Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor

Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown. Here, we describe roles for three metabolites—indole-3-ethanol, indole-3-pyruvate, and indole-3-aldehyde—which are derived from gut bacterial metabolism of the essential amino acid tryptophan, in regulating intestinal barrier function. We determined that these metabolites protect against increased gut permeability associated with a mouse model of colitis by maintaining the integrity of the apical junctional complex and its associated actin regulatory proteins, including myosin IIA and ezrin, and that these effects are dependent on the aryl hydrocarbon receptor. Our studies provide a deeper understanding of how gut microbial metabolites affect host defense mechanisms and identify candidate pathways for prophylactic and therapeutic treatments for IBDs.

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Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00063.2019 ◽

2019 ◽

Vol 317 (1) ◽

pp. G17-G39 ◽

Cited By ~ 10

Author(s):

Michael Camilleri ◽

Barbara J. Lyle ◽

Karen L. Madsen ◽

Justin Sonnenburg ◽

Kristin Verbeke ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Barrier ◽

Normal Function ◽

Model Systems ◽

Intestinal Barrier Function ◽

Dietary Interventions ◽

Labeling Regulations ◽

Gut Barrier Function ◽

And Function

A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.

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2’-fucosyllactose (2’-FL) Supplementation Improves Gut Barrier Function and Lipid Metabolism in HF-fed Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_058 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 425-425

Author(s):

Sunhye Lee ◽

Michael Goodson ◽

Wendie Vang ◽

Karen Kalanetra ◽

Daniela Barile ◽

...

Keyword(s):

Body Weight ◽

Lipid Metabolism ◽

Intestinal Permeability ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Gut Barrier ◽

Low Fat ◽

Barrier Integrity ◽

Gut Barrier Function

Abstract Objectives 2’-fucosyllactose (2’-FL), the most predominant oligosaccharide found in human milk, acts as a prebiotic with beneficial effects on the host. The aim of this study was to determine the beneficial effect of 2’-FL on intestinal barrier integrity and metabolic functions in low-fat (LF)- and high-fat (HF)-fed mice. Methods Male C57/BL6 mice (n = 32, 8/group; 6 weeks old, JAX, CA) were counter-balanced into four weight-matched groups and fed either a low-fat (LF; 10% kcal fat with 7% kcal sucrose) or HF (45% kcal fat with 17% kcal sucrose) with or without supplementation of 2’-FL in the diet [10% (w/w), 8 weeks; LF/2’-FL or HF/2’-FL; BASF, Germany]. General phenotypes (body weight, energy intake, fat and lean mass), intestinal permeability (ex vivo in Ussing chambers), lipid profiles, and microbial metabolites were assessed. Results 2’-FL significantly attenuated the HF-induced increase in body fat mass with a trend to decrease body weight gain. 2’-FL significantly decreased intestinal permeability in LF-fed mice with a trend for a decrease in HF-fed mice. This was associated with a significant increase in interleukin-22, a cytokine known to have a protective role in intestinal barrier function. Visceral adipocyte size was significantly decreased by 2’-FL in both LF- and HF-fed mice. 2’-FL suppressed HF-induced upregulation of adipogenic transcription factors peroxisome proliferator-activated receptor gamma and sterol regulatory element binding protein-1c in the liver. Lastly, 2’-FL supplementation led to a significant elevation of lactic acid concentration in the cecum of HF-fed mice, which is known to be a product from beneficial microbes. Conclusions 2’-FL supplementation improved gut barrier integrity and lipid metabolism in mice with and without the metabolic challenge of HF feeding. These findings support the use of 2’-FL in the control of gut barrier function and metabolic homeostasis under normal and abnormal physiological conditions. Funding Sources BASF (Germany).

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Gut barrier function in malnourished patients

Gut ◽

10.1136/gut.42.3.396 ◽

1998 ◽

Vol 42 (3) ◽

pp. 396-401 ◽

Cited By ~ 103

Author(s):

F K S Welsh ◽

S M Farmery ◽

K MacLennan ◽

M B Sheridan ◽

G R Barclay ◽

...

Keyword(s):

Acute Phase ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Enzyme Linked Immunosorbent Assay ◽

Molecular Evidence ◽

Gut Barrier ◽

Gut Barrier Function ◽

Hospitalised Patients ◽

Increased Risk

Background—The integrity of the gastrointestinal mucosa is a key element in preventing systemic absorption of enteric toxins and bacteria. In the critically ill, breakdown of gut barrier function may fuel sepsis. Malnourished patients have an increased risk of postoperative sepsis; however, the effects of malnutrition on intestinal barrier function in man are unknown.Aims—To quantify intestinal barrier function, endotoxin exposure, and the acute phase cytokine response in malnourished patients.Patients—Malnourished and well nourished hospitalised patients.Methods—Gastrointestinal permeability was measured in malnourished patients and well nourished controls using the lactulose:mannitol test. Endoscopic biopsy specimens were stained and morphological and immunohistochemical features graded. The polymerase chain reaction was used to determine mucosal cytokine expression. The immunoglobulin G antibody response to endotoxin and serum interleukin 6 were measured by enzyme linked immunosorbent assay.Results—There was a significant increase in intestinal permeability in the malnourished patients in association with phenotypic and molecular evidence of activation of lamina propria mononuclear cells and enterocytes, and a heightened acute phase response.Conclusions—Intestinal barrier function is significantly compromised in malnourished patients, but the clinical significance is unclear.

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Bile salt dependent lipase promotes intestinal adaptation in rats with massive small bowel resection

Bioscience Reports ◽

10.1042/bsr20180077 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 2

Author(s):

Yi Yang ◽

Tao Zheng ◽

Jiefei Zhou ◽

Huanlei Song ◽

Wei Cai ◽

...

Keyword(s):

Wnt Signaling ◽

Bile Salt ◽

Barrier Function ◽

Bowel Resection ◽

Intestinal Adaptation ◽

Intestinal Barrier ◽

Untreated Group ◽

Intestinal Barrier Function ◽

Adaptive Growth ◽

Gut Barrier Function

Intestinal adaptation is important for the short bowel syndrome (SBS) patients. Growing evidence has suggested that bile salt dependent lipase (BSDL) not only has the lipolytic activity, but also the immune-modulating and pro-proliferative activities. The purpose of the present study was to investigate the effects of BSDL on intestinal adaptive growth and gut barrier function in a rat model of SBS. Twenty-four male Sprague–Dawley rats were randomly divided into three experimental groups: sham group (rats underwent bowel transection and re-anastomosis), SBS group (rats underwent 80% bowel resection), SBS-BSDL group (SBS rats orally administered BSDL). The animals were weighed daily. The intestinal morpho-histochemical changes and intestinal barrier function were determined 14 days after the operations. Meanwhile, the expressions of Wnt signaling molecules in enterocytes were also analyzed by immunohistochemistry and Western blot. The postoperative weight gain was faster in the SBS rats treated with BSDL than in the SBS/untreated group. The SBS rats treated with BSDL had significantly greater villus height, crypt depth, and enterocyte proliferation in their residual intestines, as compared with the SBS/untreated group. The recovery of intestinal barrier function was promoted and the expressions of tight-junction proteins were increased in the SBS rats treated with BSDL. Additionally, the data indicated that the proadaptive activities of BSDL might be mediated by Wnt signaling activation in the enterocytes. These observations suggested that enteral BSDL administration promoted intestinal adaptive growth and barrier repairing by activating Wnt signaling pathway in SBS rats.

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Phytogenic Compounds for Enhancing Intestinal Barrier Function in Poultry–A Review

Planta Medica ◽

10.1055/a-1524-0358 ◽

2021 ◽

Author(s):

Urszula Latek ◽

Magdalena Chłopecka ◽

Wojciech Karlik ◽

Marta Mendel

Keyword(s):

Barrier Function ◽

Current Knowledge ◽

Intestinal Barrier ◽

Feed Additives ◽

Intestinal Barrier Function ◽

Poultry Production ◽

Gut Health ◽

Growth Promoters ◽

Gut Barrier Function ◽

Antibiotic Growth Promoters

AbstractAfter the European Union ban of antibiotic growth promoters, works on different methods of improving gut health have intensified. The poultry industry is struggling with problems that were previously controlled by antibiotic growth promoters, therefore the search for optimal solutions continues. Simultaneously, there is also increasing social pressure to minimize the use of antibiotics and replace them with alternative feed additives. A variety of available alternatives is considered safe by consumers, among which phytogenics play a significant role. However, there are still some limitations that need to be considered. The most questionable are the issues related to bioavailability, metabolism of plant derivatives in birds, and the difficulty of standardizing commercial products. There is still a need for more evidence-based recommendations for the use of phytogenics in livestock. On the other hand, a positive influence of phytogenic compounds on the health of poultry has been previously described by many researchers and practical application of these compounds has auspicious perspectives in poultry production. Supplementation with phytogenic feed additives has been shown to protect birds from various environmental threats leading to impaired intestinal barrier function. Phytogenic feed additives have the potential to improve the overall structure of intestinal mucosa as well as gut barrier function on a molecular level. Recognition of the phytogenicsʼ effect on the components of the intestinal barrier may enable the selection of the most suitable ones to alleviate negative effects of different agents. This review aims to summarize current knowledge of the influence of various phytogenic constituents on the intestinal barrier and health of poultry.

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Impact of Diet-Modulated Butyrate Production on Intestinal Barrier Function and Inflammation

Nutrients ◽

10.3390/nu10101499 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1499 ◽

Cited By ~ 79

Author(s):

Knud Bach Knudsen ◽

Helle Lærke ◽

Mette Hedemann ◽

Tina Nielsen ◽

Anne Ingerslev ◽

...

Keyword(s):

Barrier Function ◽

Dietary Fibre ◽

Inflammatory Markers ◽

Intestinal Barrier ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Intestinal Barrier Function ◽

Limiting Factor ◽

Gut Barrier Function ◽

Butyrate Production

A major challenge in affluent societies is the increase in disorders related to gut and metabolic health. Chronic over nutrition by unhealthy foods high in energy, fat, and sugar, and low in dietary fibre is a key environmental factor responsible for this development, which may cause local and systemic inflammation. A low intake of dietary fibre is a limiting factor for maintaining a viable and diverse microbiota and production of short-chain fatty acids in the gut. A suppressed production of butyrate is crucial, as this short-chain fatty acid (SCFA) can play a key role not only in colonic health and function but also at the systemic level. At both sites, the mode of action is through mediation of signalling pathways involving nuclear NF-κB and inhibition of histone deacetylase. The intake and composition of dietary fibre modulate production of butyrate in the large intestine. While butyrate production is easily adjustable it is more variable how it influences gut barrier function and inflammatory markers in the gut and periphery. The effect of butyrate seems generally to be more consistent and positive on inflammatory markers related to the gut than on inflammatory markers in the peripheral tissue. This discrepancy may be explained by differences in butyrate concentrations in the gut compared with the much lower concentration at more remote sites.

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Mode of Action of Dietary Dexamethasone May Not Be Dependent Upon Microbial Mechanisms in Broilers

Microorganisms ◽

10.3390/microorganisms7090346 ◽

2019 ◽

Vol 7 (9) ◽

pp. 346

Author(s):

Audrey F. Duff ◽

Mikayla F. A. Baxter ◽

B. Danielle Graham ◽

Billy M. Hargis ◽

Lisa R. Bielke

Keyword(s):

Barrier Function ◽

Mode Of Action ◽

Intestinal Flora ◽

Intestinal Barrier ◽

Fluorescein Isothiocyanate ◽

Intestinal Barrier Function ◽

Intestinal Microbes ◽

Opportunistic Disease ◽

Microbial Profile ◽

Gut Barrier Function

Dexamethasone (Dex), a synthetic glucocorticoid (GC), in feed has been shown to increase gut permeability via stress-mediated mechanisms, but the exact mode of action on gut barrier function is not fully understood. Stress has been reported to alter the profile and virulence of intestinal flora predisposing for opportunistic disease. This study aimed to evaluate the relationship between dietary Dex and recoverable intestinal microbial profile in broilers to better understand mode of action and refine future uses of the model. Three experiments were conducted that administered Dex-treated feed for one week in conjunction with the antibiotics BMD (bacitracin methylene disalicylate) or Baytril® (enrofloxacin) to evaluate if enteric microbial mechanisms were important in Dex-induced permeability. Serum fluorescein isothiocyanate-dextran (FITC-d) and bacterial translocation (BT) have been reported to increase after Dex treatment and were used to assess gut epithelial leakage. Shifts in bacterial profiles were also measured on selective agar. Combining Dex with BMD or Baytril resulted in increased (P < 0.05) serum FITC-d versus Dex-only. Additionally, Baytril did not reduce aerobic BT and bacterial profiles remained similar after Dex. These results suggest a minimal role of intestinal microbes in Dex-induced changes to intestinal barrier function.

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Glutamine regulates Caco-2 cell tight junction proteins

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00012.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. G726-G733 ◽

Cited By ~ 90

Author(s):

Nan Li ◽

Patricia Lewis ◽

Don Samuelson ◽

Kellym Liboni ◽

Josef Neu

Keyword(s):

Protein Expression ◽

Tight Junction ◽

Barrier Function ◽

Cellular Localization ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Cell ◽

Methionine Sulfoximine ◽

Junctional Complex ◽

Cell Monolayers

Intestinal epithelial tight junction (TJ) barrier dysfunction may lead to inflammation and mucosal injury. Glutamine (GLN) plays a role in maintenance of intestinal barrier function in various animal models and critically ill humans. Recent evidence from intestinal cell monolayers indicates that GLN maintains transepithelial resistance and decreases permeability. The mechanisms of these effects remain undefined. We hypothesized that GLN affects proteins involved in the intercellular junctional complex. GLN availability was controlled in Caco-2 monolayers by addition to the medium and treatment with methionine sulfoximine (MSO) to inhibit glutamine synthetase (GS). Expression of TJ proteins, claudin-1, occludin, and zonula occluden (ZO)-1 was measured by immunoblotting. Localization of TJ proteins was evaluated by immunofluorescence light microscopy. Structure of TJ was determined by transmission electron microscopy (TEM). Deprivation of GLN decreased claudin-1, occludin, and ZO-1 protein expression and caused a disappearance of perijunctional claudin-1 and a reduction of occludin but had no effect on ZO-1. TEM revealed that MSO-treated cells in the absence of GLN formed irregular junctional complexes between the apical lateral margins of adjoining cells. These findings indicate that TJ protein expression and cellular localization in Caco-2 cell monolayers rely on GLN. This mechanism may similarly relate to GLN-mediated modulation of intestinal barrier function in stressed animals and humans.

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Probiotic bacteria and intestinal epithelial barrier function

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00243.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. G807-G819 ◽

Cited By ~ 334

Author(s):

Christina L. Ohland ◽

Wallace K. MacNaughton

Keyword(s):

Barrier Function ◽

Defense Mechanisms ◽

Intestinal Barrier ◽

Single Layer ◽

Secretory Iga ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Epithelial Barrier Function ◽

Irritable Bowel ◽

The Many

The intestinal tract is a diverse microenvironment where more than 500 species of bacteria thrive. A single layer of epithelium is all that separates these commensal microorganisms and pathogens from the underlying immune cells, and thus epithelial barrier function is a key component in the arsenal of defense mechanisms required to prevent infection and inflammation. The epithelial barrier consists of a dense mucous layer containing secretory IgA and antimicrobial peptides as well as dynamic junctional complexes that regulate permeability between cells. Probiotics are live microorganisms that confer benefit to the host and that have been suggested to ameliorate or prevent diseases including antibiotic-associated diarrhea, irritable bowel syndrome, and inflammatory bowel disease. Probiotics likely function through enhancement of barrier function, immunomodulation, and competitive adherence to the mucus and epithelium. This review summarizes the evidence about effects of the many available probiotics with an emphasis on intestinal barrier function and the mechanisms affected by probiotics.

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The Aryl Hydrocarbon Receptor in Chronic Kidney Disease: Friend or Foe?

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.589752 ◽

2020 ◽

Vol 8 ◽

Author(s):

Yenan Mo ◽

Zhaoyu Lu ◽

Lixin Wang ◽

Chunlan Ji ◽

Chuan Zou ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Transcription Factor ◽

Kidney Disease ◽

Aryl Hydrocarbon Receptor ◽

Cell Cycle Progression ◽

Current Knowledge ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Cellular Processes ◽

Aryl Hydrocarbon

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that promotes cell responses to small molecules derived from the diet, microorganisms, metabolism and pollutants. The AhR signal regulates many basic cellular processes, including cell cycle progression, adhesion, migration, apoptosis and cell proliferation. Many studies have shown that AhR is associated with chronic kidney disease (CKD) and its complications. This article reviews the current knowledge about the role of AhR in CKD, showing that AhR mediates CKD complications, including cardiovascular disease, anemia, bone disorders, cognitive dysfunction and malnutrition, and that it influences drug metabolism in individuals with CKD. AhR enhances the intestinal barrier function to reduce the harmful effects of uremic toxins. Therefore, understanding the complex roles of AhR during CKD is important to be able to target this transcription factor safely and effectively for CKD prevention and treatment.

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