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Stroke is the second most common cause of death and one of the most common causes of disability worldwide. The intestine is home to several microorganisms that fulfill essential functions for the natural and physiological functioning of the human body. There is an interaction between the central nervous system (CNS) and the gastrointestinal system that enables bidirectional communication between them, the so-called gut-brain axis. Based on the gut-brain axis, there is evidence of a link between the gut microbiota and the regulation of microglial functions through glial activation. This interaction is partly due to the immunological properties of the microbiota and its connection with the CNS, such that metabolites produced by the microbiota can cross the gut barrier, enter the bloodstream and reach the CNS and significantly affect microglia, astrocytes and other cells of the immune system. Studies addressing the effects of short-chain fatty acids (SCFAs) on glial function and the BBB in ischemic stroke are still scarce. Therefore, this review aims to stimulate the investigation of these associations, as well as to generate new studies on this topic that can clarify the role of SCFAs after stroke in a more robust manner.

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Heavy metal exposure is a growing concern due to its adverse effects on human health, including the disruption of gut microbiota composition and function. Dietary fibers have been shown to positively impact the gut microbiota and could mitigate some of the heavy metal negative effects. This study aimed to investigate the effects of different heavy metals (As, Cd and Hg in different concentrations) on gut microbiota in the presence and absence of different dietary fibers that included fructooligosaccharides, pectin, resistant starch, and wheat bran. We observed that whereas heavy metals impaired fiber fermentation outcomes for some fiber types, the presence of fibers generally protected gut microbial communities from heavy metal-induced changes, especially for As and Cd. Notably, the protective effects varied depending on fiber types, and heavy metal type and concentration and were overall stronger for wheat bran and pectin than other fiber types. Our findings suggest that dietary fibers play a role in mitigating the adverse effects of heavy metal exposure on gut microbiota health and may have implications for the development of dietary interventions to reduce dysbiosis associated with heavy metal exposure. Moreover, fiber-type specific outcomes highlight the importance of evidence-based selection of prebiotic dietary fibers to mitigate heavy metal toxicity to the gut microbiota.

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Pregnancy is a finely tuned process, with the health and well-being of the developing fetus determined by the metabolic status and dietary intake of the mother. The maternal gut microbiome is remodeled during pregnancy, and this, coupled with the maternal nutrient intake during gestation shapes the production of metabolites that can cross the placenta and affect fetal development. As posited by the Developmental Origins of Health and Disease Hypothesis, such environmental influences can have major effects on the developing organ systems. When occurring at particularly sensitive gestational time points, these developmental programming events can have long lasting effects on offspring adaptation to the postnatal environment, and major health implications later in life. This review will summarize current knowledge on how pregnancy and maternal dietary intake intrinsically and extrinsically modify maternal gut microbiota composition and metabolite production. Further, we will assess how these factors shape the fetal landscape and ultimately contribute to offspring health. DOHaD, fetal development, metabolites, microbiome, nutrition, pregnancy, short-chain fatty acids.

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Atopic dermatitis (AD) is a chronic inflammatory skin disease that occurs in genetically predisposed individuals. It involves complex interactions among the host immune system, environmental factors (such as skin barrier dysfunction), and microbial dysbiosis. Genome-wide association studies (GWAS) have identified AD risk alleles; however, the associated environmental factors remain largely unknown. Recent evidence suggests that altered microbiota composition (dysbiosis) in the skin and gut may contribute to the pathogenesis of AD. Examples of environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, irritants, pollution, and microbial exposure. Studies have reported alterations in the gut microbiome structure in patients with AD compared to control subjects, characterized by increased abundance of Clostridium difficile and decreased abundance of short-chain fatty acid (SCFA)-producing bacteria such as Bifidobacterium. SCFAs play a critical role in maintaining host health, and reduced SCFA production may lead to intestinal inflammation in AD patients. The specific mechanisms through which dysbiotic bacteria and their metabolites interact with the host genome and epigenome to cause autoimmunity in AD are still unknown. By understanding the combination of environmental factors, such as gut microbiota, the genetic and epigenetic determinants that are associated with the development of autoantibodies may help unravel the pathophysiology of the disease. This review aims to elucidate the interactions between the immune system, susceptibility genes, epigenetic factors, and the gut microbiome in the development of AD.

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Metabolic disorders caused by the imbalance of gut microbiota have been associated with the consumption of processed foods. Thus, this study aimed to evaluate the effects of antimicrobial food additives (benzoate, sorbate, nitrite, and bisulfite) and sweeteners (saccharin, stevia, sucralose, aspartame, and cyclamate) on the growth and metabolism of some gut and potentially probiotic bacterial species. The effects on the growth of Bifidobacterium longum, Enterococcus faecium, Lactobacillus acidophilus, and Lactococcus lactis subsp. lactis cultures were investigated using a turbidimetric test and by determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). To evaluate the metabolic activity, the cultures were exposed to compounds with the highest antimicrobial activity, subjected to cultivation with inulin (1.5%), and analyzed by liquid chromatography for the production of short-chain fatty acids (acetate, propionate, and butyrate). The results showed that potassium sorbate (25 mg/mL), sodium bisulfite (0.7 mg/mL), sodium benzoate, and saccharin (5 mg/mL) presented greater antimicrobial activity against the studied species. L. lactis and L. acidophilus bacteria had reduced short-chain fatty acid production after exposure to saccharin and sorbate, and B. longum after exposure to sorbate, in comparison to controls (acetic acid reduction 1387 µg/mL and propionic 23 µg/mL p < 0.05).

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Rheumatoid Arthritis (RA) is an autoimmune disease characterized by loss of immune tolerance and chronic inflammation. It is pathogenesis complex and includes interaction between genetic and environmental factors. Current evidence supports the hypothesis that gut dysbiosis may play the role of environmental triggers of arthritis in animals and humans. Progress in the understanding of the gut microbiome and RA. has been remarkable in the last decade. In vitro and in vivo experiments revealed that gut dysbiosis could shape the immune system and cause persistent immune inflammatory responses. Furthermore, gut dysbiosis could induce alterations in intestinal permeability, which have been found to predate arthritis onset. In contrast, metabolites derived from the intestinal microbiota have an immunomodulatory and anti-inflammatory effect. However, the precise underlying mechanisms by which gut dysbiosis induces the development of arthritis remain elusive. This review aimed to highlight the mechanisms by which gut dysbiosis could contribute to the pathogenesis of RA. The overall data showed that gut dysbiosis could contribute to RA pathogenesis by multiple pathways, including alterations in gut barrier function, molecular mimicry, gut dysbiosis influences the activation and the differentiation of innate and acquired immune cells, cross-talk between gut microbiota-derived metabolites and immune cells, and alterations in the microenvironment. The relative weight of each of these mechanisms in RA pathogenesis remains uncertain. Recent studies showed a substantial role for gut microbiota-derived metabolites pathway, especially butyrate, in the RA pathogenesis.

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Atopic dermatitis (AD) is a chronic inflammatory skin disease that occurs in genetically predisposed individuals. It involves complex interactions among the host immune system, environmental factors (such as skin barrier dysfunction), and microbial dysbiosis. Genome-wide association studies (GWAS) have identified AD risk alleles; however, the associated environmental factors remain largely unknown. Recent evidence suggests that altered microbiota composition (dysbiosis) in the skin and gut may contribute to the pathogenesis of AD. Examples of environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, irritants, pollution, and microbial exposure. Studies have reported alterations in the gut microbiome structure in patients with AD compared to control subjects, characterized by increased abundance of Clostridium difficile and decreased abundance of short-chain fatty acid (SCFA)-producing bacteria such as Bifidobacterium. SCFAs play a critical role in maintaining host health, and reduced SCFA production may lead to intestinal inflammation in AD patients. The specific mechanisms through which dysbiotic bacteria and their metabolites interact with the host genome and epigenome to cause autoimmunity in AD are still unknown. By understanding the combination of environmental factors, such as gut microbiota, the genetic and epigenetic determinants that are associated with the development of autoantibodies may help unravel the pathophysiology of the disease. This review aims to elucidate the interactions between the immune system, susceptibility genes, epigenetic factors, and the gut microbiome in the development of AD.

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Studies in human microbiota dysbiosis have shown that short-chain fatty acids (SCFAs) like propionate, acetate, and particularly butyrate, positively affect energy homeostasis, behavior, and inflammation. This positive effect can be demonstrated in the reduction of butyrate-producing bacteria observed in the gut microbiota of individuals with type 2 diabetes (T2DM) and other energy-associated metabolic alterations. Butyrate is the major end product of dietary fiber bacterial fermentation in the large intestine and serves as the primary energy source for colonocytes. In addition, it plays a key role in reducing glycemia and improving body weight control and insulin sensitivity. The major mechanisms involved in butyrate regulation include key signaling pathways such as AMPK, p38, HDAC inhibition, and cAMP production/signaling. Treatment strategies using butyrate aim to increase its intestine levels, bioavailability, and improvement in delivery either through direct supplementation or by increasing dietary fiber in the diet, which ultimately generates a higher production of butyrate in the gut. In the final part of this review, we present a summary of the most relevant studies currently being carried out in humans.

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Zinc (Zn) plays an important role in metabolic homeostasis and may modulate neurological impairment related to obesity. The present study aimed to evaluate the effect of Zn supplementation on the intestinal microbiota, fatty acid profile, and neurofunctional parameters in obese male Wistar rats. Rats were fed a cafeteria diet (CAF), composed of ultra-processed and highly caloric and palatable foods, for 20 weeks to induce obesity. From week 16, Zn supplementation was started (10 mg/kg/day). At the end of the experiment, we evaluated the colon morphology, composition of gut microbiota, intestinal fatty acids, integrity of the intestinal barrier and blood-brain barrier (BBB), and neuroplasticity markers in the cerebral cortex and hippocampus. Obese rats showed dysbiosis, morphological changes, short-chain fatty acid (SCFA) reduction, and increased saturated fatty acids in the colon. BBB may also be compromised in CAF-fed animals, as claudin-5 expression is reduced in the cerebral cortex. In addition, synaptophysin was decreased in the hippocampus, which may affect synaptic function. Our findings showed that Zn could not protect obese animals from intestinal dysbiosis. However, an increase in acetate levels was observed, which suggests a partial beneficial effect of Zn. Thus, Zn supplementation may not be sufficient to protect from obesity-related dysfunctions.

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Inflammatory bowel diseases (IBDs) are characterized by inflammation in the gastrointestinal tract and include Ulcerative Colitis and Crohn's Disease. These diseases are costly to health services, substantially reduce patients' quality of life, and can lead to complications such as cancer and even death. Symptoms include abdominal pain, stool bleeding, diarrhea, and weight loss. The treatment of these diseases is symptomatic, seeking disease remission. The intestine is colonized by several microorganisms, such as fungi, viruses, and bacteria, which constitute the intestinal microbiota (IM). IM bacteria promotes dietary fibers fermentation and produces short-chain fatty acids (SCFAs) that exert several beneficial effects on intestinal health. SCFAs can bind to G protein-coupled receptors, such as GPR41 and GPR43, promoting improvements in the intestinal barrier, anti-inflammatory, and antioxidant effects. Thus, SCFAs could be a therapeutic tool for IBDs. However, the mechanisms involved in these beneficial effects of SCFAs remain poorly understood. Therefore, this paper aims to provide a review addressing the main aspects of IBDs, and a more detailed sight of SCFAs, focusing on the main effects on different aspects of the intestine with an emphasis on IBDs.

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Short-chain fatty acids (SCFAs) are carboxylic acids produced as a result of gut microbial anaerobic fermentation. They activate signaling cascades, acting as ligands of G-protein-coupled receptors, such as GPR41, GPR43, and GPR109A, that can modulate the inflammatory response and increase the intestinal barrier integrity by enhancing the tight junction proteins functions. These junctions, located in the most apical zone of epithelial cells, control the diffusion of ions, macromolecules, and the entry of microorganisms from the intestinal lumen into the tissues. In this sense, several enteric pathogens secrete diverse toxins that interrupt tight junction impermeability, allowing them to invade the intestinal tissue and to favor gastrointestinal colonization. It has been recently demonstrated that SCFAs inhibit the virulence of different enteric pathogens and have protective effects against bacterial colonization. Here, we present an overview of SCFAs production by gut microbiota and their effects on the recovery of intestinal barrier integrity during infections by microorganisms that affect tight junctions. These properties make them excellent candidates in the treatment of infectious diseases that cause damage to the intestinal epithelium.

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Short-chain fatty acids (SCFAs) are the main metabolites produced by the bacterial fermentation of dietary fiber, and they play a critical role in the maintenance of intestinal health. SCFAs are also essential for modulating different processes, and they have anti-inflammatory properties and immunomodulatory effects. As the inflammatory process predisposes the development of cancer and promotes all stages of tumorigenesis, an antitumor effect has also been associated with SCFAs. This is strongly supported by epidemiological studies showing that a diet rich in fiber is linked to a reduced risk of colon cancer and has significant clinical benefits in patients with inflammatory bowel disease (IBD). SCFAs may signal through the metabolite-sensing G protein-coupled receptors free fatty acid receptor 3 [FFAR3 or G protein-coupled receptor 41 (GPR41)], FFAR2 (GPR43), and GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCAR2) expressed in the gut epithelium and immune cells. This review summarizes the existing knowledge regarding the SCFA-mediated suppression of inflammation and carcinogenesis in IBD and colon cancer.

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OBJECTIVES: The intestinal microbiome can modulate immune function through production of microbial-derived short-chain fatty acids. We explored whether intestinal dysbiosis in children with sepsis leads to changes in microbial-derived short-chain fatty acids in plasma and stool that are associated with immunometabolic dysfunction in peripheral blood mononuclear cells. DESIGN: Prospective observational pilot study. SETTING: Single academic PICU. PATIENTS: Forty-three children with sepsis/septic shock and 44 healthy controls. MEASUREMENTS AND MAIN RESULTS: Stool and plasma samples were serially collected for sepsis patients; stool was collected once for controls. The intestinal microbiome was assessed using 16S ribosomal RNA sequencing and alpha- and beta-diversity were determined. We measured short-chain fatty acids using liquid chromatography, peripheral blood mononuclear cell mitochondrial respiration using high-resolution respirometry, and immune function using ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor-α. Sepsis patients exhibited reduced microbial diversity compared with healthy controls, with lower alpha- and beta-diversity. Reduced microbial diversity among sepsis patients (mainly from lower abundance of commensal obligate anaerobes) was associated with increased acetic and propionic acid and decreased butyric, isobutyric, and caproic acid. Decreased levels of plasma butyric acid were further associated with lower peripheral blood mononuclear cell mitochondrial respiration, which in turn, was associated with lower lipopolysaccharide-stimulated tumor necrosis factor-α. However, neither intestinal dysbiosis nor specific patterns of short-chain fatty acids were associated with lipopolysaccharide-stimulated tumor necrosis factor-α. CONCLUSIONS: Intestinal dysbiosis was associated with altered short-chain fatty acid metabolites in children with sepsis, but these findings were not linked directly to mitochondrial or immunologic changes. More detailed mechanistic studies are needed to test the role of microbial-derived short-chain fatty acids in the progression of sepsis.

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Lubiprostone, a 20-carbon synthetic fatty acid used for the treatment of constipation, is thought to act through an action on Cl- channel ClC-2. Short chain fatty acids (SCFAs) are produced and absorbed in the distal intestine. We explore whether SCFAs affect ClC-2, re-examine a possible direct effect of lubiprostone on ClC-2, and use mice deficient in ClC-2 to stringently address the hypothesis that the epithelial effect of lubiprostone targets this anion channel. Patch-clamp whole cell recordings of ClC-2 expressed in mammalian cells are used to assay SCFA and lubiprostone effects. Using chamber measurements of ion current in mice deficient in ClC-2 or CFTR channels served to analyze the target of lubiprostone in the distal intestinal epithelium. Intracellular SCFAs had a dual action on ClC-2, partially inhibiting conduction but, importantly, facilitating the voltage activation of ClC-2. Intra- or extracellular lubiprostone had no effect on ClC-2 currents. Lubiprostone elicited a secretory current across colonic epithelia that was increased in mice deficient in ClC-2, consistent with the channel's proposed proabsorptive function, but absent from those deficient in CFTR. Whilst SCFAs might exert a physiological effect on ClC-2 as part of their known proabsorptive effect, ClC-2 plays no part in the lubiprostone intestinal effect that appears mediated by CFTR activation.

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Fruta-do-lobo (Solanum lycocarpum St. Hill) is a native fruit commonly used in Brazilian folk medicine as a hypoglycemic agent. These properties are attributed to their starch, mainly its resistant fraction. Resistant starch has shown to increases the growth of Bifidobacterium and Lactobacillus in the gut, even though not being selective for these strains. In this scenario, this study aimed to investigate the potential prebiotic activity of fruta-do-lobo starch (FLS). FLS showed around 30% of resistant starch and their prebiotic potential was evaluated with five probiotic strains L. acidophilus (LA3 and LA5), L. casei (LC01) and B. animalis (BB12) and B. lactis (BLC1) in a concentration range of 1.0-2.0% of starch. In a preliminary screening, we evaluated, during 48 h, the viability of the starch with promoting growth agent. An increase in the growth of the probiotic strains tested was observed. We also evaluated the microorganism's metabolic activity by assessing the short-chain fatty acid (SCFA) production, using the best starch growth promotion conditions (2% of FLS and strains BLC1, LA5, and LC01). As expected, MRS and lactose were preferentially metabolized by BLC1, with the highest growth rates: 0.231 and 0.224 h-1, respectively. However, for this strain, the FLS growth rate (0.222 h-1) was 65% higher than FOS (0.144 h-1). Also, for LA5 FLS promoted higher growth (0.150 h-1) than FOS (0.135 h-1). Additionally, FLS promoted acetate production. These data are promising and indicate that FLS may have prebiotic potential and more studies need to be done with pathogenic microorganisms.

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Recent studies have indicated a prominent role of intestinal microbiota in regulation of several physiological aspects of the host including development and activation of the immune system and control of metabolism. In this review, we focused our discussion on bacterial metabolites produced from dietary fiber fermentation called short-chain fatty acids, which act as a link between the microbiota and host cells. Specifically, we described how modifications in their intestinal levels are associated with development of age-related pathologies including metabolic diseases and type 2 diabetes, hypertension, cardiovascular and neurodegenerative diseases. We also highlight their impact on the development of cancer.

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This study evaluated the effects of pelleted citrus pulp (PCP) added to orange peel on fermentative parameters and aerobic stability of orange peel silages. The treatments were based on different levels of PCP: 0 (control), 10% PCP, 20% PCP, and 30% PCP calculated according to the weight of orange peel (w/w), with five experimental silos per treatment stored for 60 days. Chemical composition, fermentative parameters, microbial population, and dry matter (DM) losses were performed in silages after opening the experimental silos. Furthermore, aerobic stability was evaluated for 12 days. Silages with 10 and 20% PCP presented suitable levels of DM, 226 and 302 g kg−1, respectively, and probably adequate water activity that benefited the lactic acid fermentation, but it jeopardized their aerobic stabilities. The inclusion of 10% PCP did not reduce the effluent loss compared with the control silages. Yet, 30% PCP silage showed the lowest effluent loss (93%), in contrast to the low lactic acid content (35 g kg−1) and short aerobic stability (49 h). Control silages remained stable for a longer period (115 h), but showed greater loss of N as NH3, and higher losses of DM through gas (354 g kg−1) and effluents (114 g kg−1). In short, we highlighted 20% PCP silage because of its high lactic acid bacteria (6.3 cfu g−1), high lactic acid:acetic acid ratio (1.41), low nitrogen degradation as NH3, and reduced gas (67%) and effluent (80%) productions. With the highest lactic acid (66.42 g kg−1), these well-preserved silages showed a more intense aerobic degradation, starting after 42h. The inclusion of PCP to orange peel improves the fermentation process probably due to the decrease of water activity, but decreases the aerobic stability of the silage as well.(AU)

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Fruit by-products are being investigated as non-conventional alternative sources of dietary fiber (DF). High hydrostatic pressure (HHP) treatments have been used to modify DF content as well as its technological and physiological functionality. Orange, mango and prickly pear peels untreated (OU, MU and PPU) and HHP-treated at 600 MPa (OP/55 °C and 20 min, MP/22 °C and 10 min, PPP/55 °C and 10 min) were evaluated. Untreated and treated fruit peels were subjected to fecal in vitro fermentations. The neutral sugar composition and linkage glycosidic positions were related to the production of short chain fatty acids (SCFA) resulting from the fermentation of the materials. After HHP-treatments, changes from multibranched sugars to linear sugars were observed. After 24 h of fermentation, OP yielded the highest amount of SCFA followed by PPU and MP (389.4, 282.0 and 204.6 µmol/10 mg DF, respectively). HHP treatment increased the SCFA concentration of orange and mango peel by 7 and 10.3% respectively, compared with the untreated samples after 24 h of fermentation. The results presented herein suggest that fruit peels could be used as good fermentable fiber sources, because they yielded high amounts of SCFA during in vitro fermentations.

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The use of probiotics to prevent or treat mucosal inflammation has been studied; however, the combined effect of probiotics and prebiotics is unclear. The aim of this study was to test whether oral administration of a synbiotic (Simbioflora®) preparation containing Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus acidophilus and Bifidobacterium lactis plus fructooligosaccharide could help control mucosal inflammation in experimental mucositis induced by 5-fluorouracil (5-FU). Male BALB/c mice were randomly divided into six groups: control (CTL), control + prebiotic (CTL+P), control + synbiotic (CTL+S), mucositis (MUC), mucositis + prebiotic (MUC+P), and mucositis + synbiotic (MUC+S). Mice from the CTL+S, MUC+S, CTL+P, and MUC+P groups received synbiotic or prebiotic daily by oral gavage for 13 days. Mice in the CTL and MUC groups received the same volume of saline. On day 11, mice in the MUC, MUC+P, and MUC+S groups received an intraperitoneal injection of 300 mg/kg 5-FU to induce mucositis. After 72 h, all mice were euthanised. Intestinal permeability, intestinal histology, and biochemical parameters were analysed. Group MUC showed a greater weight loss and increased intestinal permeability (0.020 counts per min [cpm]/g) compared to the CTL group (0.01 cpm/g) P<0.05. Both treatments attenuated weight loss compared to the MUC group. Nonetheless, the synbiotic caused a greater reduction in intestinal permeability (0.012 cpm/g) compared to the MUC (0.020 cpm/g) and MUC+P (0.016 cpm/g) groups P<0.05. Mice in groups MUC+P and MUC+S displayed significant recovery of lesions and maintenance of the mucus layer. There were no differences in the short-chain fatty acid concentrations in the faeces between the MUC and CTL groups (P>0.05). Increased acetate and propionate concentrations were evidenced in the faeces of the MUC+P and MUC+S groups. Only the synbiotic treatment increased the butyrate concentration (P<0.05). The results indicate that administration of synbiotic can decrease mucosal damage caused by mucositis.

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The effects of different thermal (raw versus autoclaving or boiling for 5 and 20 min) and soaking (with or without) treatments on the in vitro hindgut fermentation in pigs of undigested residue collected after in vitro foregut digestion of tropical legumes' grains (Canavalia brasiliensis; Lablab purpureus; pink, red and white Vigna unguiculata) were investigated. The undigested residue was fermented with a pig fecal inoculum to determine fermentability, gas, and short-chain fatty acid (SCFA) productions. Soaked raw legumes increased the production of SCFAs (e.g., butyric acid) and fermentability, while autoclaving reduced them. The productions of butyric acid and energy derived from SCFAs differed between legumes, with canavalia and lablab having the lowest and highest values, respectively. SCFAs and energy productions were highly related to the predicted nutrients entering the hindgut. In conclusion, different heating and soaking treatments can be applied to legumes to modulate the production of target SCFAs.

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