Microbial metabolite sensor GPR43 controls severity of experimental GVHD

Fujiwara, Hideaki; Docampo, Melissa D.; Riwes, Mary; Peltier, Daniel; Toubai, Tomomi; Henig, Israel; Wu, S. Julia; Kim, Stephanie; Taylor, Austin; Brabbs, Stuart; Liu, Chen; Zajac, Cynthia; Oravecz-Wilson, Katherine; Sun, Yaping; Núñez, Gabriel; Levine, John E.; Brink, Marcel R.M. van den; Ferrara, James L.M.; Reddy, Pavan

doi:10.1038/s41467-018-06048-w

Cited by 120 publications

(86 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, propionate binds to GPR41/43, which decreases the phosphorylation of p38 and JNK, ultimately reducing the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) in human renal cortical epithelial cells (HRCEs) [62]. Meanwhile, increased SCFAs by co-housing, antibiotic treatment, and administration of exogenous SCFAs attenuate graft-versus-host disease (GVHD) by regulating NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and the phosphorylation level of ERK, which is mediated by GPR43 on intestinal epithelial cells (IECs) [63]. By binding to its receptor, SCFAs (propionate, acetate, butyrate) reduces lipolysis, insulin sensitivity, and fat accumulation in white adipose tissues by targeting hormone-sensitive lipase (HSL) and PPARγ [64], which are critically involved in CVDs via secreting adipokines [33,65].…”

Section: Scfa Receptorsmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure. Clinical Science (2020) 134 657-676 https://doi.org/10.1042/CS20200128 cofactors in certain protein acylations, such as propionylation [14], malonylation [15], butyrylation [14], 2-hydroxyisobutyrylation [16], β-hydroxybutyrylation [17], crotonylation [18], succinylation [19], and glutarylation [20]. These discoveries give us a deeper understanding of PTM. Among PTMs, protein acetylation is the earliest discovered and most studied. Similar to protein acetylation, various studies have shown that these newly discovered PTMs are also involved in physiological and pathophysiological processes, including cardiovascular homeostasis.Here in this review, we will summarize SCFAs, protein acylations, and their emerging roles in CVDs, including atherosclerosis, hypertension, and heart failure. The metabolic pattern and FAs in CVDsThe heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart. The embryonic heart depends primarily on glycolysis as well as lactate oxidation to produce energy [21]. The newborn and adult heart shift toward the remarkable utilization of FAs to meet cardiac energy demand [5,9]. In failing hearts, a decrease in FA oxidation and an increase in glycolysis are critically involved in cardiac dysfunction [22]. As thus, the metabolic pattern is essential for maintaining cardiac and vascular functions.Diabetes, hypertension, and obesity contribute to heart failure syndrome. Accumulating evidence suggests that hypertension, ischemic hearts, and heart failure induce a shift in substrate toward the remarkable utilization of glucose to generate energy. Despite this shift, the FA oxidation remains to make much energy for the diseased heart [23]. Since FAs are the predominant substrates for cardiomyocytes, alterations in FA metabolism have been implicated as causal in cardiac diseases. FAs within cells and in the circulation are critically involved in cardiometabolic diseases. CVDs are closely associated with lifestyle and metabolic status, which affect circul...

show abstract

Section: Scfa Receptorsmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

View full text Add to dashboard Cite

show abstract

“…Restoration butyrate in intestinal tract or enhance SCFAs sensor could improve junctional integrity of intestinal epithelial cells and upregulate regulatory T cells to mitigate murine aGVHD. [19,20] Similar ideal results can be obtained by replenishment of butyrate-producing bacteria Clostridia, which highlight the mutual in uence of gut microbiota and metabolism. [19,21] Concurrently, acting as precursors for the synthesis of SCFAs, amino acid is another important metabolite in intestine.…”

Section: Introductionmentioning

confidence: 53%

Tyrosine Supplement Ameliorates Murine aGVHD by Modulation of Gut Microbiome and Metabolome

et al. 2020

Preprint

View full text Add to dashboard Cite

Background The microbial communities and their metabolic components in gut are essential for immune homeostasis and profoundly influence the host susceptibility to many immune-mediated diseases including acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the functional connections between microbiome and metabolites in aGVHD are poorly understood because of the complexity of gastrointestinal environment. Thus, we initially performed 16S ribosomal DNA gene sequencing and ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to unleash the gut microbiota and fecal metabolic phenotype in aGVHD murine model. Results A Lachnospiraceae_unclassified was significantly downregulated while the relative abundance of Clostridium XI, Clostridium XIVa and Enterococcus were increased in aGVHD happened group. Meanwhile, a lower content of tyrosine was observed in the gut of aGVHD mice. The correlation analysis revealed that tyrosine-related metabolites inversely correlated with Clostridium XIVa, Blautia and Enterococcus in aGVHD condition. In addition to explore the importance and function of tyrosine, we supplied different tyrosine content diets to mice during transplantation. Additional tyrosine supplements could improve overall survival, ameliorate symptoms at the early stage of aGVHD and changed the structure and composition of gut microbiota and fecal metabolic phenotype, while mice with aGVHD deprived from tyrosine displayed worse manifestations than vehicle. Conclusions Overall, a better understanding of the roles of gut microbiota-metabolomes interconnectedness in aGVHD could help identify disease biomarkers and offer better targets for diagnosis and treatment.

show abstract

“…This increase in O 2 may provide a potential mechanistic explanation for changes in microbiome associated with GVHD and IBD. The change in O 2 levels might lead to dysbiosis with loss of microbial diversity, decrease in commensals such as obligate anaerobes and shift towards to aerobes and pathobionts in the microbiome of patients with GVHD and IBD 43 44 45 46 47 48 49 50 51 52 53 54 55 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Fujiwara

Mathew

Kovalenko

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Keywords: mitochondria, succinate dehydrogenase, bone marrow transplantation, graft-versus-host 22 disease, intestinal epithelium 23 24 25Summary 26Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic 27 diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune 28 checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding 29 the aberrant biology of T cells in these diseases, little is known about how the fundamental biological 30 processes of the target IECs influence the disease severity. Here, through analyses of metabolic 31 pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change 32 in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated 33 mediated gastrointestinal graft-versus-host disease (GI-GVHD) often have similar symptoms and cause 50 significant morbidity and mortality 1 5 6 . Although the pathophysiology of each of these diseases is a 51 complex interplay of the environmental and genetic factors, T cell mediated damage of IECs plays a 52 vital role in the cause and severity of all of these conditions. Immunosuppression with corticosteroids, 53 and anti-cytokine therapies have shown good results with adverse effects, but are still incomplete 5 7 8 . 54The biology and treatments of these diseases are often understood and targeted from the immune cell 55 3 and inflammation perspective, but the pathogenesis and severity from host IEC target cell perspective 56 remain undefined. 57 58 Emerging data in recent years have brought into focus the central role of immune cell metabolism in the 59 regulation of intestinal inflammatory diseases. APCs, including macrophages and dendritic cells, and T 60 cells show changes in metabolic programming, including morphological alterations in mitochondria, 61transitioning from glycolysis dependence (pro-inflammatory macrophages and effector T cells) to 62 oxidative phosphorylation (OXPHOS) dependence (anti-inflammatory macrophages and memory T 63 cells) 9 10 11 and regulate intestinal T cell mediated diseases such as GI GVHD and IBD. However, 64whether the metabolism of the targets of these pathogenic T cells in these diseases, the IECs, are 65 perturbed or reprogrammed, and if so, whether this has an impact on the disease severity remains 66 unknown. The mammalian GI tract is a relatively hypoxic region and thus, IECs are uniquely adapted to 67 this hypoxic environment 12 13 . In this study, we aimed to determine the metabolic changes in IECs when 68 they are targeted by pathogenic T effector cells. We found that in the context of pathogenic T cell 69 mediated damage, the IECs demonstrated a reduction in OXPHOS and accumulated succinate as a result 70 of decrease in SDHA, a component of mitochondrial complex II. The reduction of SDHA in IECs 71 aggravated disease severity in multiple T cell mediated models such as the alloimmune mediated GI 72 GVHD, ...

show abstract

Microbial metabolite sensor GPR43 controls severity of experimental GVHD

Cited by 120 publications

References 59 publications

Short-chain fatty acid, acylation and cardiovascular diseases

Short-chain fatty acid, acylation and cardiovascular diseases

Tyrosine Supplement Ameliorates Murine aGVHD by Modulation of Gut Microbiome and Metabolome

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Contact Info

Product

Resources

About