Publications by authors named "Laurence Macia"

56 Publications

#CXCR5/CXCL13 pathway, a key driver for migration of regulatory B10 cells, is defective in patients with rheumatoid arthritis.

Rheumatology (Oxford) 2021 Aug 11. Epub 2021 Aug 11.

CHU and University of Montpellier, Rheumatology, Montpellier, France.

Objectives: Chemokines (CKs) are key players of immune-cell homing and differentiation. CK receptors (CKRs) can be used to define T-cell functional subsets. We aimed to characterize the CKR profile of the regulatory B-cell subset B10+ cells and investigate the CKs involved in their migration and differentiation in healthy donors (CTLs) and patients with rheumatoid arthritis (RA).

Methods: RNA sequencing and cytometry were used to compare CKR expression between B10+ and B10neg cells. Migration of B10+ and B10neg cells and interleukin 10 (IL-10) secretion of B cells in response to recombinant CKs or synovial fluid (SF) were assessed.

Results: CXCR5 was expressed at a higher level on the B10+ cell surface as compared with other B cells (referred to as B10neg cells). In line with this, its ligand CXCL13 preferentially attracted B10+ cells over B10neg cells. Interestingly, synovial fluid from RA patients contained high levels of CXCL13 and induced strong and preferential migration of B10+ cells. Besides its role in attracting B10+ cells, CXCL13 also promoted IL-10 secretion by B cells. In RA patients, the level of CXCR5 on B cell surface was reduced. The preferential migration of RA B10+ cells toward CXCL13-rich SF was lost and CXCL13 stimulation triggered less IL-10 secretion than in healthy donors.

Conclusion: Our results identify that the CXCR5/CXCL13 axis is essential for B10+ cell biology but is defective in RA. Restoring the preferential migration of B10+ within the affected joints to better control inflammation may be part of therapeutic approach for RA.
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http://dx.doi.org/10.1093/rheumatology/keab639DOI Listing
August 2021

Dietary carbohydrate, particularly glucose, drives B cell lymphopoiesis and function.

iScience 2021 Aug 10;24(8):102835. Epub 2021 Jul 10.

Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.

While diet modulates immunity, its impact on B cell ontogeny remains unclear. Using mixture modeling, a large-scale isocaloric dietary cohort mouse study identified carbohydrate as a major driver of B cell development and function. Increasing dietary carbohydrate increased B cell proportions in spleen, mesenteric lymph node and Peyer's patches, and increased antigen-specific immunoglobulin G production after immunization. This was linked to increased B lymphopoiesis in the bone marrow. Glucose promoted early B lymphopoiesis and higher total B lymphocyte numbers than fructose. It drove B cell development through glycolysis and oxidative phosphorylation, independently of fatty acid oxidation and reduced B cell apoptosis in early development via mTOR activation, independently of interleukin-7. Ours is the first comprehensive study showing the impact of macronutrients on B cell development and function. It shows the quantitative and qualitative interplay between dietary carbohydrate and B cells and argues for dietary modulation in B cell-targeting strategies.
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http://dx.doi.org/10.1016/j.isci.2021.102835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333167PMC
August 2021

The maternal gut microbiome during pregnancy and offspring allergy and asthma.

J Allergy Clin Immunol 2021 Sep 24;148(3):669-678. Epub 2021 Jul 24.

Institute for Physical and Mental Health and Clinical Transformation, Deakin University, Geelong, Australia; Child Health Research Unit, Barwon Health, Geelong, Australia; the Centre For Food Allergy Research, Murdoch Children's Research Institute, Parkville. Electronic address:

Environmental exposures during pregnancy that alter both the maternal gut microbiome and the infant's risk of allergic disease and asthma include a traditional farm environment and consumption of unpasteurized cow's milk, antibiotic use, dietary fiber, and psychosocial stress. Multiple mechanisms acting in concert may underpin these associations and prime the infant to acquire immune competence and homeostasis following exposure to the extrauterine environment. Cellular and metabolic products of the maternal gut microbiome can promote the expression of microbial pattern recognition receptors, as well as thymic and bone marrow hematopoiesis relevant to regulatory immunity. At birth, transmission of maternally derived bacteria likely leverages this in utero programming to accelerate postnatal transition from a T2- to T1- and T17-dominant immune phenotype and maturation of regulatory immune mechanisms, which in turn reduce the child's risk of allergic disease and asthma. Although our understanding of these phenomena is rapidly evolving, the field is relatively nascent, and we are yet to translate existing knowledge into interventions that substantially reduce disease risk in humans. Here, we review evidence that the maternal gut microbiome impacts the offspring's risk of allergic disease and asthma, discuss challenges and future directions for the field, and propose the hypothesis that maternal carriage of Prevotella copri during pregnancy decreases the offspring's risk of allergic disease via production of succinate, which in turn promotes bone marrow myelopoiesis of dendritic cell precursors in the fetus.
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http://dx.doi.org/10.1016/j.jaci.2021.07.011DOI Listing
September 2021

Impact of dietary carbohydrate type and protein-carbohydrate interaction on metabolic health.

Nat Metab 2021 06 8;3(6):810-828. Epub 2021 Jun 8.

Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.

Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.
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http://dx.doi.org/10.1038/s42255-021-00393-9DOI Listing
June 2021

Fiber Derived Microbial Metabolites Prevent Acute Kidney Injury Through G-Protein Coupled Receptors and HDAC Inhibition.

Front Cell Dev Biol 2021 8;9:648639. Epub 2021 Apr 8.

Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Camperdown, NSW, Australia.

Short-chain fatty acids (SCFA) derived from gut microbial fermentation of fiber have been shown to exert anti-inflammatory and immune-modulatory properties in acute kidney injury (AKI). However the direct mechanistic link between SCFAs, diet and the gut microbiome is yet to be established. Using the murine model of folic-acid nephropathy (FAN), we examined the effect of dietary fiber on development of AKI (day 2) and subsequent chronic kidney disease (CKD) (day 28). FAN was induced in wild-type and knockout mice lacking G protein-coupled receptors , , or . Mice were randomized to high-fiber or normal-chow diets, or SCFAs in drinking water. We used 16S rRNA sequencing to assess the gut microbiome and H-NMR spectroscopy for metabolic profiles. Mice fed high-fiber were partially protected against development of AKI and subsequent CKD, exhibiting better kidney function throughout, less tubular injury at day 2 and less interstitial fibrosis and chronic inflammation at day 28 vs controls. Fiber modified the gut microbiome and alleviated dysbiosis induced by AKI, promoting expansion of SCFA-producing bacteria and , which increased fecal and serum SCFA concentrations. SCFA treatment achieved similar protection, but not in the absence of GPR41 or GPR109A. Histone deacetylase activity (HDAC) was inhibited in kidneys of high-fiber fed mice. We conclude that dietary manipulation of the gut microbiome protects against AKI and subsequent CKD, mediated by HDAC inhibition and activation of GPR41 and GPR109A by SCFAs. This study highlights the potential of the gut microbiome as a modifiable target in the prevention of AKI.
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http://dx.doi.org/10.3389/fcell.2021.648639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060457PMC
April 2021

How Changes in the Nutritional Landscape Shape Gut Immunometabolism.

Nutrients 2021 Mar 2;13(3). Epub 2021 Mar 2.

The Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.

Cell survival, proliferation and function are energy-demanding processes, fuelled by different metabolic pathways. Immune cells like any other cells will adapt their energy production to their function with specific metabolic pathways characteristic of resting, inflammatory or anti-inflammatory cells. This concept of immunometabolism is revolutionising the field of immunology, opening the gates for novel therapeutic approaches aimed at altering immune responses through immune metabolic manipulations. The first part of this review will give an extensive overview on the metabolic pathways used by immune cells. Diet is a major source of energy, providing substrates to fuel these different metabolic pathways. Protein, lipid and carbohydrate composition as well as food additives can thus shape the immune response particularly in the gut, the first immune point of contact with food antigens and gastrointestinal tract pathogens. How diet composition might affect gut immunometabolism and its impact on diseases will also be discussed. Finally, the food ingested by the host is also a source of energy for the micro-organisms inhabiting the gut lumen particularly in the colon. The by-products released through the processing of specific nutrients by gut bacteria also influence immune cell activity and differentiation. How bacterial metabolites influence gut immunometabolism will be covered in the third part of this review. This notion of immunometabolism and immune function is recent and a deeper understanding of how lifestyle might influence gut immunometabolism is key to prevent or treat diseases.
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http://dx.doi.org/10.3390/nu13030823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999246PMC
March 2021

Gut Microbial Metabolites Induce Donor-Specific Tolerance of Kidney Allografts through Induction of T Regulatory Cells by Short-Chain Fatty Acids.

J Am Soc Nephrol 2020 07 1;31(7):1445-1461. Epub 2020 Jun 1.

Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.

Background: Short-chain fatty acids derived from gut microbial fermentation of dietary fiber have been shown to suppress autoimmunity through mechanisms that include enhanced regulation by T regulatory cells (Tregs).

Methods: Using a murine kidney transplantation model, we examined the effects on alloimmunity of a high-fiber diet or supplementation with the short-chain fatty acid acetate. Kidney transplants were performed from BALB/c(H2) to B6(H2) mice as allografts in wild-type and recipient mice lacking the G protein-coupled receptor GPR43 (the metabolite-sensing receptor of acetate). Allograft mice received normal chow, a high-fiber diet, or normal chow supplemented with sodium acetate. We assessed rejection at days 14 (acute) and 100 (chronic), and used 16S rRNA sequencing to determine gut microbiota composition pretransplantation and post-transplantation.

Results: Wild-type mice fed normal chow exhibited dysbiosis after receiving a kidney allograft but not an isograft, despite the avoidance of antibiotics and immunosuppression for the latter. A high-fiber diet prevented dysbiosis in allograft recipients, who demonstrated prolonged survival and reduced evidence of rejection compared with mice fed normal chow. Allograft mice receiving supplemental sodium acetate exhibited similar protection from rejection, and subsequently demonstrated donor-specific tolerance. Depletion of CD25 Tregs or absence of the short-chain fatty acid receptor GPR43 abolished this survival advantage.

Conclusions: Manipulation of the microbiome by a high-fiber diet or supplementation with sodium acetate modified alloimmunity in a kidney transplant model, generating tolerance dependent on Tregs and GPR43. Diet-based therapy to induce changes in the gut microbiome can alter systemic alloimmunity in mice, in part through the production of short-chain fatty acids leading to Treg cell development, and merits study as a potential clinical strategy to facilitate transplant acceptance.
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http://dx.doi.org/10.1681/ASN.2019080852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350991PMC
July 2020

Immune Modulation of Monocytes Dampens the IL-17 γδ T Cell Response and Associated Psoriasis Pathology in Mice.

J Invest Dermatol 2020 12 7;140(12):2398-2407.e1. Epub 2020 May 7.

Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Psoriasis is a chronic inflammatory autoimmune skin condition that affects millions of people worldwide. It is driven by IL-17-producing CD4 and γδ T cells and targeted by current anti-IL-17 or anti-IL-23 mAb therapies. These treatments are expensive, increase the risk of opportunistic infections, and do not specifically target the inflammatory cascade. Other cells, including inflammatory monocytes, have been shown to migrate to psoriatic plaques in both human disease and the imiquimod-induced mouse model and could thus constitute potential alternative therapeutic targets. In the mouse, immune modifying particles (IMPs) specifically target Ly6C inflammatory monocytes migrating to the site of inflammation, sequestering them in the spleen. In this project, we determined whether IMPs could mitigate the development of imiquimod -induced psoriasis in mice. IMP treatment significantly reduced imiquimod-induced psoriasis severity, decreasing dermal infiltration of Ly6C monocytes as well as early-stage monocyte-derived dermal macrophages. This was associated with reduced levels of hallmark cytokines IL-23 and IL-1β as well as associated IL-17-producing γδ T cells. Our work highlights the crucial importance of inflammatory monocytes in the development of this disease as well as a therapeutic potential for IMP in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2020.03.973DOI Listing
December 2020

Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid-Mediated Activation of G Protein-Coupled Receptors GPR43 and GPR109A.

J Am Soc Nephrol 2020 06 1;31(6):1267-1281. Epub 2020 May 1.

Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia

Background: Studies have reported "dysbiotic" changes to gut microbiota, such as depletion of gut bacteria that produce short-chain fatty acids (SCFAs) through gut fermentation of fiber, in CKD and diabetes. Dietary fiber is associated with decreased inflammation and mortality in CKD, and SCFAs have been proposed to mediate this effect.

Methods: To explore dietary fiber's effect on development of experimental diabetic nephropathy, we used streptozotocin to induce diabetes in wild-type C57BL/6 and knockout mice lacking the genes encoding G protein-coupled receptors GPR43 or GPR109A. Diabetic mice were randomized to high-fiber, normal chow, or zero-fiber diets, or SCFAs in drinking water. We used proton nuclear magnetic resonance spectroscopy for metabolic profiling and 16S ribosomal RNA sequencing to assess the gut microbiome.

Results: Diabetic mice fed a high-fiber diet were significantly less likely to develop diabetic nephropathy, exhibiting less albuminuria, glomerular hypertrophy, podocyte injury, and interstitial fibrosis compared with diabetic controls fed normal chow or a zero-fiber diet. Fiber beneficially reshaped gut microbial ecology and improved dysbiosis, promoting expansion of SCFA-producing bacteria of the genera and , which increased fecal and systemic SCFA concentrations. Fiber reduced expression of genes encoding inflammatory cytokines, chemokines, and fibrosis-promoting proteins in diabetic kidneys. SCFA-treated diabetic mice were protected from nephropathy, but not in the absence of GPR43 or GPR109A. , SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions.

Conclusions: Dietary fiber protects against diabetic nephropathy through modulation of the gut microbiota, enrichment of SCFA-producing bacteria, and increased SCFA production. GPR43 and GPR109A are critical to SCFA-mediated protection against this condition. Interventions targeting the gut microbiota warrant further investigation as a novel renoprotective therapy in diabetic nephropathy.
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http://dx.doi.org/10.1681/ASN.2019101029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269358PMC
June 2020

Maternal carriage of Prevotella during pregnancy associates with protection against food allergy in the offspring.

Nat Commun 2020 03 24;11(1):1452. Epub 2020 Mar 24.

The Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.

In mice, the maternal microbiome influences fetal immune development and postnatal allergic outcomes. Westernized populations have high rates of allergic disease and low rates of gastrointestinal carriage of Prevotella, a commensal bacterial genus that produces short chain fatty acids and endotoxins, each of which may promote the development of fetal immune tolerance. In this study, we use a prebirth cohort (n = 1064 mothers) to conduct a nested case-cohort study comparing 58 mothers of babies with clinically proven food IgE mediated food allergy with 258 randomly selected mothers. Analysis of the V4 region of the 16S rRNA gene in fecal samples shows maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring. This association was confirmed using targeted qPCR and was independent of infant carriage of P. copri. Larger household size, which is a well-established protective factor for allergic disease, strongly predicts maternal carriage of P. copri.
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http://dx.doi.org/10.1038/s41467-020-14552-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093478PMC
March 2020

Host- and Microbiota-Derived Extracellular Vesicles, Immune Function, and Disease Development.

Int J Mol Sci 2019 Dec 22;21(1). Epub 2019 Dec 22.

School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia.

Extracellular vesicles (EVs) are blebs of either plasma membrane or intracellular membranes carrying a cargo of proteins, nucleic acids, and lipids. EVs are produced by eukaryotic cells both under physiological and pathological conditions. Genetic and environmental factors (diet, stress, etc.) affecting EV cargo, regulating EV release, and consequences on immunity will be covered. EVs are found in virtually all body fluids such as plasma, saliva, amniotic fluid, and breast milk, suggesting key roles in immune development and function at different life stages from in utero to aging. These will be reviewed here. Under pathological conditions, plasma EV levels are increased and exacerbate immune activation and inflammatory reaction. Sources of EV, cells targeted, and consequences on immune function and disease development will be discussed. Both pathogenic and commensal bacteria release EV, which are classified as outer membrane vesicles when released by Gram-negative bacteria or as membrane vesicles when released by Gram-positive bacteria. Bacteria derived EVs can affect host immunity with pathogenic bacteria derived EVs having pro-inflammatory effects of host immune cells while probiotic derived EVs mostly shape the immune response towards tolerance.
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http://dx.doi.org/10.3390/ijms21010107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982009PMC
December 2019

Dysfunctional microbiota with reduced capacity to produce butyrate as a basis for allergic diseases.

J Allergy Clin Immunol 2019 12 22;144(6):1513-1515. Epub 2019 Oct 22.

Department of Microbiology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia; Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.10.009DOI Listing
December 2019

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia.

Nat Commun 2019 07 10;10(1):3031. Epub 2019 Jul 10.

Charles Perkins Centre Nepean, The University of Sydney, Penrith, 2750, NSW, Australia.

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.
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http://dx.doi.org/10.1038/s41467-019-10703-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620275PMC
July 2019

Impact of the Food Additive Titanium Dioxide (E171) on Gut Microbiota-Host Interaction.

Front Nutr 2019 14;6:57. Epub 2019 May 14.

The Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.

The interaction between gut microbiota and host plays a central role in health. Dysbiosis, detrimental changes in gut microbiota and inflammation have been reported in non-communicable diseases. While diet has a profound impact on gut microbiota composition and function, the role of food additives such as titanium dioxide (TiO), prevalent in processed food, is less established. In this project, we investigated the impact of food grade TiO on gut microbiota of mice when orally administered via drinking water. While TiO had minimal impact on the composition of the microbiota in the small intestine and colon, we found that TiO treatment could alter the release of bacterial metabolites and affect the spatial distribution of commensal bacteria by promoting biofilm formation. We also found reduced expression of the colonic mucin 2 gene, a key component of the intestinal mucus layer, and increased expression of the beta defensin gene, indicating that TiO significantly impacts gut homeostasis. These changes were associated with colonic inflammation, as shown by decreased crypt length, infiltration of CD8 T cells, increased macrophages as well as increased expression of inflammatory cytokines. These findings collectively show that TiO is not inert, but rather impairs gut homeostasis which may in turn prime the host for disease development.
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http://dx.doi.org/10.3389/fnut.2019.00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534185PMC
May 2019

Ingestion of resistant starch by mice markedly increases microbiome-derived metabolites.

FASEB J 2019 07 29;33(7):8033-8042. Epub 2019 Mar 29.

Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.

Recent research has shown significant health benefits deriving from high-dietary fiber or microbiome-accessible carbohydrate consumption. Compared with native starch (NS), dietary resistant starch (RS) is a high microbiome-accessible carbohydrate that significantly alters the gut microbiome. The aim of this study was to determine the systemic metabolic effects of high microbiome-accessible carbohydrate. Male C57BL/6 mice were divided into 2 groups and fed either NS or RS for 18 wk ( = 20/group). Metabolomic analyses revealed that plasma levels of numerous metabolites were significantly different between the RS-fed and NS-fed mice, many of which are microbiome-derived. Most strikingly, we observed a 22-fold increase in gut microbiome-derived tryptophan metabolite indole-3-propionate (IPA), which was positively correlated with several gut microbiota, including , , and , with having the most consistently increased abundance of all the IPA-associated taxa across all RS-fed mice. In addition, major changes were observed for metabolites solely or primarily metabolized in the gut (, trimethylamine--oxide), metabolites that have a significant entero-hepatic circulation (, bile acids), lipid metabolites (, cholesterol sulfate), metabolites indicating increased energy turnover (, tricarboxylic acid cycle intermediates and ketone bodies), and increased antioxidants such as reduced glutathione. Our findings reveal potentially novel mediators of high microbiome-accessible carbohydrate-derived health benefits.-Koay,Y. C., Wali. J. A., Luk, A. W. S., Macia, L., Cogger, V. C., Pulpitel, T. J., Wahl, D., Solon-Biet, S. M., Holmes, A., Simpson, S. J., O'Sullivan, J. F. Ingestion of resistant starch by mice markedly increases microbiome-derived metabolites.
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http://dx.doi.org/10.1096/fj.201900177RDOI Listing
July 2019

IL-10 Producing B Cells Ability to Induce Regulatory T Cells Is Maintained in Rheumatoid Arthritis.

Front Immunol 2018 3;9:961. Epub 2018 May 3.

Montpellier University, Montpellier, France.

Despite growing evidence highlighting the relevance of increasing IL-10-producing B cells (B10cells) in autoimmune diseases, their functions in patients are still unknown. The aim of this study was to evaluate the functions of CpG-induced B10 cells isolated from healthy controls (HC) and rheumatoid arthritis (RA) patients, on naïve T cell differentiation. We demonstrated that CpG-induced B10 cells from HC drove naïve T cell differentiation toward regulatory T cells (Treg cells) and IL-10-producing T cells (Tr1) through IL-10 secretion and cellular contacts. B10 cells from HC did not decrease T helper 1 (Th1) nor and tumor necrosis factor α producing T cell (TNFα T cell) differentiation. We showed that in RA, B10 cells could also induce Treg cells and Tr1 from naïve T cells. Contrary to HC, B10 cells from RA patients increased naïve T cell conversion into Th1. Interestingly, PD-L2, a programmed death-1 (PD-1) ligand that inhibits PD-L1 and promotes Th1 differentiation, was overexpressed on RA B10 cells compared to HC B10 cells. Together, our findings showed that CpG-induced B10 cells may be used to increase Treg cells in patients with RA. However, CpG may not be the most adequate stimuli as CpG-induced B10 cells also increased inflammatory T cells in those patients.
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http://dx.doi.org/10.3389/fimmu.2018.00961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943500PMC
July 2019

The nutritional geometry of liver disease including non-alcoholic fatty liver disease.

J Hepatol 2018 02 6;68(2):316-325. Epub 2017 Nov 6.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Sydney, NSW, Australia. Electronic address:

Nutrition has a profound effect on chronic liver disease, especially non-alcoholic fatty liver disease (NAFLD). Most observational studies and clinical trials have focussed on the effects of total energy intake, or the intake of individual macronutrients and certain micronutrients, such as vitamin D, on liver disease. Although these studies have shown the importance of nutrition on hepatic outcomes, there is not yet any unifying framework for understanding the relationship between diet and liver disease. The Geometric Framework for Nutrition (GFN) is an innovative model for designing nutritional experiments or interpreting nutritional data that can determine the effects of nutrients and their interactions on animal behaviour and phenotypes. Recently the GFN has provided insights into the relationship between dietary energy and macronutrients on obesity and ageing in mammals including humans. Mouse studies using the GFN have disentangled the effects of macronutrients on fatty liver and the gut microbiome. The GFN is likely to play a significant role in disentangling the effects of nutrients on liver disease, especially NAFLD, in humans.
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http://dx.doi.org/10.1016/j.jhep.2017.10.005DOI Listing
February 2018

The maternal microbiome during pregnancy and allergic disease in the offspring.

Semin Immunopathol 2017 11 16;39(6):669-675. Epub 2017 Oct 16.

Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.

There is substantial epidemiological and mechanistic evidence that the increase in allergic disease and asthma in many parts of the world in part relates to changes in microbial exposures and diet acting via the composition and metabolic products of the intestinal microbiome. The majority of research in this field has focused on the gut microbiome during infancy, but it is increasingly clear that the maternal microbiome during pregnancy also has a key role in preventing an allergy-prone immune phenotype in the offspring. The mechanisms by which the maternal microbiome influences the developing fetal immune system include alignment between the maternal and infant regulatory immune status and transplacental passage of microbial metabolites and IgG. Interplay between microbial stimulatory factors such as lipopolysaccharides and regulatory factors such as short-chain fatty acids may also influence on fetal immune development. However, our understanding of these pathways is at an early stage and further mechanistic studies are needed. There are also no data from human studies relating the composition and metabolic activity of the maternal microbiome during pregnancy to the offspring's immune status at birth and risk of allergic disease. Improved knowledge of these pathways may inform novel strategies for tackling the increase in allergic disorders in the modern world.
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http://dx.doi.org/10.1007/s00281-017-0652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711986PMC
November 2017

The nutrition-gut microbiome-physiology axis and allergic diseases.

Immunol Rev 2017 07;278(1):277-295

Infection and Immunity Program, Department of Biochemistry, Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.

Dietary and bacterial metabolites influence immune responses. This raises the question whether the increased incidence of allergies, asthma, some autoimmune diseases, cardiovascular disease, and others might relate to intake of unhealthy foods, and the decreased intake of dietary fiber. In recent years, new knowledge on the molecular mechanisms underpinning a 'diet-gut microbiota-physiology axis' has emerged to substantiate this idea. Fiber is fermented to short chain fatty acids (SCFAs), particularly acetate, butyrate, and propionate. These metabolites bind 'metabolite-sensing' G-protein-coupled receptors such as GPR43, GPR41, and GPR109A. These receptors play fundamental roles in the promotion of gut homeostasis and the regulation of inflammatory responses. For instance, these receptors and their metabolites influence Treg biology, epithelial integrity, gut homeostasis, DC biology, and IgA antibody responses. The SCFAs also influence gene transcription in many cells and tissues, through their inhibition of histone deacetylase expression or function. Contained in this mix is the gut microbiome, as commensal bacteria in the gut have the necessary enzymes to digest dietary fiber to SCFAs, and dysbiosis in the gut may affect the production of SCFAs and their distribution to tissues throughout the body. SCFAs can epigenetically modify DNA, and so may be one mechanism to account for diseases with a 'developmental origin', whereby in utero or post-natal exposure to environmental factors (such as nutrition of the mother) may account for disease later in life. If the nutrition-gut microbiome-physiology axis does underpin at least some of the Western lifestyle influence on asthma and allergies, then there is tremendous scope to correct this with healthy foodstuffs, probiotics, and prebiotics.
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http://dx.doi.org/10.1111/imr.12556DOI Listing
July 2017

Detrimental Impact of Microbiota-Accessible Carbohydrate-Deprived Diet on Gut and Immune Homeostasis: An Overview.

Front Immunol 2017 12;8:548. Epub 2017 May 12.

Nutritional Immunometabolism Node Laboratory, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.

Dietary fibers are non-digestible polysaccharides functionally known as microbiota-accessible carbohydrates (MACs), present in inadequate amounts in the Western diet. MACs are a main source of energy for gut bacteria so the abundance and variety of MACs can modulate gut microbial composition and function. This, in turn, impacts host immunity and health. In preclinical studies, MAC-deprived diet and disruption of gut homeostasis aggravate the development of inflammatory diseases, such as allergies, infections, and autoimmune diseases. The present review provides a synopsis on the impact of a low-MAC diet on gut homeostasis or, more specifically, on gut microbiota, gut epithelium, and immune cells.
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http://dx.doi.org/10.3389/fimmu.2017.00548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427073PMC
May 2017

Metabolite-Sensing G Protein-Coupled Receptors-Facilitators of Diet-Related Immune Regulation.

Annu Rev Immunol 2017 04;35:371-402

Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; email: , , ,

Nutrition and the gut microbiome regulate many systems, including the immune, metabolic, and nervous systems. We propose that the host responds to deficiency (or sufficiency) of dietary and bacterial metabolites in a dynamic way, to optimize responses and survival. A family of G protein-coupled receptors (GPCRs) termed the metabolite-sensing GPCRs bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. Members of this family include GPR43, GPR41, GPR109A, GPR120, GPR40, GPR84, GPR35, and GPR91. In addition, bile acid receptors such as GPR131 (TGR5) and proton-sensing receptors such as GPR65 show similar features. A consistent feature of this family of GPCRs is that they provide anti-inflammatory signals; many also regulate metabolism and gut homeostasis. These receptors represent one of the main mechanisms whereby the gut microbiome affects vertebrate physiology, and they also provide a link between the immune and metabolic systems. Insufficient signaling through one or more of these metabolite-sensing GPCRs likely contributes to human diseases such as asthma, food allergies, type 1 and type 2 diabetes, hepatic steatosis, cardiovascular disease, and inflammatory bowel diseases.
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http://dx.doi.org/10.1146/annurev-immunol-051116-052235DOI Listing
April 2017

Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.

Nat Immunol 2017 05 27;18(5):552-562. Epub 2017 Mar 27.

Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.

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.
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http://dx.doi.org/10.1038/ni.3713DOI Listing
May 2017

Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic Cells.

J Immunol 2017 03 18;198(5):2172-2181. Epub 2017 Jan 18.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands;

The gastrointestinal tract is continuously exposed to many environmental factors that influence intestinal epithelial cells and the underlying mucosal immune system. In this article, we demonstrate that dietary fiber and short chain fatty acids (SCFAs) induced the expression of the vitamin A-converting enzyme RALDH1 in intestinal epithelial cells in vivo and in vitro, respectively. Furthermore, our data showed that the expression levels of RALDH1 in small intestinal epithelial cells correlated with the activity of vitamin A-converting enzymes in mesenteric lymph node dendritic cells, along with increased numbers of intestinal regulatory T cells and a higher production of luminal IgA. Moreover, we show that the consumption of dietary fiber can alter the composition of SCFA-producing microbiota and SCFA production in the small intestines. In conclusion, our data illustrate that dietary adjustments affect small intestinal epithelial cells and can be used to modulate the mucosal immune system.
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http://dx.doi.org/10.4049/jimmunol.1600165DOI Listing
March 2017

Dietary fiber and the short-chain fatty acid acetate promote resolution of neutrophilic inflammation in a model of gout in mice.

J Leukoc Biol 2017 01 5;101(1):275-284. Epub 2016 Aug 5.

Immunopharmacology Group, Department of Biochemistry and Immunology, Federal University of Minas Gerais, Minas Gerais, Brazil;

Gout is a disease characterized by the deposition of monosodium urate (MSU) crystals in the joints. Continuous gout episodes may lead to unresolved inflammatory responses and tissue damage. We investigated the effects of a high-fiber diet and acetate, a short-chain fatty acid (SCFA) resulting from the metabolism of fiber by gut microbiota, on the inflammatory response in an experimental model of gout in mice. Injection of MSU crystals into the knee joint of mice induced neutrophil influx and inflammatory hypernociception. The onset of inflammatory response induced by MSU crystals was not altered in animals given a high-fiber diet, but the high-fiber diet induced faster resolution of the inflammatory response. Similar results were obtained in animals given the SCFA acetate. Acetate was effective, even when given after injection of MSU crystals at the peak of the inflammatory response and induced caspase-dependent apoptosis of neutrophils that accounted for the resolution of inflammation. Resolution of neutrophilic inflammation was associated with decreased NF-κB activity and enhanced production of anti-inflammatory mediators, including IL-10, TGF-β, and annexin A1. Acetate treatment or intake of a high-fiber diet enhanced efferocytosis, an effect also observed in vitro with neutrophils treated with acetate. In conclusion, a high-fiber diet or one of its metabolic products, acetate, controls the inflammatory response to MSU crystals by favoring the resolution of the inflammatory response. Our studies suggest that what we eat plays a determinant role in our capacity to fine tune the inflammatory response.

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http://dx.doi.org/10.1189/jlb.3A1015-453RRRDOI Listing
January 2017

Avenues to autoimmune arthritis triggered by diverse remote inflammatory challenges.

J Autoimmun 2016 09 12;73:120-9. Epub 2016 Jul 12.

Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, 3800 VIC, Australia. Electronic address:

Environmental factors contribute to development of autoimmune diseases. For instance, human autoimmune arthritis can associate with intestinal inflammation, cigarette smoking, periodontal disease, and various infections. The cellular and, molecular pathways whereby such remote challenges might precipitate arthritis or flares remain unclear. Here, we used a transfer model of self-reactive arthritis-inducing CD4(+) cells from KRNtg mice that, upon transfer, induce a very mild form of autoinflammatory arthritis in recipient animals. This model enabled us to identify external factors that greatly aggravated disease. We show that several distinct challenges precipitated full-blown arthritis, including intestinal inflammation through DSS-induced colitis, and bronchial stress through Influenza infection. Both triggers induced strong IL-17 expression primarily in self-reactive CD4(+) cells in lymph nodes draining the site of inflammation. Moreover, treatment of mice with IL-1β greatly exacerbated arthritis, while transfer of KRNtg CD4(+) cells lacking IL-1R significantly reduced disease and IL-17 expression. Thus, IL-1β enhances the autoaggressive potential of self-reactive CD4(+) cells, through increased Th17 differentiation, and this influences inflammatory events in the joints. We propose that diverse challenges that cause remote inflammation (lung infection or colitis, etc.) result in IL-1β-driven Th17 differentiation, and this precipitates arthritis in genetically susceptible individuals. Thus the etiology of autoimmune inflammatory arthritis likely relates to diverse triggers that converge to a common pathway involving IL-1β production and Th17 cell distribution.
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http://dx.doi.org/10.1016/j.jaut.2016.06.018DOI Listing
September 2016

Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways.

Cell Rep 2016 06;15(12):2809-24

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Department of Physiology, Faculty of Medicine, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address:

The incidence of food allergies in western countries has increased dramatically in recent decades. Tolerance to food antigens relies on mucosal CD103(+) dendritic cells (DCs), which promote differentiation of regulatory T (Treg) cells. We show that high-fiber feeding in mice improved oral tolerance and protected from food allergy. High-fiber feeding reshaped gut microbial ecology and increased the release of short-chain fatty acids (SCFAs), particularly acetate and butyrate. High-fiber feeding enhanced oral tolerance and protected against food allergy by enhancing retinal dehydrogenase activity in CD103(+) DC. This protection depended on vitamin A in the diet. This feeding regimen also boosted IgA production and enhanced T follicular helper and mucosal germinal center responses. Mice lacking GPR43 or GPR109A, receptors for SCFAs, showed exacerbated food allergy and fewer CD103(+) DCs. Dietary elements, including fiber and vitamin A, therefore regulate numerous protective pathways in the gastrointestinal tract, necessary for immune non-responsiveness to food antigens.
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http://dx.doi.org/10.1016/j.celrep.2016.05.047DOI Listing
June 2016

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk.

Immunity 2016 06 7;44(6):1392-405. Epub 2016 Jun 7.

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:

Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense.
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http://dx.doi.org/10.1016/j.immuni.2016.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936415PMC
June 2016
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