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Butyrate: implications for intestinal function.

Purpose of review Butyrate is physiologically produced by the microbial fermentation of dietary fibers and plays a plurifunctional role in intestinal cells. This review examines the recent findings regarding the role and mechanisms by which butyrate regulates intestinal metabolism and discusses how these findings could improve the treatment of several gastrointestinal disorders. Recent findings Butyrate is more than a primary nutrient that provides energy to colonocytes and acts as a cellular mediator in those cells through several mechanisms. One remarkable property of butyrate is its ability to inhibit histone deacetylases, which is associated with the direct effects of butyrate and results in gene regulation, immune modulation, cancer suppression, cell differentiation, intestinal barrier regulation, oxidative stress reduction, diarrhea control, visceral sensitivity and intestinal motility modulation. All of these actions make butyrate an important factor for the maintenance of gut health. Summary From studies published over 30 years, there is no doubt of the important role that butyrate plays in maintaining intestinal homeostasis. However, despite these effects, clinical studies are still required to validate the routine use of butyrate in clinical practice and, specifically, in the treatment of intestinal diseases.

Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis

Butyrate is a four-carbon short-chain fatty acid that improves colonic trophism. Although several studies have shown the benefits of butyrate enemas in ulcerative colitis (UC), studies using the oral route are rare in the literature. In the present study, we evaluated the effect of butyrate intake in the immune response associated to UC. For that, mice were fed control or butyrate (0.5% sodium butyrate) diets for 14 days. Acute UC was induced by dextran sulphate sodium (DSS, 2.5%), replacing drinking water. The results showed that, in UC animals, oral butyrate significantly improved trophism and reduced leukocyte (eosinophil and neutrophil) infiltration in the colon mucosa and improved the inflammatory profile (activated macrophage, B and T lymphocytes) in cecal lymph nodes. In the small intestine, although mucosa histology was similar among groups, DSS treatment reduced duodenal transforming growth factor-β, increased interleukin-10 concentrations and increased memory T lymphocytes and dendritic cells in Peyers patches. Butyrate supplementation was able to revert these alterations. When cecal butyrate concentration was analyzed in cecal content, it was still higher in the healthy animals receiving butyrate than in the UC+butyrate and control groups. In conclusion, our results show that oral administration of sodium butyrate improves mucosa lesion and attenuates the inflammatory profile of intestinal mucosa, local draining lymph nodes and Peyers patches of DSS-induced UC. Our results also highlight the potential use of butyrate supplements as adjuvant in UC treatment.

The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation

BackgroundThis study evaluated the relationship between ulcerative colitis and obesity, which are both chronic diseases characterized by inflammation and increases in immune cells and pro-inflammatory cytokines.MethodsMice with chronic ulcerative colitis induced by 2 cycles of dextran sodium sulfate (DSS) in the first and fourth week of the experiment were fed a high-fat diet (HFD) to induce obesity by 8 weeks. The animals were divided into 4 \ groups (control, colitis, HFD and colitis + HFD).ResultsObesity alone did not raise histopathology scores, but the combination of obesity and colitis worsened the scores in the colon compared to colitis group. Despite the reduction in weight gain, there was increased inflammatory infiltrate in both the colon and visceral adipose tissue of colitis + HFD mice due to increased infiltration of macrophages, neutrophils and lymphocytes. Intravital microscopy of VAT microvasculature showed an increase in leukocyte adhesion and rolling and overexpression of adhesion molecules compared to other groups. Moreover, circulating lymphocytes, monocytes and neutrophils in the spleen and cecal lymph nodes were increased in the colitis + HFD group.ConclusionOur results demonstrated the relationship between ulcerative colitis and obesity as aggravating factors for each disease, with increased inflammation in the colon and adipose tissue and systemic alterations observed in the spleen, lymph nodes and bloodstream.

Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFκB activation.

BACKGROUND & AIMS Butyrate is a four-carbon fatty acid that presents anti-inflammatory, anti-oxidative and apoptotic properties in colon and several cell lines. Because atherosclerosis has important oxidative and inflammatory components, butyrate could reduce oxidation and inflammation, impairing atherogenesis. We evaluated the effects of butyrate supplementation of butyrate on atherosclerosis and its mechanisms of action. METHODS AND RESULTS ApoE knockout mice were fed on chow diet or 1% butyrate-supplemented chow diet (Butyrate) for 10 weeks to assess atherosclerosis lesions area and inflammatory status. Macrophage and endothelial cells were also pretreated with butyrate (0.5 mM) for 2 h before oxLDL stimulation to study oxLDL uptake and pro and anti-inflammatory cytokine production. Butyrate reduced atherosclerosis in the aorta by 50%. In the aortic valve, butyrate reduced CCL2, VCAM1 and MMP2 productions in the lesion site, resulting in a lower migration of macrophage and increased collagen depositions in the lesion and plaque stability. When EA.hy926 cells were pretreated with butyrate, oxLDL uptake, CD36, VCAM1, CCL2 TNF, IL1β and IL6 productions were reduced, whereas IL10 production was increased. These effects were accompanied by a lower activation of NFκB due to a lower nuclear translocation of the p65 subunit. CONCLUSION Oral butyrate is able to slow the progression of atherosclerosis by reducing adhesion and migration of macrophages and increasing plaque stability. These actions are linked to the reduction of CD36 in macrophages and endothelial cells, decreased pro-inflammatory cytokines and lower activation of NFκB all of these data support a possible role for butyrate as an atheroprotective agent.

Pretreatment With L-Citrulline Positively Affects the Mucosal Architecture and Permeability of the Small Intestine in a Murine Mucositis Model

BACKGROUND Mucositis is a common complication in patients undergoing radiotherapy and chemotherapy. It is associated with pain, poor quality of life, and malnutrition, leading to an increased number of hospital admissions and prolonged hospitalization. The use of immunonutrients may be an alternative treatment option, which may help to improve patient outcome. OBJECTIVE Here we assessed the impact of L-citrulline (CIT) on a murine model of 5-fluorouracil (5FU)-induced mucositis. METHODS Swiss male mice were randomized into 4 groups: control, CIT, 5FU, and 5FU+CIT. Mice were fed with commercial chow and supplemented with an oral solution of alanine (control and 5FU groups) or CIT (CIT and 5FU+CIT groups). On the seventh day, mice received intraperitoneal phosphate-buffered saline or 5FU (200 mg/kg, single dose) to induce mucositis. On the 10th day, mice were euthanized, and the blood and small intestines were harvested. Body weight, morphology, histopathology score (hematoxylin and eosin) of the small intestine (from 0-12), myeloperoxidase activity, oxidative stress level, and intestinal permeability were assessed. RESULTS We observed significant weight loss after the administration of 5FU in both treated and control animals. CIT administration contributed to a partial recovery of the mucosal architecture as well as an intermediate reduction of the histopathologic score, and functional intestinal permeability was partially rescued. CONCLUSIONS CIT administration attenuated 5FU-mediated damage to the mucosal architecture of the small intestine, decreasing the size of the injured areas and promoting decreased intestinal permeability.

Oral butyrate reduces oxidative stress in atherosclerotic lesion sites by a mechanism involving NADPH oxidase down-regulation in endothelial cells

Butyrate is a 4-carbon fatty acid that has antiinflammatory and antioxidative properties. It has been demonstrated that butyrate is able to reduce atherosclerotic development in animal models by reducing inflammatory factors. However, the contribution of its antioxidative effects of butyrate on atherogenesis has not yet been studied. We investigated the influence of butyrate on oxidative status, reactive oxygen species (ROS) release and oxidative enzymes (NADPH oxidase and iNOS) in atherosclerotic lesions of ApoE(-/-) mice and in oxLDL-stimulated peritoneal macrophages and endothelial cells (EA.hy926). The lesion area in aorta was reduced while in the aortic valve, although lesion area was unaltered, superoxide production and protein nitrosylation were reduced in butyrate-supplemented mice. Peritoneal macrophages from the butyrate group presented a lower free radical release after zymosan stimulus. When endothelial cells were pretreated with butyrate before oxLDL stimulus, the CCL-2 and superoxide ion productions and NADPH oxidase subunit p22phox were reduced. In macrophage cultures, in addition to a reduction in ROS release, nitric oxide and iNOS expression were down-regulated. The data suggest that one mechanism related to the effect of butyrate on atherosclerotic development is the reduction of oxidative stress in the lesion site. The reduction of oxidative stress related to NADPH oxidase and iNOS expression levels associated to butyrate supplementation attenuates endothelium dysfunction and macrophage migration and activation in the lesion site.

L-Arginine Pretreatment Reduces Intestinal Mucositis as Induced by 5-FU in Mice

Beneficial effects of L-arginine on immune responses and bowel function have been reported. Mucositis is a side effect of chemotherapy treatment that affects approximately 40% of patients. This complication is characterized by inflammation that affects the gastrointestinal tract, increasing permeability and causing abdominal pain, nausea, vomiting, and diarrhea, which worsen the patients nutritional status and increases morbimortality. The aim of this study was to evaluate the effect of pretreating with 2% L-arginine supplementation in water on mucositis as induced by 5-fluorouracil (5-FU; a single dose of 200 mg/kg body weight) in Swiss male mice. The effect of L-arginine on weight, intestinal permeability, morphology, and the histopathological score of the small intestine (from 0 to 12), oxidative stress, myeloperoxidase (MPO), and N-acetylglucosaminidase (NAG) activities were evaluated. Intestinal length improvement was observed, in addition to the partial recovery of the mucosal architecture. L-arginine attenuated the histopathological score and MPO activity. There was also an improvement in intestinal permeability, despite weight loss after 5-FU administration. In conclusion, L-arginine can positively impact intestinal mucositis by promoting partial mucosal recovery, reducing inflammation and improving intestinal permeability.

Combination of Azathioprine and Aminosalicylate Treatment Prevent Risk of Cardiovascular Disease in Women with Ulcerative Colitis by Reducing Inflammation.

Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease with involvement of the immune system. Chronic inflammatory diseases have been associated with increased risk of cardiovascular disease (CVD) but few studies have assessed this risk in patients with UC and the influence of drug treatment. Thus, we evaluated the risk of development of CVD in women with UC in clinical remission, considering the drug treatment. Material/Methods Twenty-one women with UC participated in this study: 12 used aminosalicylates (ASA group) and 9 used azathioprine added to aminosalicylates (AZA+ASA group). The healthy control group was matched for age. We evaluated blood pressure, body composition, and biochemical and immunological parameters. Results Compared to the respective control group, the UC groups showed expansion of body fat and less lean body mass. Blood pressure, pro-inflammatory cytokines, nitric oxide, C reactive protein, erythrocyte sedimentation rate (ESR), and anti-oxidized LDL antibodies were higher in UC groups. Only AZA+ASA group showed increased anti-inflammatory cytokines (IL-10 and TGF-β). Framingham scores showed higher risk of CVD in UC groups. UC groups were compared and women treated with azathioprine showed reduction of total protein, globulin, ESR, and lymphocytes, with increased IL-6, TNF, IL-10, and TGF-β. Conclusions Our data suggest that women with UC in clinical remission have a higher risk for development of atherosclerosis and CVD when compared to the control group, while women treated with azathioprine seem more protected than those treated only with aminosalicylates, due to better regulation of the inflammatory process.

Sodium butyrate modulates adipocyte expansion, adipogenesis, and insulin receptor signaling by upregulation of PPAR-γ in obese Apo E knockout mice

OBJECTIVES Studies suggest that sodium butyrate reduces obesity-associated inflammation and insulin resistance in in vitro and in vivo models. Apo E-/- mice have high basal oxidative stress and naturally develop dyslipidemia and atherosclerosis. Because these disorders are present in obesity, the aim of this study was to determine whether Apo E-/- mice could be a more realistic model for studying obesity and insulin resistance. METHODS We evaluated the action of orally administered sodium butyrate on adipose tissue expansion and insulin resistance using diet-induced obese Apo E-/- mice. RESULTS Findings from the present study demonstrated that obese mice fed a sodium butyrate-supplemented diet presented a modest reduction of weight gain associated with reduction of adipocyte expansion, induction of adipogenesis and angiogenesis, and adiponectin production. Sodium butyrate also improved insulin sensitivity, by increasing insulin receptor expression associated with activation of Akt signaling pathway. These results were associated with increased peroxisome proliferator-activated receptor-γ expression and nuclear factor-κB downregulation. CONCLUSION These results suggested that oral supplementation of butyrate could be useful as an adjuvant in the treatment of obesity, metabolic syndrome, and insulin resistance.