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1.
Curr Protoc ; 3(3): e695, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36913546

ABSTRACT

Atopic dermatitis (AD) is a chronic, relapsing, and extremely pruritic inflammatory skin disease with a particular impact on children. AD pathogenesis is not yet fully understood, and there is no curative treatment for this disease. Therefore, several genetically or chemically-induced AD mouse models have been developed. These preclinical mouse models are an indispensable research tool for studying AD pathogenesis and evaluating the efficacy of new candidate AD therapeutics. A commonly used mouse model of AD has been developed using the topical application of a low-calcemic analog of vitamin D3, MC903, to induce AD-like inflammatory phenotypes that closely resemble human AD. Moreover, this model shows a minimal effect on systemic calcium metabolism that is observed in the vitamin D3-induced AD model. Thus, an expanding number of studies use the MC903-induced AD model to interrogate AD pathobiology in vivo and to test new candidate small molecule and monoclonal antibody therapies. This protocol describes in detail functional measurements including the measurement of skin thickness, which is a surrogate marker for ear skin inflammation, as well as itch assessment, histological evaluation to assess the structural changes associated with AD skin inflammation, and preparation of single-cell suspensions from ear skin and draining lymph nodes for the assessment of inflammatory leukocyte subset infiltration in these tissues using flow cytometry. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Topical application of MC903 induces AD-like skin inflammation Support Protocol 1: Measurement of ear skin thickness Support Protocol 2: Itch assessment Support Protocol 3: Dissection of ear skin and ear draining lymph nodes Support Protocol 4: Histological evaluation and quantification Support Protocol 5: Preparation of single-cell suspension from ear skin and draining lymph nodes for the assessment of inflammatory immune cell infiltration using flow cytometry.


Subject(s)
Dermatitis, Atopic , Child , Humans , Mice , Animals , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/drug therapy , Cytokines/metabolism , Cytokines/pharmacology , Skin/pathology , Inflammation/pathology , Cholecalciferol/adverse effects
2.
Cell Rep ; 41(11): 111817, 2022 12 13.
Article in English | MEDLINE | ID: mdl-36516756

ABSTRACT

During mycobacterial infections, pathogenic mycobacteria manipulate both host immune and stromal cells to establish and maintain a productive infection. In humans, non-human primates, and zebrafish models of infection, pathogenic mycobacteria produce and modify the specialized lipid trehalose 6,6'-dimycolate (TDM) in the bacterial cell envelope to drive host angiogenesis toward the site of forming granulomas, leading to enhanced bacterial growth. Here, we use the zebrafish-Mycobacterium marinum infection model to define the signaling basis of the host angiogenic response. Through intravital imaging and cell-restricted peptide-mediated inhibition, we identify macrophage-specific activation of NFAT signaling as essential to TDM-mediated angiogenesis in vivo. Exposure of cultured human cells to Mycobacterium tuberculosis results in robust induction of VEGFA, which is dependent on a signaling pathway downstream of host TDM detection and culminates in NFATC2 activation. As granuloma-associated angiogenesis is known to serve bacterial-beneficial roles, these findings identify potential host targets to improve tuberculosis disease outcomes.


Subject(s)
Mycobacterium marinum , Mycobacterium tuberculosis , Tuberculosis , Animals , Humans , Zebrafish/microbiology , Macrophages/metabolism , Signal Transduction , Granuloma/pathology , NFATC Transcription Factors/metabolism
3.
Pathogens ; 11(6)2022 Jun 02.
Article in English | MEDLINE | ID: mdl-35745496

ABSTRACT

Atopic dermatitis (AD) is a globally prevalent skin inflammation with a particular impact on children. Current therapies for AD are challenged by the limited armamentarium and the high heterogeneity of the disease. A novel promising therapeutic target for AD is the microbiota. Numerous studies have highlighted the involvement of the skin and gut microbiota in the pathogenesis of AD. The resident microbiota at these two epithelial tissues can modulate skin barrier functions and host immune responses, thus regulating AD progression. For example, the pathogenic roles of Staphylococcus aureus in the skin are well-established, making this bacterium an attractive target for AD treatment. Targeting the gut microbiota is another therapeutic strategy for AD. Multiple oral supplements with prebiotics, probiotics, postbiotics, and synbiotics have demonstrated promising efficacy in both AD prevention and treatment. In this review, we summarize the association of microbiota dysbiosis in both the skin and gut with AD, and the current knowledge of the functions of commensal microbiota in AD pathogenesis. Furthermore, we discuss the existing therapies in manipulating both the skin and gut commensal microbiota to prevent or treat AD. We also propose potential novel therapies based on the cutting-edge progress in this area.

4.
Microbiome ; 10(1): 9, 2022 01 19.
Article in English | MEDLINE | ID: mdl-35045871

ABSTRACT

BACKGROUND: Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status. RESULTS: HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention. CONCLUSION: Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D. TRIAL REGISTRATION: ACTRN12618001391268. Registered 20 August 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792 Video Abstract.


Subject(s)
Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Microbiota , Animals , Diabetes Mellitus, Type 2/microbiology , Dietary Supplements , Fatty Acids, Volatile , Humans , Mice
5.
Clin Transl Immunology ; 10(1): e1233, 2021.
Article in English | MEDLINE | ID: mdl-33489123

ABSTRACT

OBJECTIVES: During gastrointestinal infection, dysbiosis can result in decreased production of microbially derived short-chain fatty acids (SCFAs). In response to the presence of intestinal pathogens, we examined whether an engineered acetate- or butyrate-releasing diet can rectify the deficiency of SCFAs and lead to the resolution of enteric infection. METHODS: We tested whether a high acetate- or butyrate-producing diet (HAMSA or HAMSB, respectively) condition Citrobacter rodentium infection in mice and assess its impact on host-microbiota interactions. We analysed the adaptive and innate immune responses, changes in gut microbiome function, epithelial barrier function and the molecular mechanism via metabolite sensing G protein-coupled receptor 43 (GPR43) and IL-22 expression. RESULTS: HAMSA diet rectified the deficiency in acetate production and protected against enteric infection. Increased SCFAs affect the expression of pathogen virulence genes. HAMSA diet promoted compositional and functional changes in the gut microbiota during infection similar to healthy microbiota from non-infected mice. Bacterial changes were evidenced by the production of proteins involved in acetate utilisation, starch and sugar degradation, amino acid biosynthesis, carbohydrate transport and metabolism. HAMSA diet also induced changes in host proteins critical in glycolysis, wound healing such as GPX1 and epithelial architecture such as EZR1 and PFN1. Dietary acetate assisted in rapid epithelial repair, as shown by increased colonic Muc-2, Il-22, and anti-microbial peptides. We found that acetate increased numbers of colonic IL-22 producing TCRαß+CD8αß+ and TCRγδ+CD8αα+ intraepithelial lymphocytes expressing GPR43. CONCLUSION: HAMSA diet may be an effective therapeutic approach for fighting inflammation and enteric infections and offer a safe alternative that may impact on human health.

6.
Adv Exp Med Biol ; 1307: 499-519, 2021.
Article in English | MEDLINE | ID: mdl-32193865

ABSTRACT

Diet-microbiota related inflammatory conditions such as obesity, autoimmune type 1 diabetes (T1D), type 2 diabetes (T2D), cardiovascular disease (CVD) and gut infections have become a stigma in Western societies and developing nations. This book chapter examines the most relevant pre-clinical and clinical studies about diet-gut microbiota approaches as an alternative therapy for diabetes. We also discuss what we and others have extensively investigated- the power of dietary short-chain fatty acids (SCFAs) technology that naturally targets the gut microbiota as an alternative method to prevent and treat diabetes and its related complications.


Subject(s)
Diabetes Mellitus, Type 2/diet therapy , Fatty Acids, Volatile/administration & dosage , Gastrointestinal Microbiome , Immunotherapy , Diet , Humans
7.
Cells ; 9(9)2020 09 01.
Article in English | MEDLINE | ID: mdl-32882837

ABSTRACT

Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of Il-1ß and Tnf-a and increased Il-10, Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity.


Subject(s)
Obesity/blood , Obesity/drug therapy , Prodrugs/administration & dosage , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/drug effects , Triglycerides/administration & dosage , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Butyrates/blood , Cytokines/metabolism , Diet, High-Fat/adverse effects , Gastrointestinal Microbiome , Gene Knockout Techniques , Inflammation/drug therapy , Inflammation/metabolism , Insulin Resistance , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/etiology , Receptors, G-Protein-Coupled/genetics , Triglycerides/blood , Weight Gain/drug effects
8.
Cells, v. 9, n. 9, 2007, set. 2020
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-3181

ABSTRACT

Obesity is linked with altered microbial short-chain fatty acids (SCFAs), which are a signature of gut dysbiosis and inflammation. In the present study, we investigated whether tributyrin, a prodrug of the SCFA butyrate, could improve metabolic and inflammatory profiles in diet-induced obese mice. Mice fed a high-fat diet for eight weeks were treated with tributyrin or placebo for another six weeks. We show that obese mice treated with tributyrin had lower body weight gain and an improved insulin responsiveness and glucose metabolism, partly via reduced hepatic triglycerides content. Additionally, tributyrin induced an anti-inflammatory state in the adipose tissue by reduction of Il-1β and Tnf-a and increased Il-10, Tregs cells and M2-macrophages. Moreover, improvement in glucose metabolism and reduction of fat inflammatory states associated with tributyrin treatment were dependent on GPR109A activation. Our results indicate that exogenous targeting of SCFA butyrate attenuates metabolic and inflammatory dysfunction, highlighting a potentially novel approach to tackle obesity

9.
Nat Commun ; 10(1): 3031, 2019 07 10.
Article in English | MEDLINE | ID: mdl-31292453

ABSTRACT

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Subject(s)
Acetates/blood , Fetus/immunology , Pre-Eclampsia/immunology , Prenatal Exposure Delayed Effects/immunology , T-Lymphocytes, Regulatory/immunology , Acetates/administration & dosage , Acetates/immunology , Acetates/metabolism , Adult , Animals , Animals, Newborn , Case-Control Studies , Child Development , Child, Preschool , Dietary Supplements , Female , Fetus/cytology , Fetus/diagnostic imaging , Gastrointestinal Microbiome/immunology , Germ-Free Life/immunology , Humans , Immune Tolerance/immunology , Infant , Infant, Newborn , Longitudinal Studies , Maternal-Fetal Exchange/immunology , Mice , Organ Size/immunology , Pre-Eclampsia/blood , Pre-Eclampsia/diagnosis , Pregnancy , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/prevention & control , Prospective Studies , Thymus Gland/cytology , Thymus Gland/diagnostic imaging , Thymus Gland/growth & development , Thymus Gland/immunology , Transcription Factors/immunology , Transcription Factors/metabolism , Ultrasonography, Prenatal , Young Adult , AIRE Protein
10.
Front Immunol ; 9: 2617, 2018.
Article in English | MEDLINE | ID: mdl-30532751

ABSTRACT

The rising global incidence of autoimmune and inflammatory conditions can be attributed to changes in the large portion of the immune system that belongs to our gastrointestinal tract (GI). The intestinal immune system serves as a gatekeeper to prevent pathogenic invasions and to preserve a healthier gut microbiota. The gut microbiota has been increasingly studied as a fundamental contributor to the state of health and disease. From food fermentation, the gut microbiota releases metabolites or short chain fatty acids (SCFAs), which have anti-inflammatory properties and preserve gut homeostasis. Immune responses against food and microbial antigens can cause inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease. As such, many autoimmune and inflammatory diseases also have a "gut origin". A large body of evidence in recent years by ourselves and others has uncovered the link between the immune system and the SCFAs in specific diseases such as autoimmune type 1 diabetes (T1D), obesity and type 2 diabetes (T2D), cardiovascular disease, infections, allergies, asthma, and IBD. Thus, the power of these three gut dynamic components-the mucosal immunity, the microbiota, and diet-can be harnessed in tandem for the prevention and treatment of many inflammatory and infectious diseases.


Subject(s)
Autoimmune Diseases/immunology , Gastrointestinal Microbiome , Hypersensitivity/immunology , Immunity, Mucosal , Infections/immunology , Inflammation/immunology , Intestinal Mucosa/immunology , Animals , Autoimmune Diseases/microbiology , Diet , Dysbiosis , Homeostasis , Humans , Hypersensitivity/microbiology , Infections/microbiology , Inflammation/microbiology , Intestinal Mucosa/microbiology
13.
Nat Immunol ; 18(5): 552-562, 2017 05.
Article in English | MEDLINE | ID: mdl-28346408

ABSTRACT

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.


Subject(s)
Acetates/metabolism , B-Lymphocytes/immunology , Butyrates/metabolism , Colon/metabolism , Diabetes Mellitus, Type 1/diet therapy , Dysbiosis/diet therapy , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmunity , B-Lymphocytes/microbiology , Cells, Cultured , Colon/pathology , Diet Therapy , Gastrointestinal Microbiome , Interleukins/blood , Mice , Mice, Inbred NOD , T-Lymphocytes, Regulatory/microbiology
14.
Clin Transl Immunology ; 5(5): e82, 2016 May.
Article in English | MEDLINE | ID: mdl-27350881

ABSTRACT

It is now convincingly clear that diet is one of the most influential lifestyle factors contributing to the rise of inflammatory diseases and autoimmunity in both developed and developing countries. In addition, the modern 'Western diet' has changed in recent years with increased caloric intake, and changes in the relative amounts of dietary components, including lower fibre and higher levels of fat and poor quality of carbohydrates. Diet shapes large-bowel microbial ecology, and this may be highly relevant to human diseases, as changes in the gut microbiota composition are associated with many inflammatory diseases. Recent studies have demonstrated a remarkable role for diet, the gut microbiota and their metabolites-the short-chain fatty acids (SCFAs)-in the pathogenesis of several inflammatory diseases, such as asthma, arthritis, inflammatory bowel disease, colon cancer and wound-healing. This review summarizes how diet, microbiota and gut microbial metabolites (particularly SCFAs) can modulate the progression of inflammatory diseases and autoimmunity, and reveal the molecular mechanisms (metabolite-sensing G protein-coupled receptor (GPCRs) and inhibition of histone deacetylases (HDACs)). Therefore, considerable benefit could be achieved simply through the use of diet, probiotics and metabolites for the prevention and treatment of inflammatory diseases and autoimmunity.

16.
J Elder Abuse Negl ; 25(4): 294-304, 2013.
Article in English | MEDLINE | ID: mdl-23768413

ABSTRACT

We have previously described high rates of executive function impairment in clients referred by Adult Protective Services (APS) to geriatric psychiatry for decision-making capacity assessments. The purpose of this study was to determine the independent relationship between neuropsychological screening instruments, particularly instruments sensitive to executive function, and performance-based functional tasks in elder referrals. Our retrospective medical review (n = 75/157 referrals completed all neuropsychological and functional assessments) revealed that only the Executive Interview (EXIT25) contributed independent variance to money management performance (R(2) = 0.29, p < 0.001), telephone use ability (R(2) = 0.39, p < 0.001), and summed performance (R(2) = 0.45, p < 0.001). Executive instruments may specifically inform decision-making capacity assessments.


Subject(s)
Activities of Daily Living/psychology , Elder Abuse/psychology , Executive Function , Geriatric Assessment , Aged , Aged, 80 and over , Cognition , Female , Humans , Male , Middle Aged , Neuropsychological Tests
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