Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation.

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.

Tributyrin Supplementation Rescues Chronic-Binge Ethanol-Induced Oxidative Stress in the Gut-Lung Axis in Mice.

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.

The Postbiotic Butyrate Mitigates Gut Mucosal Disruption Caused by Acute Ethanol Exposure.

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.

Alcohol and Immunology: Mechanisms of multi-organ damage. Summary of the 2022 alcohol and Immunology research interest group (AIRIG) meeting.

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.

Forty-fifth ASPEN Presidential Address: Medical nutrition therapy, is it time to get personal?

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.

Targeting the Gut Microbiota and Host Immunity with a Bacilli-Species Probiotic during Antibiotic Exposure in Mice.

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.

The gut barrier and chronic diseases.

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.

The Immunomodulatory Functions of Butyrate.

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.

A Single Human-Relevant Fast Food Meal Rapidly Reorganizes Metabolomic and Transcriptomic Signatures in a Gut Microbiota-Dependent Manner.

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.

Microbiota reprogramming for treatment of alcohol-related liver disease.

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.

A Spore-Forming Probiotic Supplement Improves the Intestinal Immune Response and Protects the Intestinal Health During Recurrent Clostridioides difficile Colonization in Mice.

BACKGROUND: Around 15%-30% of patients develop recurrent Clostridioides difficile infection (CDI) as conventional therapies disrupt protective gut microbiota. We tested if supplementation with a spore-forming probiotic would protect intestinal health in a mouse model of recurrent CD colonization. METHODS: Methods: Female CF-1 mice were exposed to CD spores (4-log10 colony-forming units/10 µL) and then randomly assigned to receive either saline (CD-S) or probiotic (CD-PRO). Control mice received only saline (control). Following confirmation of initial CD colonization, mice were treated with vancomycin (10 days). After 5 days, mice recolonized with CD were treated again with vancomycin (10 days) and euthanized 5 days later. Fecal samples were collected at select time points for bacterial analysis. Following euthanasia, blood samples, cecum contents, and the intestine were collected for analysis. RESULTS: Probiotic supplementation mitigated the antibiotic-induced changes in cecum weight (P < .001). Probiotic-supplemented mice had increased messenger RNA expression of several immune parameters, accompanied by lower serum iron levels compared with CD-S mice (P < .05). Lower expressions of TNF α and calprotectin (P ≤ .05) were observed in CD-PRO mice compared with CD-S. The probiotics also supported the expression of intestinal tight junction proteins, which were diminished in the proximal colon of CD-S mice (P < .05). CONCLUSION: Mice supplemented with targeted spore-forming probiotics exhibited improved immune responses and nutrition immunity properties, which were linked with less inflammation and enhanced intestinal barrier proteins during recurrent CD colonization.

Role of Microbiome and Antibiotics in Autoimmune Diseases.

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.

Early-Life Gut Microbiome-The Importance of Maternal and Infant Factors in Its Establishment.

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.

Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure.

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.

Targeted Approaches for In Situ Gut Microbiome Manipulation.

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.

Impact of Diet on Inflammatory Bowel Disease Symptoms: An Adolescent Viewpoint.

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.

Dietitians' Evaluation of Clearing Luminal Occlusions of Gunk (DECLOG): A Pilot Feasibility Study.

BACKGROUND: Tube clogging is the most frequent mechanical complication associated with enteral nutrition. The objective of this study was to assess the efficacy of a protocol incorporating prophylactic use of a declogging system with enhanced patient education and monitoring to proactively reduce the incidence of tube occlusions in the home care setting. METHODS: A convenient sample of patients discharged from hospital to home enteral nutrition (HEN) was screened for eligibility and randomized to control group (standard care) or study group (standard care with prophylactic protocol and monitoring). Study patients received 4 enzyme declogging kits before discharge and were instructed to administer them every 7 days for 4 weeks. RESULTS: Seventeen of 49 (35%) patients reported tube occlusions. The incidence of tube occlusion in the control group was not statistically different than in the study group (29% vs 39%, P = 0.44). There was no difference between the 2 groups for negative tube outcomes, such as tube occlusion (P = 0.44), emergency department visit (P = 0.24), tube replacement (P = 0.99), or hospital readmission (P = 0.33). Continuous feeding method (P = 0.037), small-bowel feeding tubes (P = 0.016), and tube diameter <14 French (P = 0.069) were associated with tube occlusions. CONCLUSION: A prophylactic protocol using an enzyme declogging system did not lessen the likelihood of tube occlusions when compared with standard care. Multiple factors are associated with tube occlusion. More research investigating the use of a declogging system to prevent clogging incidence in patients receiving HEN is warranted.