermogenesis of BAT and IWAT, which may be associated with increasing the concentration of SCFAs.

Short-Chain Fatty Acids as a Potential Treatment for Infections: a Closer Look at the Lungs.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that SCFAs play a role in the control of infections through direct action both on microorganisms and on host signaling. This review summarizes the main microbicidal effects of SCFAs and discusses studies highlighting the effect of SCFAs in the virulence and viability of microorganisms. We also describe the diverse and complex modes of action of the SCFAs on the immune system in the face of infections with a specific focus on bacterial and viral respiratory infections. A growing body of evidence suggests that SCFAs protect against lung infections. Finally, we present potential strategies that may be leveraged to exploit the biological properties of SCFAs for increasing effectiveness and optimizing patient benefits.

Microbiome Links Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease and Dietary Fiber via the Gut-Lung Axis: A Narrative Review.

Existing comprehensive management strategies for COPD effectively relieve the symptoms of patients, delay the deterioration of lung function, and prevent the progression of COPD through various means and multidisciplinary interventions. However, there has been limited progress in therapies that address the underlying causes of COPD pathogenesis. Recent studies have identified specific changes in the gut and pulmonary microbiota in response to exposure to smoke that can cause or exacerbate CS-COPD by regulating the inflammatory immune response in the lungs through the gut-lung axis. As a convenient and controllable intervention, modifying the diet to include more dietary fiber can effectively improve the prognosis of CS-COPD. Gut microbiota ferment dietary fiber to produce short-chain fatty acids, which connect the microbial communities in the lung and gut mucosa across the gut-lung axis, playing an anti-inflammatory and immunosuppressive role in the lungs. Given that the effect of dietary fiber on gut microbiota was highly similar to that of quitting smoking on gut microbiota, we assume that microbiota might be a potential therapeutic target for dietary fiber to alleviate and prevent CS-COPD. This study examines the similarities between pulmonary and gut microbiota changes in the presence of smoking and dietary fiber. It also highlights the mechanism by which SCFAs link pulmonary and gut microbiota in CS-COPD and analyzes the anti-inflammatory and immunomodulatory effects of short-chain fatty acids on CS-COPD via the gut-lung axis.

Promotion of wound healing by acetate in murine colonic epithelial cell via c-Jun N-terminal kinase activation.

BACKGROUND AND AIM: Mucosal healing is an important clinical goal in patients with inflammatory bowel disease. Recently, short-chain fatty acids (SCFAs) have been reported to have multifaceted effects to host. However, the effects of SCFAs on wound healing in intestinal epithelial cells are unclear. In the present study, we investigated the effects of acetate, one of the major SCFAs, on the wound healing of murine colonic epithelial cells. METHODS: Young adult mouse colonic epithelial cells were used to determine the effect of acetate using wound healing assay. Mitogen-activated protein kinase and Rho kinase inhibitor were used to elucidate intracellular signal of wound healing treated with acetate. Meanwhile, Rho activation assays were utilized to measure Rho activation levels. To assess in vivo effects, C57B6 mice with dextran sodium sulfate for 7 days were treated with enema administration of acetate for 7 days. Body weight, disease activity index, colon length, and mucosal break ratio in histology were examined. RESULTS: Acetate enhanced wound healing and fluorescence intensity of actin stress fiber compared with control. These effects were canceled with pretreatment of c-Jun N-terminal kinase (JNK) inhibitor or Rho kinase inhibitor. Furthermore, JNK inhibitor reduced the activation of Rho induced by acetate. In the dextran sodium sulfate-induced colitis model, the mice with enema treatment of acetate significantly exhibited recovery. CONCLUSIONS: In this study, we demonstrated that acetate promoted murine colonic epithelial cell wound healing via activation of JNK and Rho signaling pathways. These findings suggested that acetate could have applications as a therapeutic agent for patients with intestinal mucosal damage, such as inflammatory bowel disease.

The interplay among gut microbiota, hypertension and kidney diseases: The role of short-chain fatty acids.

The bacteria community living in the gut maintains a symbiotic relationship with the host and its unbalance has been associated with progression of a wide range of intestinal and extra intestinal conditions. Hypertension and chronic kidney disease (CKD) are closely associated diseases with high incidence rates all over the world. Increasing data have supported the involvement of gut microbiome in the blood pressure regulation and the impairment of CKD prognosis. In hypertension, the reduced number of short-chain fatty acids (SCFAs) producing bacteria is associated with modifications in gut environment, involving reduction of the hypoxic gut profile and worsening of the microbial balance, leading to a loss of epithelial barrier integrity, development of gut inflammation and the reduction of SCFAs plasma levels. These modifications compromise the blood pressure regulation and, as a consequence, favor the end organ damage, also affecting the kidneys. In CKD, impaired renal function leads to accumulation of high levels of uremic toxins that reach the intestine and cause alterations in bacteria composition and fecal metabolite profile, inducing a positive feedback that allows translocation of endotoxins into the bloodstream, which enhances local kidney inflammation and exacerbate kidney injury, compromising even more CKD prognosis. In line with these data, the use of prebiotics, probiotics and fecal microbiota transplantation are becoming efficient therapies to improve the gut dysbiosis aiming hypertension and CKD treatment. This review describes how changes in gut microbiota composition can affect the development of hypertension and the progression of kidney diseases, highlighting the importance of the gut microbial composition uncovering to improve human health maintenance and, especially, for the development of new alternative therapies.

Impact of Different Types of Diet on Gut Microbiota Profiles and Cancer Prevention and Treatment.

: Diet is frequently considered as a food regimen focused on weight loss, while it is actually the sum of food consumed by the organism. Western diets, modern lifestyle, sedentary behaviors, smoking habits, and drug consumption have led to a significant reduction of gut microbial diversity, which is linked to many non-communicable diseases (NCDs). The latter kill 40 million people each year, equivalent to more than 70% of all deaths globally. Among NCDs, tumors play a major role, being responsible for 29% of deaths from NCDs. A link between diet, microbiota, and cancer prevention and treatment has recently been unveiled, underlining the importance of a new food culture based on limiting dietary surplus and on preferring healthier foods. Here, we review the effects of some of the most popular "cancer-specific" diets on microbiota composition and their potential impact on cancer prevention and treatment.

Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations.

KEY POINTS: Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders. ABSTRACT: There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.

Gut Bacteria Products Prevent AKI Induced by Ischemia-Reperfusion.

Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis. However, it was also associated with an increase in autophagy. Moreover, SCFAs inhibited histone deacetylase activity and modulated the expression levels of enzymes involved in chromatin modification. In vitro analyses showed that SCFAs modulated the inflammatory process, decreasing the maturation of dendritic cells and inhibiting the capacity of these cells to induce CD4(+) and CD8(+) T cell proliferation. Furthermore, SCFAs ameliorated the effects of hypoxia in kidney epithelial cells by improving mitochondrial biogenesis. Notably, mice treated with acetate-producing bacteria also had better outcomes after AKI. Thus, we demonstrate that SCFAs improve organ function and viability after an injury through modulation of the inflammatory process, most likely via epigenetic modification.

Histone deacetylase inhibitors and cell death.

Histone deacetylases (HDACs) are a vast family of enzymes involved in chromatin remodeling and have crucial roles in numerous biological processes, largely through their repressive influence on transcription. In addition to modifying histones, HDACs also target many other non-histone protein substrates to regulate gene expression. Recently, HDACs have gained growing attention as HDAC-inhibiting compounds are being developed as promising cancer therapeutics. Histone deacetylase inhibitors (HDACi) have been shown to induce differentiation, cell cycle arrest, apoptosis, autophagy and necrosis in a variety of transformed cell lines. In this review, we mainly discuss how HDACi may elicit a therapeutic response to human cancers through different cell death pathways, in particular, apoptosis and autophagy.

Short-chain fatty acids produced by synbiotic mixtures in skim milk differentially regulate proliferation and cytokine production in peripheral blood mononuclear cells.

Short chain fatty acids (SCFAs) are major products of prebiotic fermentation and confer human health benefits such as immune-regulation. In this study, reconstituted skim milk supplemented with prebiotics (RSMP) including inulin, hi-maize or ß-glucan was fermented by probiotic strains of Lactobacillus spp. and Bifidobacteria spp. After 24 h of fermentation, probiotics growth and SCFAs production were investigated and the produced SCFAs were extracted. Inulin and Lactobacillus rhamnosus GG ATCC 53013 (LGG) combination released highest concentrations of SCFAs compared to LGG and hi-maize or ß-glucan. Extracted SCFAs were then used for in vitro immune modulation study in human peripheral blood mononuclear cells (PBMCs). In lipopolysaccharide (LPS)-stimulated PBMCs, SCFAs particularly butyrate down-regulated tumor necrosis factor alpha, interleukin (IL)-12, interferon gamma (IFN-γ) and transforming growth factor beta-1 (TGF-ß1), and up-regulated IL-4, IL-10, while no significant effect was noted in non-LPS-stimulated PBMCs. The results indicate that SCFAs regulated cytokine milieu in LPS-stimulated PBMCs to anti-inflammatory cytokines.