Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention.

The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.

The SC10-RNase promoter displays changes in DNA methylation patterns through pistil development in self-incompatible Nicotiana alata.

In Solanaceae, self-incompatibility is a genetic mechanism that prevents endogamy in plant populations. Expression of the S-determinants, S-RNase, and SLF, is tightly regulated during pistil and pollen development. However, the molecular mechanism of gene expression regulation in S-RNase-based self-incompatibility systems must be better understood. Here, we identified a 1.3 Kbp sequence upstream to the coding region of the functional SC10-RNase allele from the self-incompatible Nicotiana alata, which directs SC10-RNase expression in mature pistils. This SC10-RNase promoter includes a 300 bp region with minimal elements that sustain the SC10-RNase expression. Likewise, a fragment of a transposable element from the Gypsy family of retrotransposons is also present at the -320 bp position. Nevertheless, its presence does not affect the expression of the SC10-RNase in mature pistils. Additionally, we determined that the SC10-RNase promoter undergoes different DNA methylation states during pistil development, being the mCHH methylation context the most frequent close to the transcription start site at pistil maturity. We hypothesized that the Gypsy element at the SC10-RNase promoter might contribute to the DNA methylation remodeling on the three sequence contexts analyzed here. We propose that mCHH methylation enrichment and other regulatory elements in the S-RNase coding region regulate the specific and abundant SC10-RNase expression in mature pistils in N. alata.

The effect of mindfulness-based stress reduction on rejection sensitivity and resilience in patients with thalassemia: a randomized controlled trial.

BACKGROUND: Thalassemia is a genetic and chronic congenital disorder composed of physical problems that severely impair patients' cognitive, psychological and social processes. The rehabilitation of patients is particularly important because they have a high rejection sensitivity and low resilience. The present study aimed to determine the effects of mindfulness-based stress reduction counseling on rejection sensitivity and resilience in patients with thalassemia referring to a dedicated disease center in Kerman, Iran. MATERIALS AND METHODS: We conducted this randomized controlled trial study on 66 patients with thalassemia referring to the Kerman Thalassemia Center in Kerman, Iran in 2022. Using convenience sampling and the stratified block randomization method, we divided the samples into two intervention (N = 33) and control (N = 33) groups. Patients in the intervention group received eight 60-min online mindfulness-based stress reduction counseling sessions (one session per week) and completed the Rejection Sensitivity Questionnaire, Adult Version (A-RSQ) and the Conner-Davidson Resilience Scale before and after the intervention. We collected data using the SPSS 25 trial and descriptive statistics (frequency, percentage, mean and standard deviation), Chi-Square test, Independent-samples t-test, Fisher's exact test, and Analysis of covariance. A significance level of 0.05 was considered. RESULTS: We found no significant difference in the mean scores of rejection sensitivity between the intervention (8.75 ± 4.86) and control groups (9.87 ± 5.16) before the intervention. Mean scores for rejection sensitivity were 10.23 ± 4.94 in the control group and 7.11 ± 4.13 in the intervention group after the intervention, the results of analysis of covariance showed that, there was a significant difference between two groups after the intervention (F = 7.52, p = 0.008). The mean resilience score in the control group was 63.69 ± 19.43, while it was 67.72 ± 17.98 in the intervention group before the intervention and there is no significant difference between them, but the mean resilience scores in the control and intervention groups were 58.06 ± 22.81 and 74.18 ± 17.46 after the intervention, respectively. the results of analysis of covariance showed that, there was a significant difference between two groups after the intervention (F = 9.28, p = 0.004). CONCLUSION: Our results showed that in addition to other physical treatments, mindfulness-based stress reduction counseling was effective in reducing the patient's rejection sensitivity and increasing the resilience of patients with thalassemia.

Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection.

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.

A unified control method combined with improved TSF and LADRC for SRMs Using modified grey wolf optimization algorithm.

This paper proposes a unified control method based on an improved grey wolf optimization algorithm to improve the performance of the switched reluctance motors (SRMs) to cope with various operating conditions. Compared with the single control mode of traditional SRMs, an SRM with 12/10 poles is called a multimode switched reluctance motor, which can be used not only as a six-phase motor but also as a three-phase motor. The control method proposed is based on a 12/10 pole SRMs. In the TSRM mode, an improved torque sharing function with parameters is utilized to reduce torque ripple and widen the speed range. In the SSRM mode, the linear active disturbance rejection control (LADRC) method is used to increase the anti-interference ability of the system. For the switching modes, an improved gray wolf optimization algorithm is designed to ensure smooth switching. The global optimal solution is obtained by introducing the coyote group to avoid falling into the local optimal solution. Finally, the experimental results prove the effectiveness of the control method.

Omics-based biomarkers for diagnosis and prediction of kidney allograft rejection.

Kidney transplantation is the preferred treatment for patients with end-stage kidney disease, because it prolongs survival and improves quality of life. Allograft biopsy is the gold standard for diagnosing allograft rejection. However, it is invasive and reactive, and continuous monitoring is unrealistic. Various biomarkers for diagnosing allograft rejection have been developed over the last two decades based on omics technologies to overcome these limitations. Omics technologies are based on a holistic view of the molecules that constitute an individual. They include genomics, transcriptomics, proteomics, and metabolomics. The omics approach has dramatically accelerated biomarker discovery and enhanced our understanding of multifactorial biological processes in the field of transplantation. However, clinical application of omics-based biomarkers is limited by several issues. First, no large-scale prospective randomized controlled trial has been conducted to compare omics-based biomarkers with traditional biomarkers for rejection. Second, given the variety and complexity of injuries that a kidney allograft may experience, it is likely that no single omics approach will suffice to predict rejection or outcome. Therefore, integrated methods using multiomics technologies are needed. Herein, we introduce omics technologies and review the latest literature on omics biomarkers predictive of allograft rejection in kidney transplant recipients.

Self-incompatibility requires GPI anchor remodeling by the poppy PGAP1 ortholog HLD1.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are tethered to the outer leaflet of the plasma membrane where they function as key regulators of a plethora of biological processes in eukaryotes. Self-incompatibility (SI) plays a pivotal role regulating fertilization in higher plants through recognition and rejection of "self" pollen. Here, we used Arabidopsis thaliana lines that were engineered to be self-incompatible by expression of Papaver rhoeas SI determinants for an SI suppressor screen. We identify HLD1/AtPGAP1, an ortholog of the human GPI-inositol deacylase PGAP1, as a critical component required for the SI response. Besides a delay in flowering time, no developmental defects were observed in HLD1/AtPGAP1 knockout plants, but SI was completely abolished. We demonstrate that HLD1/AtPGAP1 functions as a GPI-inositol deacylase and that this GPI-remodeling activity is essential for SI. Using GFP-SKU5 as a representative GPI-AP, we show that the HLD1/AtPGAP1 mutation does not affect GPI-AP production and targeting but affects their cleavage and release from membranes in vivo. Our data not only implicate GPI-APs in SI, providing new directions to investigate SI mechanisms, but also identify a key functional role for GPI-AP remodeling by inositol deacylation in planta.

Influence of various shapes of alumina nanoparticle in integrated polysulfone membrane for separation of lignin from woody biomass and salt rejection.

Lignin valorization is essential in proposing an economic perspective as a raw material for valuable compounds. The bio-refineries require adequate processing to improve the high purity of lignin. Meanwhile, nanofiltration is fascinated attention to obtain high purity value-added products. The effect of alumina nanoparticles on the fabrication of mixed matrix membranes (MMM) has contributed to improvising filtration performance. However, incorporating nanoparticles is a significant issue regarding appropriate size and shape integrated into membrane for better filtration efficiency. The influence of shapes of alumina nanoparticles has been investigated into polysulfone (PSf) membranes for salt and lignin separation. The morphology of alumina was tailored with spindle, cubic, and spherical shapes synthesized at a different calcination temperature of 250, 500, 700 and 900 °C, respectively. The phase transitions were confirmed in X-ray diffraction (XRD) analysis, and the shape of the nanoparticles was observed in a high-resolution transmission electron microscope (HRTEM). The separation efficiency of membranes was tested with salt rejection using sodium sulfate, calcium chloride, potassium sulfate, and sodium chloride. The lignin was extracted from prehydrolysed sawdust, and the synthetic lignosulfonic acid sodium salt solution was separated. The higher lignin rejection of 98.6% and 97.9% were obtained for cubic shaped gamma phase alumina mixed matrix membrane. The high rejection of lignin occurred due to narrow pores channels that could resist the transfer of lignin through the membrane. The results proved that the controllable organization of PSf/alumina mixed matrix membranes could apply for lignocellulose compounds with good efficiency.

Bioactive compounds in green tea may improve transplant tolerance: A computational systems biology analysis.

BACKGROUND: Green tea (Camellia sinensis) has bioactive compounds that have been shown to possess nutritive effects on various biomolecular processes such as immunomodulation. This research explores the immunomodulatory effects of green tea in reducing transplant rejection. METHOD: The study employs computational systems biology: 1) to identify biomolecular mechanisms of immunomodulation in transplant rejection; 2) to identify the bioactive compounds of green tea and their specific effects on mechanisms of immunomodulation in transplant rejection; and, 3) to predict the quantitative effects of those bioactive compounds on immunomodulation in transplant rejection. RESULTS: Three bioactive compounds of green tea - epicatechin (EC), gallic acid (GA), and epigallocatechin gallate (EGCG), were identified for their potential effects on immunomodulation of transplant rejection. Of the three, EGCG was the only one determined to enhance anti-inflammatory activity by: 1) upregulating synthesis of HO-1 that is known to promote Treg and Th2 phenotypes associated with enabling transplant tolerance; and, 2) downregulating pro-inflammatory cytokines IL-2, IL-17, IFN-γ, TNF-α, NO, IL-6, and IL-1ß that are known to promote Th1 and Th17 phenotypes associated with transplant rejection. CONCLUSIONS: To the best of our knowledge, this study provides the first molecular mechanistic understanding the clinical nutritive value of green tea, specifically the bioactive compound EGCG, in enabling transplant tolerance.

Dual Corneal-Graft Rejection after mRNA Vaccine (BNT162b2) for COVID-19 during the First Six Months of Follow-Up: Case Report, State of the Art and Ethical Concerns.

Present mass vaccination against Coronavirus Disease-19 (COVID-19) is the most widely used health policy and the most promising approach to curb the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic globally. However, new side effects are emerging from the mass vaccination not described during the experimental stages. In the present study, we discuss a case of acute corneal graft rejection, which has occurred 25 years after transplantation and 13 days after the administration of the BNT162b2 vaccine (Comirnaty, BioNTech/Pfizer), which was followed-up for a period of six months. In this period, the corneal inflammation appeared twice but was successfully managed with topical therapy and supplementation of Vitamin D. A risk of corneal graft rejection must be included in the list of potential vaccine complications, in order to inform the transplanted patient to undergo a preliminary and a follow-up ocular examination, and eventually to include corneal graft in the list of contraindications to vaccination.

Is ABO-Incompatible Living Donor Liver Transplantation Really a Good Alternative for Pediatric Recipients?

BACKGROUND: ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been proposed to compensate for donor shortage. To date, few studies have reported detailed ABOi LDLT results in large series of pediatric patients. C4d complement deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in solid organ transplantation. METHODS: A retrospective case-control study was conducted, comparing clinical outcomes of each of 34 consecutive pediatric ABOi LDLT recipients with those of 2 non-ABOi pairs (n = 68), matched according to pre-transplant diagnostic criteria, age, and date of transplantation. In addition, we studied the C4d immunostaining pattern in 22 ABOi and in 36 non-ABOi recipients whose liver biopsy was performed within the first 4 post-transplant weeks for suspected acute rejection. RESULTS: The incidence of biliary complications was higher in ABOi recipients (p < 0.05), as were the incidence of acute humoral rejection (p < 0.01) and the incidence of retransplantation (p < 0.05). All children who required retransplantation were older than 1 year at the time of ABOi LDLT. Positive C4d immunostaining was observed in 13/22 (59%) ABOi recipients versus 3/36 (8.3%) non-ABOi recipients (p < 0.0001). CONCLUSIONS: ABOi LDLT is a feasible option for pediatric end-stage liver disease but carries increased risks for the recipient, especially for children older than 1 year, even with a specific preparation protocol. C4d immunostaining may be a hallmark of acute humoral rejection in ABOi liver transplantation.

Pollen-Pistil Interactions as Reproductive Barriers.

Pollen-pistil interactions serve as important prezygotic reproductive barriers that play a critical role in mate selection in plants. Here, we highlight recent progress toward understanding the molecular basis of pollen-pistil interactions as reproductive isolating barriers. These barriers can be active systems of pollen rejection, or they can result from a mismatch of required male and female factors. In some cases, the barriers are mechanistically linked to self-incompatibility systems, while others represent completely independent processes. Pollen-pistil reproductive barriers can act as soon as pollen is deposited on a stigma, where penetration of heterospecific pollen tubes is blocked by the stigma papillae. As pollen tubes extend, the female transmitting tissue can selectively limit growth by producing cell wall-modifying enzymes and cytotoxins that interact with the growing pollen tube. At ovules, differential pollen tube attraction and inhibition of sperm cell release can act as barriers to heterospecific pollen tubes.

The Effect of Ceramic Membranes' Structure on the Oil and Ions Removal in Pre-Treatment of the Desalter Unit Wastewater.

Salts, organic materials, and hazardous materials can be found regularly in the effluent from a desalter unit of crude oil. These materials should be separated from the wastewater. Four kinds of inexpensive and innovative ceramic microfiltration membranes (mullite, mullite-alumina (MA 50%), mullite-alumina-zeolite (MAZ 20%), and mullite-zeolite (MZ 40%)) were synthesized in this research using locally available inexpensive raw materials such as kaolin clay, natural zeolite, and alpha-alumina powders. Analyses carried out on the membranes include XRD, SEM, void fraction, the average diameter of the pores, and the ability to withstand mechanical stress. Effluent from the desalter unit was synthesized in the laboratory using the salts most present in the desalter wastewater (NaCl, MgCl2, and CaCl2) and crude oil. This synthesized wastewater was treated with prepared ceramic membranes. It was discovered that different salt concentrations (0, 5000, 25,000, 50,000, 75,000, and 100,000 mg L-1) affected the permeate flux (PF), oil rejection, and ion rejection by the membrane. Results showed that in a lower concentration of salts (5000 and 25,000 mg L-1), PF of all types of ceramic membranes was increased significantly, while in the higher concentration, PF declined due to polarization concentration and high fouling effects. Oil and ion rejection was increased slightly by increasing salt dosage in wastewater due to higher ionic strength. Monovalent (Na+) and multivalent (Ca2+ and Mg2+) ion rejection was reported about 5 to 13%, and 23 to 40% respectively. Oil rejection varied from 96.2 to 99.2%.

Ammonium ultra-selective membranes for wastewater treatment and nutrient enrichment: Interplay of surface charge and hydrophilicity on fouling propensity and ammonium rejection.

Membrane fouling and ammonium transmembrane diffusion simultaneously pose great challenges in membrane-based pre-concentration of domestic wastewater for efficient subsequent resources recovery (i.e., energy and nutrients). Herein, amine-functionalized osmotic membranes were fabricated by optimizing the grafting pathway of polyamidoamine (PAMAM) dendrimer to mitigate fouling and ammonium transmembrane diffusion. Compared to the control membrane, the PAMAM-grafted membranes with abundant primary amine groups possessed substantially increased hydrophilicity and positive charges (i.e., protonated primary amines) and thus exhibited superior anti-fouling capability and ammonium selectivity. With further increasing the PAMAM grafting ratio, the membrane exhibited a steady enhancement in ammonium selectivity and eventually achieved an ultra-high ammonium rejection of 99.4%. Nevertheless, the anti-fouling capability of such ammonium ultra-selective membrane was weakened due to the suppression of the adverse impact of excessive positive charges over the beneficial effect of increased surface hydrophilicity. This in turn leads to a drop of ammonium rejection below 90% during domestic wastewater concentration. This study demonstrates that the membrane with a moderate primary amine loading could achieve the highest anti-fouling capability with only less than 10% flux decline and meanwhile maintain an excellent ammonium rejection above 94% during raw domestic wastewater concentration. This work provides theoretical guidance for fabricating simultaneously enhanced anti-fouling and ammonia-rejecting membranes.

A closed-loop self-righting controller for seated balance in the coronal and diagonal planes following spinal cord injury.

Spinal cord injury (SCI) often results in loss of the ability to keep the trunk erect and stable while seated. Functional neuromuscular stimulation (FNS) can cause muscles paralyzed by SCI to contract and assist with trunk stability. We have extended the results of a previously reported threshold-based controller for restoring upright posture using FNS in the sagittal plane to more challenging displacements of the trunk in the coronal plane. The system was applied to five individuals with mid-thoracic or higher SCI, and in all cases the control system successfully restored upright sitting. The potential of the control system to maintain posture in forward-sideways (diagonal) directions was also tested in three of the subjects. In all cases, the controller successfully restored posture to erect. Clinically, these results imply that a simple, threshold based control scheme can restore upright sitting from forward, lateral or diagonal leaning without a chest strap; and that removal of barriers to upper extremity interaction with the surrounding environment could potentially allow objects to be more readily retrieved from around the wheelchair. Technical performance of the system was assessed in terms of three variables: response time, recovery time and percent maximum deviation from erect. Overall response and recovery times varied widely among subjects in the coronal plane (415±213 ms and 1381±883 ms, respectively) and in the diagonal planes (530±230 ms and 1800±820 ms, respectively). Average response time was significantly lower (p < 0.05) than the recovery time in all cases. The percent maximum deviation from erect was of the order of 40% or less for 9 out of 10 cases in the coronal plane and 5 out of 6 cases in diagonal directions.

Nutrition Support in Liver Transplantation and Postoperative Recovery: The Effects of Vitamin D Level and Vitamin D Supplementation in Liver Transplantation.

Vitamin D plays an important role in the arena of liver transplantation. In addition to affecting skeletal health significantly, it also clinically exerts immune-modulatory properties. Vitamin D deficiency is one of the nutritional issues in the perioperative period of liver transplantation (LT). Although vitamin D deficiency is known to contribute to higher incidences of acute cellular rejection (ACR) and graft failure in other solid organ transplantation, such as kidneys and lungs, its role in LT is not well understood. The aim of this study was to investigate the clinical implication of vitamin D deficiency in LT. LT outcomes were reviewed in a retrospective cohort of 528 recipients during 2014-2019. In the pre-transplant period, 55% of patients were vitamin-D-deficient. The serum vitamin D level was correlated with the model for end-stage liver disease (MELD-Na) score. Vitamin D deficiency in the post-transplant period was associated with lower survival after LT, and the post-transplant supplementation of vitamin D was associated with a lower risk of ACR. The optimal vitamin D status and vitamin D supplementation in the post-transplant period may prolong survival and reduce ACR incidence.

Association between 25(OH) vitamin D and graft survival in renal transplanted children.

BACKGROUND: In children, vitamin D deficiency is common after renal transplantation. Besides promoting bone and muscle development, vitamin D has immunomodulatory effects, which could protect kidney allografts. The purpose of this study was to assess the association between vitamin D status and the occurrence of renal rejection. METHODS: We studied a retrospective cohort of 123 children, who were transplanted at a single institution between September 2008 and April 2019. Patients did not receive vitamin D supplementation systematically. In addition, factors influencing vitamin D status were analyzed using univariate and multivariate analyses. RESULTS: Median 25-hydroxy-vitamin D (25-OH-D) concentration was close to reference values at the time of transplantation (30 ng/mL (min-max 5-100)), but rapidly decreased within the first 3 months to 19 ng/mL (min-max 3-91) (P < .001). The overall acute rejection rate was 7%. The clinical rejection rate (5% vs 9%), subclinical rejection (12% vs 36%), and borderline changes (21% vs 28%) were not statistically different during the follow-up between the 3-month 25-OH-D < 20 ng/mL and 3-month 25-OH-D > 20 ng/mL groups. There was a correlation between the 25-OH-D levels and PTH concentration at 3 months (r = -.2491, P = .01), but no correlation between the 3-month 25-OH-D and the season of the year (F = 0.19, P = .90; F = 1.34, P = .27, respectively). Multivariate analyses revealed that age and mGFR at 3 months, were independent predictors of mGFR at 12 months. CONCLUSION: Our data show that vitamin D deficiency can develop rapidly after transplantation; vitamin D levels at 3 months are not associated with lower mGFR or a higher rejection rate at 1 year in children as opposed to adult recipients.

HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice.

Background: Previous animal experiments and clinical studies indicated the critical role of Th17 cells in lung transplant rejection. Therefore, the downregulation of Th17 cell function in lung transplant recipients is of great interest. Methods: We established an orthotopic mouse lung transplantation model to investigate the role of histone deacetylase 6-specific inhibitor (HDAC6i), Tubastatin A, in the suppression of Th17 cells and attenuation of pathologic lesions in lung allografts. Moreover, mechanism studies were conducted in vitro. Results: Tubastatin A downregulated Th17 cell function in acute lung allograft rejection, prolonged the survival of lung allografts, and attenuated acute rejection by suppressing Th17 cell accumulation. Consistently, exogenous IL-17A supplementation eliminated the protective effect of Tubastatin A. Also, hypoxia-inducible factor-1α (HIF-1α) was overexpressed in a lung transplantation mouse model. HIF-1α deficiency suppressed Th17 cell function and attenuated lung allograft rejection by downregulating retinoic acid-related orphan receptor γt (ROR γt) expression. We showed that HDAC6i downregulated HIF-1α transcriptional activity under Th17-skewing conditions in vitro and promoted HIF-1α protein degradation in lung allografts. HDAC6i did not affect the suppression of HIF-1α-/- naïve CD4+ T cell differentiation into Th17 cell and attenuation of acute lung allograft rejection in HIF-1α-deficient recipient mice. Conclusion: These findings suggest that Tubastatin A downregulates Th17 cell function and suppresses acute lung allograft rejection, at least partially, via the HIF-1α/ RORγt pathway.

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

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(H2d) to B6(H2b) 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.