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We aimed to test how the postbiotic butyrate impacts select gut bacteria, small intestinal epithelial integrity, and microvascular endothelial activation during acute ethanol exposure in mice and primary human intestinal microvascular endothelial cells (HIMECs). Supplementation during an acute ethanol challenge with or without tributyrin, a butyrate prodrug, was delivered to C57BL/6 mice. A separate group of mice received 3 days of clindamycin prior to the acute ethanol challenge. Upon euthanasia, blood endotoxin, cecal bacteria, jejunal barrier integrity, and small intestinal lamina propria dendritic cells were assessed. HIMECs were tested for activation following exposure to ethanol ± lipopolysaccharide (LPS) and sodium butyrate. Tributyrin supplementation protected a butyrate-generating microbe during ethanol and antibiotic exposure. Tributyrin rescued ethanol-induced disruption in jejunal epithelial barrier, elevated plasma endotoxin, and increased mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) expression in intestinal microvascular endothelium. These protective effects of tributyrin coincided with a tolerogenic dendritic response in the intestinal lamina propria. Lastly, sodium butyrate pre- and co-treatment attenuated the direct effects of ethanol and LPS on MAdCAM-1 induction in the HIMECs from a patient with ulcerative colitis. Tributyrin supplementation protects small intestinal epithelial and microvascular barrier integrity and modulates microvascular endothelial activation and dendritic tolerizing function during a state of gut dysbiosis and acute ethanol challenge.
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Células Endoteliales , Etanol , Ratones , Humanos , Animales , Etanol/farmacología , Ácido Butírico/farmacología , Ácido Butírico/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Mucosa Intestinal/metabolismoRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to provide an update regarding the gut barrier and its involvement with chronic diseases, as well as to review biomarkers for identification of gut barrier integrity. This review is timely and relevant as our knowledge is increasing regarding the role of the gut microbiome and the gut barrier in health and disease. RECENT FINDINGS: This review provides an overview of: the gut barrier, which is complex and comprised of the mucus layer and the intestinal apical junctional protein complex; the gut microbiome in its relation to regulating the integrity of the gut barrier; select acute and chronic conditions that are known to be associated with gut dysbiosis and impaired gut integrity or 'leaky gut'; and current means for identifying loss in gut barrier integrity. SUMMARY: Many chronic conditions are associated with gut dysbiosis and systemic inflammation. Identifying whether the gut barrier is compromised in these conditions could help to inform potential therapeutics as a means to correct losses in gut barrier integrity and mitigate associated medical conditions.
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Disbiosis , Microbioma Gastrointestinal , Enfermedad Crónica , Humanos , Inflamación/metabolismo , Mucosa Intestinal/metabolismoRESUMEN
PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder (FGID) encountered by the pediatrician and consultant. The primary focus of this review is to provide an update on beneficial nutritional interventions for managing this patient population with discussion on gut microbiome effects. RECENT FINDINGS: A common complaint among the pediatric population is IBS-related recurrent abdominal pain. The prevalence of IBS is estimated to range between 6 and 14% and is defined by the Rome III criteria for FGIDs. Recent studies highlight the role of nutritional interventions in mitigating symptoms of IBS. Although eliminating foods that aggravate IBS gastrointestinal symptoms have become a main nutritional approach for acute management of IBS, recent literature reflects how this may impact the gut microbiome and potentially have long-term implications. SUMMARY: There are emerging studies suggesting IBS symptomatic improvement with different dietary interventions in the pediatric population, but most of what is known at this time has been extrapolated from the adult literature.
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Síndrome del Colon Irritable/dietoterapia , Niño , Dieta Baja en Carbohidratos , Dieta Mediterránea , Microbioma Gastrointestinal , Humanos , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/microbiología , Probióticos/uso terapéuticoRESUMEN
The intestinal microvascular endothelium plays a crucial role in orchestrating host responses to inflammation within the gastrointestinal tract. This review delves into the unique aspects of intestinal microvascular endothelial cells, distinct from those of larger vessels, in mediating leukocyte recruitment, maintaining barrier integrity, and regulating angiogenesis during inflammation. Specifically, their role in the pathogenesis of inflammatory bowel diseases, where dysregulated endothelial functions contribute to the disease progression, is reviewed. Furthermore, this review discusses the isolation technique for these cells and commonly used adhesion molecules for in vitro and in vivo experiments. In addition, we reviewed the development and therapeutic implications of a biologic agent targeting the interaction between α4ß7 integrin on T lymphocytes and mucosal addressin cellular adhesion molecule-1 on gut endothelium. Notably, vedolizumab, a humanized monoclonal antibody against α4ß7 integrin, has shown promising outcomes in inflammatory bowel diseases and other gastrointestinal inflammatory conditions, including chronic pouchitis, immune checkpoint inhibitor-induced colitis, and acute cellular rejection post-intestinal transplantation.
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Excessive alcohol consumption increases the severity and worsens outcomes of pulmonary infections, often due to oxidative stress and tissue damage. While the mechanism behind this relationship is multifaceted, recent evidence suggests ethanol-induced changes to the gut microbiome impact the gut-lung axis. To assess this, a chronic-binge ethanol feeding mouse model was used to determine how ethanol altered the gut microbiome, small intestinal epithelial barrier, and immune responses, as well as neutrophil abundance and oxidative stress in the lungs, and how supporting gut health with tributyrin supplementation during chronic-binge ethanol exposure affected these responses. We found that ethanol consumption altered gut bacterial taxa and metabolic processes, distorted small intestinal immune responses, and induced both bacteria and endotoxin translocation into the lymphatic and circulatory systems. These changes were associated with increased neutrophil (Ly6G) presence and markers of oxidative stress, lipocalin-2 and myeloperoxidase, in the lungs. Importantly, tributyrin supplementation during ethanol exposure rescued gut bacterial function (p < 0.05), small intestinal barrier integrity, and immune responses, as well as reducing both Ly6G mRNA (p < 0.05) and lipocalin-2 mRNA (p < 0.01) in the lungs. These data suggest ethanol-associated disruption of gut homeostasis influenced the health of the lungs, and that therapeutics supporting gut health may also support lung health.
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The time could not be riper for the field of nutrition as it moves into the forefront being recognized as a major influencer in the prevention and management of many diseases. The approach to nutrition support therapy, which includes oral diet and enteral and parenteral nutrition, has historically involved approaching patients in the same "one size fits all" manner. However, as research methodologies have advanced over the past decade, data suggest that although people may be grouped into having a particular disease or condition, their nutrition therapeutic intervention may be optimized if it is personalized. This thought-provoking session will discuss current dietary guidelines and provide evidence and pose opportunities toward a future direction incorporating a personalized therapeutic nutrition support approach, which takes into consideration the metabolic capacity of the gut microbiome.
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Nutrición Enteral , Apoyo Nutricional , Humanos , Dieta , Nutrición Enteral/métodos , Estado Nutricional , Nutrición Parenteral/métodosRESUMEN
On October 26th, 2022 the annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite symposium at the annual meeting of the Society for Leukocyte Biology in Hawaii. The 2022 meeting focused broadly on the immunological consequences of acute, chronic, and prenatal alcohol exposure and how these contribute to damage in multiple organs and tissues. These included alcohol-induced neuroinflammation, impaired lung immunity, intestinal dysfunction, and decreased anti-microbial and anti-viral responses. In addition, research presented covered multiple pathways behind alcohol-induced cellular dysfunction, including mitochondrial metabolism, cellular bioenergetics, gene regulation, and epigenetics. Finally, the work presented highlighted potential biomarkers and novel avenues of treatment for alcohol-induced organ damage.
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Efectos Tardíos de la Exposición Prenatal , Opinión Pública , Embarazo , Femenino , Humanos , Inflamación/inducido químicamente , Etanol/efectos adversos , HawaiiRESUMEN
Antibiotic therapy is necessary for the treatment of bacterial infections; however, it can also disrupt the balance and function of commensal gut microbes and negatively affect the host. Probiotics have been tested as a means to counteract the negative effects of antibiotic therapy, but many probiotics are also likely destroyed by antibiotics when taken together. Here we aimed to test the efficacy of a non-pathogenic spore-forming Bacillus-species containing a probiotic blend provided during antibiotic therapy on host immune defenses in mice. Mice were exposed to antibiotics and supplemented with or without the probiotic blend and compared to control mice. Fecal and cecal contents were analyzed for gut microbes, and intestinal tissue was tested for the expression of key enzymes involved in vitamin A metabolism, serum amyloid A, and inflammatory markers in the intestine. The probiotic blend protected against antibiotic-induced overgrowth of gram-negative bacteria and gammaproteobacteria in the cecum which correlated with host immune responses. Regional responses in mRNA expression of enzymes involved with vitamin A metabolism occurred between antibiotic groups, and intestinal inflammatory markers were mitigated with the probiotic blend. These data suggest prophylactic supplementation with a spore-forming Bacillus-containing probiotic may protect against antibiotic-induced dysregulation of host immune responses.
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The gastrointestinal (GI) system contains many different types of immune cells, making it a key immune organ system in the human body. In the last decade, our knowledge has substantially expanded regarding our understanding of the gut microbiome and its complex interaction with the gut immune system. Short chain fatty acids (SCFA), and specifically butyrate, play an important role in mediating the effects of the gut microbiome on local and systemic immunity. Gut microbial alterations and depletion of luminal butyrate have been well documented in the literature for a number of systemic and GI inflammatory disorders. Although a substantial knowledge gap exists requiring the need for further investigations to determine cause and effect, there is heightened interest in developing immunomodulatory therapies by means of reprogramming of gut microbiome or by supplementing its beneficial metabolites, such as butyrate. In the current review, we discuss the role of endogenous butyrate in the inflammatory response and maintaining immune homeostasis within the intestine. We also present the experimental models and human studies which explore therapeutic potential of butyrate supplementation in inflammatory conditions associated with butyrate depletion.
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BACKGROUND: A major contributor to cardiometabolic disease is caloric excess, often a result of consuming low cost, high calorie fast food. Studies have demonstrated the pivotal role of gut microbes contributing to cardiovascular disease in a diet-dependent manner. Given the central contributions of diet and gut microbiota to cardiometabolic disease, we hypothesized that microbial metabolites originating after fast food consumption can elicit acute metabolic responses in the liver. METHODS: We gave conventionally raised mice or mice that had their microbiomes depleted with antibiotics a single oral gavage of a liquified fast food meal or liquified control rodent chow meal. After four hours, mice were sacrificed and we used untargeted metabolomics of portal and peripheral blood, 16S rRNA gene sequencing, targeted liver metabolomics, and host liver RNA sequencing to identify novel fast food-derived microbial metabolites and their acute effects on liver function. RESULTS: Several candidate microbial metabolites were enriched in portal blood upon fast food feeding, and were essentially absent in antibiotic-treated mice. Strikingly, at four hours post-gavage, fast food consumption resulted in rapid reorganization of the gut microbial community and drastically altered hepatic gene expression. Importantly, diet-driven reshaping of the microbiome and liver transcriptome was dependent on an intact microbial community and not observed in antibiotic ablated animals. CONCLUSIONS: Collectively, these data suggest a single fast food meal is sufficient to reshape the gut microbial community in mice, yielding a unique signature of food-derived microbial metabolites. Future studies are in progress to determine the contribution of select metabolites to cardiometabolic disease progression and the translational relevance of these animal studies.
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The early-life microbiome is gaining appreciation as a major influencer in human development and long-term health. Multiple factors are known to influence the initial colonization, development, and function of the neonatal gut microbiome. In addition, alterations in early-life gut microbial composition is associated with several chronic health conditions such as obesity, asthma, and allergies. In this review, we focus on both maternal and infant factors known to influence early-life gut colonization. Also reviewed is the important role of infant feeding, including evidence-based strategies for maternal and infant supplementation with the goal to protect and/or restore the infant gut microbiome.
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Microbioma Gastrointestinal/fisiología , Antibacterianos/efectos adversos , Lactancia Materna , Parto Obstétrico/métodos , Suplementos Dietéticos , Femenino , Feto/microbiología , Humanos , Lactante , Fórmulas Infantiles , Salud del Lactante , Recién Nacido , Fenómenos Fisiologicos Nutricionales Maternos , Leche Humana/química , Leche Humana/microbiología , Obesidad/complicaciones , Obesidad/microbiología , Prebióticos/administración & dosificación , Prebióticos/análisis , Embarazo , Complicaciones del Embarazo/microbiología , Probióticos/administración & dosificaciónRESUMEN
The global rise in the incidence of autoimmune diseases has paralleled the widespread use of antibiotics. Recently, the gut microbiome has been shown to be key in the development and maturation of a normal immune system, and a range of microbial disturbances have been associated with the development and activity of several autoimmune diseases. Here, we aim to provide an overview of the mechanistic crosstalk between the human microbiome, the immune system, and antibiotics. The disease-associated microbial gut dysbiosis, the potential role of antibiotics in the development and treatment of autoimmune diseases, and the manipulation of the gut microbiome with prebiotics and probiotics is discussed using 2 key autoimmune diseases as an example: inflammatory bowel disease and type 1 diabetes. Although some data suggest that widespread use of antibiotics may facilitate autoimmunity through gut dysbiosis, there are also data to suggest antibiotics may hold the potential to improve disease activity. Currently, the effect of fecal microbiota transplantation on several autoimmune diseases is being studied in clinical trials, and several preclinical studies are revealing promising results with probiotic and prebiotic therapies.
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Antibacterianos , Enfermedades Autoinmunes , Microbioma Gastrointestinal/fisiología , Animales , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/microbiología , Enfermedades Autoinmunes/terapia , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/microbiología , Disbiosis/inducido químicamente , Disbiosis/microbiología , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/microbiología , Sistema Inmunológico/fisiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Tejido Linfoide/inmunología , Tejido Linfoide/microbiología , Prebióticos/administración & dosificación , Probióticos/uso terapéuticoRESUMEN
In the past decade knowledge has expanded regarding the importance of the gut microbiota in maintaining intestinal homeostasis and overall health. During this same time, we have also gained appreciation for the role of the gut-liver axis in the development of liver diseases. Alcohol overconsumption is one of the leading causes of liver failure globally. However, not all people with alcohol use disorder progress to advanced stages of liver disease. With advances in technology to investigate the gut microbiome and metabolome, we are now beginning to delineate alcohol's effects on the gut microbiome in relation to liver disease. This review presents our current understanding on the role of the gut microbiota during alcohol exposure, and various therapeutic attempts that have been made to reprogram the gut microbiota with the goal of alleviating alcoholic-related liver disease.
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Microbioma Gastrointestinal , Hepatopatías Alcohólicas/terapia , Animales , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Humanos , Hepatopatías Alcohólicas/fisiopatología , ProbióticosRESUMEN
The 2019 Dudrick Research Symposium, entitled "Targeted Approaches for In Situ Gut Microbiome Manipulation," was held on March 25, 2019, at the American Society for Parenteral and Enteral Nutrition (ASPEN) 2019 Nutrition Science & Practice Conference in Phoenix, AZ. The Dudrick Symposium honors the many pivotal and innovative contributions to the development and advancement of parenteral nutrition (PN) made by Dr Stanley J. Dudrick, physician scientist, academic leader, and a founding member of ASPEN. As the 2018 recipient of the Dudrick award, Dr Gail Cresci organized and chaired the symposium. The symposium addressed the evolving field of nutrition manipulation of the gut microbiome as a means to mitigate disease and support health. Presentations focused on (1) the role of prebiotics as a means to beneficially support gut microbiome composition and function and health; (2) designer synbiotics targeted to support metabolic by-products altered by ethanol exposure and microbial effectors that manipulate host metabolic outcomes; and, lastly, (3) types of intervention designs used to study diet-gut microbiome interactions in humans and a review of findings from recent interventions, which tested the effects of diet on the microbiome and the microbiome's effect on dietary exposures. New molecular techniques and multiomic approaches have improved knowledge of the structure and functional activity of the gut microbiome; however, challenges remain in establishing causal relationships between changes in the gut microbial-community structure and function and health outcomes in humans.
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Microbioma Gastrointestinal , Dieta , Humanos , Estado Nutricional , Prebióticos , Probióticos , SimbióticosRESUMEN
Alcohol overconsumption disrupts the gut microbiota and intestinal barrier, which decreases the production of beneficial microbial metabolic byproducts and allows for translocation of pathogenic bacterial-derived byproducts into the portal-hepatic circulation. As ethanol is known to damage liver sinusoidal endothelial cells (LSEC), here we evaluated dietary supplementation with a previously studied synbiotic on gut microbial composition, and hepatocyte and LSEC integrity in mice exposed to ethanol. We tested a chronic-binge ethanol feeding mouse model in which C57BL/6 female mice were fed ethanol (5% vol/vol) for 10 days and provided a single ethanol gavage (5 g/kg body weight) on day 11, 6 h before euthanasia. An ethanol-treatment group also received oral supplementation daily with a synbiotic; and an ethanol-control group received saline. Control mice were pair-fed and isocalorically substituted maltose dextran for ethanol over the entire exposure period; they received a saline gavage daily. Ethanol exposure decreased gut microbial abundance and diversity. This was linked with diminished expression of adherens junction proteins in hepatocytes and dysregulated expression of receptors for advanced glycation end-products; and this coincided with reduced expression of endothelial barrier proteins. Synbiotic supplementation mitigated these effects. These results demonstrate synbiotic supplementation, as a means to modulate ethanol-induced gut dysbiosis, is effective in attenuating injury to hepatocyte and liver endothelial barrier integrity, highlighting a link between the gut microbiome and early stages of acute liver injury in ethanol-exposed mice.
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Consumo Excesivo de Bebidas Alcohólicas/microbiología , Suplementos Dietéticos , Disbiosis/terapia , Etanol/farmacología , Sustancias Protectoras/farmacología , Simbióticos/administración & dosificación , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Modelos Animales de Enfermedad , Disbiosis/etiología , Células Endoteliales/microbiología , Femenino , Microbioma Gastrointestinal , Hepatocitos/microbiología , Hígado/citología , Hígado/microbiología , Ratones , Ratones Endogámicos C57BLRESUMEN
Background: Dietary modification shows promise as therapy in inflammatory bowel disease (IBD); however, it is unknown whether adolescents are interested in a dietary approach. Methods: Cross-sectional survey of adolescents with IBD ages 14-21 on disease knowledge, dietary habits, and perceptions of diet therapy. Results: A total of 132 subjects (48.5% female), mean age of 17.8 years and median disease length of 5 years (range 0, 16), completed the survey. Diet was perceived as a symptom trigger by 59.8% of subjects, and 45.4% had tried using diet as a treatment for symptom resolution, often without physician supervision and with limited success. Subjects experiencing active disease symptoms as determined by Manitoba IBD Index were more likely to be currently modifying their diet compared to subjects without active disease symptoms (odds ratio = 4.11, confidence interval = 1.58, 10.73, P = 0.003). Conclusions: Adolescents with IBD perceive a relationship between diet and disease symptoms and are interested in dietary modification as a symptom management option.