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

Wu, Huiling; Singer, Julian; Kwan, Tak; Loh, Yik Wen; Wang, Chuanmin; Tan, Jian; Li, Yan J.; Lai, Christina; Macia, Laurence; Alexander, Stephen I.; Chadban, Steven J.

doi:10.1681/asn.2019080852

Cited by 63 publications

(55 citation statements)

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“…Several authors have described the ability of certain SCFAs, such as acetate and butyrate, to modulate the immune system. Concretely, acetate is able to induce an elevation in Treg populations [9,47]. We found an expansion in acetate-producing bacteria induced by MMF treatment in DOCA-salt rats, which could be involved in the higher numbers of Treg and IL-10 found in MLN and aorta from the DOCA-MMF group.…”

Section: Discussionmentioning

confidence: 61%

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

et al. 2020

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Microbiota is involved in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzed whether MMF improves dysbiosis in mineralocorticoid-induced hypertension. Male Wistar rats were assigned to three groups: untreated (CTR), deoxycorticosterone acetate (DOCA)-salt, and DOCA treated with MMF for 4 weeks. MMF treatment reduced systolic BP, improved endothelial dysfunction, and reduced oxidative stress and inflammation in aorta. A clear separation in the gut bacterial community between CTR and DOCA groups was found, whereas the cluster belonging to DOCA-MMF group was found to be intermixed. No changes were found at the phylum level among all experimental groups. MMF restored the elevation in lactate-producing bacteria found in DOCA-salt joined to an increase in the acetate-producing bacteria. MMF restored the percentage of anaerobic bacteria in the DOCA-salt group to values similar to control rats. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. This study demonstrates for the first time that MMF reduces gut dysbiosis in DOCA-salt hypertension models. This effect seems to be related to its capacity to improve gut integrity due to reduced sympathetic drive in the gut associated with reduced brain neuroinflammation.

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Section: Discussionmentioning

confidence: 61%

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

et al. 2020

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“…Despite the fact that some studies have identified an association between plasma concentrations of TMAO and adverse cardiovascular outcomes in patients with chronic kidney disease [ 15 , 16 ] and in hemodialysis patients [ 17 ], the potential role of these osmolytes in graft survival in renal transplant recipients is still unknown. Considering that modification of the gut microbiome by dietary intervention may enhance survival of the allograft, as observed in a rodent kidney transplant model [ 18 ], and the fact that TMAO may contribute to renal fibrosis [ 19 ], the aim of the present study was to evaluate the potential association of TMAO and its dietary determinants with the risk of graft failure in renal transplant recipients (RTRs) and its clinical value.…”

Section: Introductionmentioning

confidence: 99%

Association of Circulating Trimethylamine N-Oxide and Its Dietary Determinants with the Risk of Kidney Graft Failure: Results of the TransplantLines Cohort Study

et al. 2021

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Background. Due to the critical shortage of kidneys for transplantation, the identification of modifiable factors related to graft failure is highly desirable. The role of trimethylamine-N-oxide (TMAO) in graft failure remains undetermined. Here, we investigated the clinical utility of TMAO and its dietary determinants for graft failure prediction in renal transplant recipients (RTRs). Methods. We included 448 RTRs who participated in the TransplantLines Cohort Study. Cox proportional-hazards regression analyses were performed to study the association of plasma TMAO with graft failure. Net Benefit, which is a decision analysis method, was performed to evaluate the clinical utility of TMAO and dietary information in the prediction of graft failure. Results. Among RTRs (age 52.7 ± 13.1 years; 53% males), the baseline median TMAO was 5.6 (3.0–10.2) µmol/L. In multivariable regression analysis, the most important dietary determinants of TMAO were egg intake (Std. β = 0.09 [95%CI, 0.01; 0.18]; p = 0.03), fiber intake (Std. β = −0.14 [95%CI, −0.22, −0.05]; p = 0.002), and fish and seafood intake (Std. β = 0.12 [95%CI, 0.03,0.21]; p = 0.01). After a median follow-up of 5.3 (4.5–6.0) years, graft failure was observed in 58 subjects. TMAO was associated with an increased risk of graft failure, independent of age, sex, the body mass index (BMI), blood pressure, lipids, albuminuria, and the Estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio per 1-SD increase of TMAO, 1.62 (95% confidence interval (CI): 1.22; 2.14, p < 0.001)). A TMAO and dietary enhanced prediction model offered approximately double the Net Benefit compared to a previously reported, validated prediction model for future graft failure, allowing the detection of 21 RTRs per 100 RTRs tested, with no false positives versus 10 RTRs, respectively. Conclusions. A predictive model for graft failure, enriched with TMAO and its dietary determinants, yielded a higher Net Benefit compared with an already validated model. This study suggests that TMAO and its dietary determinants are associated with an increased risk of graft failure and that it is clinically meaningful.

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“…Wu and colleagues could show that mice receiving a kidney allograft, but not an isograft, exhibited gut microbial dysbiosis and allograft rejection when fed a normal chow diet, which was prevented by feeding a high-fiber diet or a normal chow diet supplemented with acetate. These beneficial effects were mediated by T reg cells in an FFAR2-dependent manner, as FFAR2-deficient mice were not protected [ 121 ]. In addition to hematopoietic cells, renal resident cell types such as tubular epithelial cells and podocytes have also been found to express FFAR2 and react with reduced proinflammatory and profibrotic gene expressions upon hyperglycemic insult when FFA2 receptors were stimulated.…”

Section: Free Fatty Acid Receptors 2 and 3 (Ffar2 And Ffar3)mentioning

confidence: 99%

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

Grundmann

Bender

Schamberger

et al. 2021

IJMS

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The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

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

Cited by 63 publications

References 50 publications

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

Association of Circulating Trimethylamine N-Oxide and Its Dietary Determinants with the Risk of Kidney Graft Failure: Results of the TransplantLines Cohort Study

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

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