scholarly journals Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Heather M. Kahalehili ◽  
Nolan K. Newman ◽  
Jamie M. Pennington ◽  
Siva K. Kolluri ◽  
Nancy I. Kerkvliet ◽  
...  
Keyword(s):  
Small Intestine ◽  
Th17 Cells ◽  
Immune Modulation ◽  
Dietary Intervention ◽  
Nod Mice ◽  
Intestinal Microbiome ◽  
Dietary Recommendations ◽  
Targeted Interventions ◽  
Microbial Dysbiosis ◽  
Microbe Interactions

The diet represents one environmental risk factor controlling the progression of type 1 diabetes (T1D) in genetically susceptible individuals. Consequently, understanding which specific nutritional components promote or prevent the development of disease could be used to make dietary recommendations in prediabetic individuals. In the current study, we hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will regulate the progression of T1D in nonobese diabetic (NOD) mice. During digestion, I3C is metabolized into ligands for the aryl hydrocarbon receptor (AhR), a transcription factor that when systemically activated prevents T1D. In NOD mice, an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity. In the absence of this systemic response, the dietary intervention led to exacerbated insulitis. Consistent with the compartmentalization of AhR activation, dietary I3C did not alter T helper cell differentiation in the spleen or pancreatic draining lymph nodes. Instead, dietary I3C increased the percentage of CD4+RORγt+Foxp3- (Th17 cells) in the lamina propria, intraepithelial layer, and Peyer’s patches of the small intestine. The immune modulation in the gut was accompanied by alterations to the intestinal microbiome, with changes in bacterial communities observed within one week of I3C supplementation. A transkingdom network was generated to predict host-microbe interactions that were influenced by dietary I3C. Within the phylum Firmicutes, several genera (Intestinimonas, Ruminiclostridium 9, and unclassified Lachnospiraceae) were negatively regulated by I3C. Using AhR knockout mice, we validated that Intestinimonas is negatively regulated by AhR. I3C-mediated microbial dysbiosis was linked to increases in CD25high Th17 cells. Collectively, these data demonstrate that site of AhR activation and subsequent interactions with the host microbiome are important considerations in developing AhR-targeted interventions for T1D.

scholarly journals Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management

Gut ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2080-2091 ◽  
Author(s):  
Benjamin Misselwitz ◽  
Matthias Butter ◽  
Kristin Verbeke ◽  
Mark R Fox
Keyword(s):  
Small Intestine ◽  
Clinical Outcome ◽  
Dietary Intervention ◽  
Visceral Hypersensitivity ◽  
Intestinal Microbiome ◽  
Chromosome 2 ◽  
Lactose Malabsorption ◽  
Abdominal Symptoms ◽  
Increased Risk ◽  
Physiological Tests

Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo −13’910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.

scholarly journals Diurnal changes in the murine small intestine are disrupted by obesogenic Western Diet feeding and microbial dysbiosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah E. Martchenko ◽  
David Prescott ◽  
Alexandre Martchenko ◽  
Maegan E. Sweeney ◽  
Dana J. Philpott ◽  
...  
Keyword(s):  
Small Intestine ◽  
Western Diet ◽  
Time Dependent ◽  
Intestinal Microbiome ◽  
Diurnal Changes ◽  
Microbial Dysbiosis ◽  
Increased Risk ◽  
Small Intestinal ◽  
Immune Changes ◽  
Feeding And Fasting

AbstractIntestinal functions demonstrate circadian rhythms thought to be entrained, in part, by an organisms’ intrinsic feeding and fasting periods as well as by the intestinal microbiome. Circadian disruption as a result of ill-timed nutrient exposure and obesogenic feeding poses an increased risk to disease. As such, the aim of this study was to assess the relationships between dietary timing, composition, and the microbiome with regard to rhythmic small intestinal structure and mucosal immunity. Rodent chow (RC)-mice exhibited time-dependent increases in small intestinal weight, villus height, and crypt depth as well as an increased proportion of CD8αα+ cells and concomitant decrease in CD8αβ+ cells at the onset of the feeding period (p < 0.05–0.001). Western diet (WD)-animals displayed disrupted time-dependent patterns in intestinal structure and lymphocyte populations (p < 0.05–0.01). Antibiotic-induced microbial depletion abrogated the time- and diet-dependent patterns in both RC- and WD-mice (p < 0.05–0.001). However, although germ-free-mice displayed altered rhythms, fecal microbial transfer from RC-mice was generally unsuccessful in restoring structural and immune changes in these animals. This study shows that adaptive changes in the small intestine at the onset of the feeding and fasting periods are disrupted by WD-feeding, and that these changes are dependent, in part, on the intestinal microbiome.

scholarly journals Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zheng Fu ◽  
Joseph W. Dean ◽  
Lifeng Xiong ◽  
Michael W. Dougherty ◽  
Kristen N. Oliff ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Intestine ◽  
Th17 Cells ◽  
Tissue Remodeling ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Tuft Cell ◽  
Mitochondrial Transcription Factor A

AbstractRORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

scholarly journals Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production

2008 ◽  
Vol 205 (1) ◽  
pp. 207-218 ◽  
Author(s):  
Renu Jain ◽  
Danielle M. Tartar ◽  
Randal K. Gregg ◽  
Rohit D. Divekar ◽  
J. Jeremiah Bell ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Acid Decarboxylase ◽  
Type I ◽  
Pancreatic Cell ◽  
Disease Stages ◽  
Free Antigen

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

scholarly journals Liver X Receptor regulates Th17 and RORγt+ Treg cells by distinct mechanisms

2019 ◽  
Author(s):  
Sara M. Parigi ◽  
Srustidhar Das ◽  
Annika Frede ◽  
Rebeca F. Cardoso ◽  
Kumar Parijat Tripathi ◽  
...  
Keyword(s):  
Lymph Node ◽  
Nuclear Receptors ◽  
Th17 Cells ◽  
Immune Modulation ◽  
Treg Cells ◽  
Liver X Receptor ◽  
Commensal Bacteria ◽  
T Helper ◽  
Mesenteric Lymph ◽  
Th Cell

AbstractThe gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, is a major driver of intestinal CD4+ T helper (Th) cell differentiation. Dietary compounds can be sensed by nuclear receptors (NRs) that consequently exerts pleiotropic effects including immune modulation. However, how NRs regulate distinct intestinal Th subsets remain poorly understood. Here, we found that under homeostatic condition Liver X receptor (LXR), a sensor of cholesterol metabolites, controls RORγt+ Treg and Th17 cells in the intestine draining mesenteric lymph node (MLN). Mechanistically, while lack of LXR signaling in CD11c+ myeloid cells led to an increase in RORγt+ Treg, modulation of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, LXRα modulated only the Th17 cells, but not RORγt+ Treg in the MLN and horizontal transfer of microbiota between LXRα−/− and WT mice was sufficient to partially increase the MLN Th17 in WT mice. While LXRα deficiency increased the abundance of Ruminococcaceae and Lachnospiraceae bacterial families compared to the WT littermates, microbiota ablation including ablation of SFB was not sufficient to dampen LXRα-mediated expansion of MLN Th17. Altogether, our results suggest that LXR modulates RORγt+ Treg and Th17 cells in the MLN through distinct mechanisms.

scholarly journals Application of n-of-1 Clinical Trials in Personalized Nutrition Research: A Trial Protocol for Westlake N-of-1 Trials for Macronutrient Intake (WE-MACNUTR)

2020 ◽  
Vol 4 (9) ◽  
Author(s):  
Yunyi Tian ◽  
Yue Ma ◽  
Yuanqing Fu ◽  
Ju-Sheng Zheng
Keyword(s):  
Dietary Intervention ◽  
Population Level ◽  
Postprandial Blood Glucose ◽  
Macronutrient Intake ◽  
Dietary Recommendations ◽  
Carbohydrate Diet ◽  
Glucose Response ◽  
Low Carbohydrate Diet ◽  
Nutrition Research ◽  
The Individual

ABSTRACT Personalized dietary recommendations can help with more effective disease prevention. This study aims to investigate the individual postprandial glucose response to diets with diverse macronutrient proportions at both the individual level and population level, and explore the potential of the novel single-patient (n-of-1) trial for personalization of diet. Secondary outcomes include individual phenotypic responses and the effects of dietary ingredients on the composition of gut microbiota. Westlake N-of-1 Trials for Macronutrient Intake is a multiple crossover feeding trial consisting of 3 successive 12-d dietary intervention pairs including a 6-d washout period before each 6-d isocaloric dietary intervention: a 6-d high-fat, low-carbohydrate diet, and a 6-d low-fat, high-carbohydrate diet. The results will help provide personalized dietary recommendations for macronutrients in terms of postprandial blood glucose responses. The proposed n-of-1 trial methods could help in optimizing individual health and advancing health care. This trial was registered with clinicaltrials.gov (NCT04125602).

scholarly journals Health and disease markers correlate with gut microbiome composition across thousands of people

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ohad Manor ◽  
Chengzhen L. Dai ◽  
Sergey A. Kornilov ◽  
Brett Smith ◽  
Nathan D. Price ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Lifestyle Factors ◽  
Clinical Markers ◽  
Human Gut ◽  
Microbiome Composition ◽  
Targeted Interventions ◽  
Human Gut Microbiome ◽  
Host Diet ◽  
Microbe Interactions ◽  
Host Microbe Interactions

Abstract Variation in the human gut microbiome can reflect host lifestyle and behaviors and influence disease biomarker levels in the blood. Understanding the relationships between gut microbes and host phenotypes are critical for understanding wellness and disease. Here, we examine associations between the gut microbiota and ~150 host phenotypic features across ~3,400 individuals. We identify major axes of taxonomic variance in the gut and a putative diversity maximum along the Firmicutes-to-Bacteroidetes axis. Our analyses reveal both known and unknown associations between microbiome composition and host clinical markers and lifestyle factors, including host-microbe associations that are composition-specific. These results suggest potential opportunities for targeted interventions that alter the composition of the microbiome to improve host health. By uncovering the interrelationships between host diet and lifestyle factors, clinical blood markers, and the human gut microbiome at the population-scale, our results serve as a roadmap for future studies on host-microbe interactions and interventions.

scholarly journals A Review of Dietary Therapy for IBD and a Vision for the Future

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 947 ◽  
Author(s):  
Nicole Green ◽  
Talya Miller ◽  
David Suskind ◽  
Dale Lee
Keyword(s):  
Dietary Intervention ◽  
Epidemiological Studies ◽  
Intestinal Microbiome ◽  
Care Plan ◽  
Dietary Therapy ◽  
Dietary Interventions ◽  
Exclusive Enteral Nutrition ◽  
Chronic Inflammatory Condition ◽  
And Shifts ◽  
The Impact

Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract. The rising incidence of IBD has been associated with urbanization and shifts toward a Westernized diet. The intestinal microbiome has been a focus of disease pathogenesis and also therapeutic intervention. Dietary therapy for IBD has been well-studied with exclusive enteral nutrition, a formula-based diet with the exclusion of foods. In addition, interest in food-based exclusion diets has been increasing, with patients and families leading the charge. Challenges with dietary therapy for IBD include the lack of understanding of a detailed mechanistic pathway to explain the impact of diet on IBD pathogenesis and the difficult nature of designing and implementing dietary clinical trials. Epidemiological studies have demonstrated associations and intervention studies have demonstrated efficacy, but specific dietary targets remain as hypotheses at present. Current IBD therapy focuses on suppression of the immune system, yet the incomplete efficacy of present drugs suggests that other therapies must be developed and employed. Dietary interventions, with known ability to modulate the intestinal microbiome, are a unique opportunity to improve outcomes in IBD. Dietary intervention trials are challenging, and capturing both broad dietary patterns as well as exposure to individual food compounds is important. With increasing patient interest and preliminary research in dietary therapy indicating efficacy, it is imperative to further advance the science of utilizing diet in IBD, as well as to support patients by proactively addressing diet within their care plan.

scholarly journals Role of Gut Microbiota in Hepatocarcinogenesis

2019 ◽  
Vol 7 (5) ◽  
pp. 121 ◽  
Author(s):  
Haripriya Gupta ◽  
Gi Soo Youn ◽  
Min Jea Shin ◽  
Ki Tae Suk
Keyword(s):  
Gut Microbiota ◽  
Animal Studies ◽  
Intestinal Barrier ◽  
Intestinal Microbiome ◽  
Future Research ◽  
Pathophysiological Mechanism ◽  
Microbial Dysbiosis ◽  
Gut Barrier Function ◽  
Hepatic Diseases ◽  
Causal Nexus

Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulates over decades. Observations from recent studies have accounted for the involvement of the gut–liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis can cause the intestinal microbiome to serve as the main source of portal-vein endotoxins, such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on clinical as well as animal studies involving the gut microbiota, with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, which represent key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.

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