scholarly journals Gut Microbiome-Derived Uremic Toxin Levels in Hemodialysis Patients on Different Phosphate Binder Therapies

2021 ◽  
pp. 1-10
Author(s):  
Lin-Chun Wang ◽  
Leticia M. Tapia ◽  
Xia Tao ◽  
Joshua E. Chao ◽  
Ohnmar Thwin ◽  
...  
Keyword(s):  
Liver Function ◽  
Gut Microbiome ◽  
Phosphate Binder ◽  
Serum Levels ◽  
Colonic Transit ◽  
Serum Phosphorus ◽  
Phosphate Binders ◽  
Uremic Toxin ◽  
Sevelamer Carbonate ◽  
Patient Reported

<b><i>Introduction:</i></b> Constipation is prevalent in patients with kidney failure partly due to the use of medication, such as phosphate binders. We hypothesized that serum levels of gut microbiome-derived uremic toxins (UTOX) may be affected by the choice of phosphate binder putatively through its impact on colonic transit time. We investigated two commonly prescribed phosphate binders, sevelamer carbonate (SEV) and sucroferric oxyhydroxide (SFO), and their association with gut microbiome-derived UTOX levels in hemodialysis (HD) patients. <b><i>Methods:</i></b> Weekly blood samples were collected from 16 anuric HD participants during the 5-week observational period. All participants were on active phosphate binder monotherapy with either SFO or SEV for at least 4 weeks prior to enrollment. Eight UTOX (7 gut microbiome-derived) and tryptophan were quantified using liquid chromatography-mass spectrometry. Serum phosphorus, nutritional, and liver function markers were also measured. For each substance, weekly individual levels, the median concentration per participant, and differences between SFO and SEV groups were reported. Patient-reported bowel movements, by the Bristol Stool Scale (BSS), and pill usage were assessed weekly. <b><i>Results:</i></b> The SEV group reported a 3.3-fold higher frequency of BSS stool types 1 and 2 (more likely constipated, <i>p</i> &#x3c; 0.05), whereas the SFO group reported a 1.5-fold higher frequency of BSS stool types 5–7 (more likely loose stool and diarrhea, not significant). Participants in the SFO group showed a trend toward better adherence to phosphate binder therapy (SFO: 87.6% vs. SEV: 66.6%, not significant). UTOX, serum phosphorus, nutritional and liver function markers, and tryptophan were not different between the two groups. <b><i>Conclusion:</i></b> There was no difference in the gut microbiome-derived UTOX levels between phosphate binders (SFO vs. SEV), despite SFO therapy resulting in fewer constipated participants. This pilot study may inform study design of future clinical trials and highlights the importance of including factors beyond bowel habits and their association with UTOX levels.

P0272COMPARATIVE GUT MICROBIOME DIFFERENCES BETWEEN FERRIC CITRATE AND CALCIUM CARBONATE PHOSPHATE BINDER TREATMENT IN HEMODIALYSIS PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Ping-Hsun Wu ◽  
Yi-Ting Lin ◽  
Po-Yu Liu ◽  
Mei-Chuan Kuo ◽  
Yi wen Chiu
Keyword(s):  
Calcium Carbonate ◽  
Gut Microbiome ◽  
Phosphate Binder ◽  
Hemodialysis Patients ◽  
Ferric Citrate ◽  
Phosphate Binders ◽  
Uremic Toxin ◽  
Phosphate Binding ◽  
Microbial Composition ◽  
Linear Discriminant

Abstract Background and Aims Gut microbiome alteration increases uremic toxin levels inducing chronic inflammation and leading morbidity and mortality in patients with chronic kidney disease. Phosphate-binding agents may potentially change the composition of the gut microbiota. However, the limited clinical study investigates the microbiome difference between iron-containing and calcium-containing phosphate binders. The aim of this study was to compare the microbiota composition in hemodialysis patients treated with ferric citrate or calcium carbonate. Method The stool microbiota was investigated in hemodialysis patients with ferric citrate used (n=8) and calcium carbonate used (n=46) by 16S rRNA next-generation gene sequencing profiling. The altered microbiota between two different phosphate binders was analyzed. Differences in the microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Results Hemodialysis patients with calcium carbonate used revealed significantly reduced microbial species diversity (Shannon index and Simpson index) and increased microbial dysbiosis index compared with ferric citrate users. Compared to patients taking calcium carbonate, a distinct microbial community structure in patients taking ferric citrate, with an increased abundance of Bacteroidetes phylum and decreased abundance of phylum Firmicutes. In comparison between two phosphate binder users, members of the order Lactobacillales were prominent in calcium carbonate therapy, including family Streptococcaceae and genus Streptococcus. In contrast, taxa of the genus Ruminococcaceae, Flavonifractor, and Cronobacter were enriched in ferric citrate phosphate binder users. Conclusion The fecal microbiota was richer and more diverse in the ferric citrate group than in the calcium carbonate group. Hemodialysis patients with ferric citrate used were associated with differences in the gut microbiome composition compared to calcium carbonate users.

P1411THE EFFICACY AND SAFETY OF THE SUCROFFERRIC OXYHYDXIDE IN HEMODIALYSIS PATIENTS : RESULTS OF A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Evgeny Shutov ◽  
Galina Kotlyarova ◽  
Ksenia Lysenko ◽  
Galina Ryabinskaya ◽  
Sergey Lashutin
Keyword(s):  
Randomized Controlled Trial ◽  
Phosphate Binder ◽  
Controlled Trial ◽  
Transferrin Saturation ◽  
Serum Phosphate ◽  
Phosphate Binders ◽  
Randomized Controlled ◽  
Prospective Randomized Controlled Trial ◽  
Sevelamer Carbonate ◽  
Fgf 23

Abstract Background and Aims The treatment of hyperphosphatemia is the main goal in the treatment of mineral and bone disorders in patients with CKD. However, the results of the correction of hyperphosphatemia remain unsatisfactory. This is due to the absence of effective and safe medicines. In our prospective randomized controlled trial were evaluated the effects of a 16-week treatment with new phosphate binder - sucroferric oxyhydroxide and a sevelamer carbonate (“sevelamer”) on CKD-MBD parameters in patients on hemodialysis with hyperphosphatemia. Method After a 2-4-week washout period from previous phosphate binders, 50 stable patients with hyperphosphatemia (P &gt; 5.5 mg / dl) were randomized at a 1: 1 ratio to receive sucroferric oxyhydroxide (n = 25) or sevelamer (n = 25) for treatment up to 16 weeks. In all patients were evaluated levels of P, Ca, PTH, ferritin, transferrin saturation, Hb, FGF-23, soluble Klotho, CRP - monthly. The dose of both medications was adjusted according to serum phosphate. Results Phosphate binder therapy of sucroferric oxyhydroxide was associated with a significant decrease in serum phosphate from 6.8 ± 1.5 to 5.27 ± 0.99 mg/dl (p &lt;0.01); however, treatment with sevelamer did not decrease in the level of P: 6.32 ± 1.5 vs 6.35 ± 1.9 mgl/dl. The number of tablets was lower in the sucroferric oxyhydroxide group (mean ± SD 2.0 ± 1.5 tablets / day) compared with sevelamer (mean ± SD 6.1 ± 3.2 tablets / day). The average intact fibroblast growth factor-23 (FGF-23), PTH, transferrin saturation and ferritin did not significantly change in both groups. Klotho changed only in patients received sucroferric oxyhydroxide, an increase of 25% (р &lt; 0.05) and we also noted in this group an increase in Hb level from 105.6 ± 15.7 to 111.9 ± 22.3 g/l (p &lt;0.05) by the end of the study, simultaneously level of CRP significantly decreased (P &lt; 0.01) by 50% . During the study, 6 patients in the group with sucroferric oxyhydroxide and 5 in the sevelamer group dropped out due to dyspeptic symptoms. Conclusion Sucroferric oxyhydroxide is a new effective phosphate binder with a comparable safety profile to a sevelamer. Treatment with this drug can significantly increase the level of Hb, and Klotho and reduce level of inflammation.

MO1034PHOSPHATE EQUIVALENT (PEQ) EDUCATION SYSTEM: AN EFFICIENT SELF-ADJUSTMENT PHOSPHATE BINDER DOSAGE TOOL IN DIALYSIS PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Dimitris Xydakis ◽  
Ergini Antonaki ◽  
Antonia Papadaki ◽  
Konstantinos Kostakis ◽  
Michail Tzanakakis ◽  
...  
Keyword(s):  
Education System ◽  
Phosphate Binder ◽  
Serum Phosphate ◽  
Serum Phosphorus ◽  
Fixed Dose ◽  
Phosphate Binders ◽  
Serum Phosphate Level ◽  
Intervention Period ◽  
Dialysis Patients ◽  
Dialysis Unit

Abstract Background and Aims Hyperphosphatemia is common in end-stage renal disease (ESRD) because of impaired renal phosphate excretion and is treated by dietary measures, dialysis techniques and the use of phosphate binder medication. It is one of the most important cardiovascular risk factors for dialysis patients. Our goal was to involve dialysis patients in the achievement of phosphate targets by self-adjusting the dose of Phosphate Binders (PB) on a meal-to-meal basis, according to the individual dietary P intake Method We conducted an interventional prospective single-arm study with a pre-post design. The inclusion criteria were patients with ESRD who had been receiving dialysis for more than three months, with dialysis schedule for four hours per session, three times per week, and who were older than 18 years of age. The primary endpoints of the study were the number of patients who reached the goal of serum phosphate before and after the training program and the weekly mean serum phosphate levels evaluated after the intervention period and compare them with the pre-intervention baseline levels. The secondary end-point was the burden of PB daily. All patients were trained in a self-administer PB program. A self-adjusted PB dose card was developed based on the phosphate food content list published by the National Technical University of Athens. The aim was to allow patients to immediately calculate the iP content of any food they consume easily. Phosphate Equivalent (PEQ) was defined as the weight of phosphorus having the same phosphate impact as a given weight of food. One PEQ corresponded in 100 mg of inorganic phosphorous and to one tablet of PB (one tablet of 800 mg of sevelamer). After 4 weeks (weeks 1-4) of washout from previous phosphate binders, eligible patients with serum phosphorus concentrations ≥ 6 mg/dl were included in the study. All patients received standard dietary phosphate counseling and a fixed dosing regimen of sevelamer PB was prescribed according to KDIGO and dialysis unit protocols for eight weeks (weeks 5-12 – pre-intervention period) In the 13th week, patients were asked to practice the self-administer PB program for eight more weeks. Results A total of 97 patients were screened for the study. 21 patients were excluded. 74 patients completed the study. The percentage of patients with uncontrolled phosphate levels reduced from 56.76% (42 out of 74) to 36.48 % (27 out of 74) in the post-intervention period. Of 9 patients who initially had a serum phosphorus level ≥9 mg/dl, 8 were reverted to phosphorus levels &lt; 6 mg/dl at the end of the PEQ intervention period. There was a significant reduction of phosphate levels (prePEQ 7.42 ± 1.43 mg/dl vs. postPEQ 5.59 ± 1.82 mg/dL, p=0.036) and Ca × P levels (prePEQ: 67.1 ± 11.5 mg2/dL2; postPEQ: 51.9 ± 13.4 mg2/dL2, p=0.021) after patient education. There was a non-significant increase on serum calcium (pre PEQ: 8.13 ± 1.18 mg/dL; post PEQ: 8.56 ± 0.83mg/dL, p=0.515) and iPTH (prePEQ: 411 ± 376 pg/mL; postPEQ: 381 ± 321 pg/mL,p=0.13) Conclusion Our work shows that providing the patients with a relatively simple tool about the use of phosphate binders as PEQ is, we had a positive effect on the dialysis patients’ knowledge about the use of PB, phosphate content of their meals, and increase their sense of the necessity of the treatment and it was proved more effective than the standard fixed dose method. Using the PEQ education system was rewarding in an additional 20% of the patients with previous uncontrolled hyperphosphatemia. The PEQ education system is an efficient self-adjustment phosphate binder dosage tool in dialysis patients in reducing the serum phosphate level in our hemodialysis patients.

scholarly journals Sevelamer Carbonate Crystal-Induced Colitis

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
T. Lai ◽  
A. Frugoli ◽  
B. Barrows ◽  
M. Salehpour
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Phosphate Binder ◽  
Recurrent Abdominal Pain ◽  
Case Vignette ◽  
Phosphate Binders ◽  
Sodium Polystyrene Sulfonate ◽  
Sevelamer Carbonate ◽  
Stage Renal Disease ◽  
End Stage

Hyperphosphatemia is a common and well-described complication of end-stage renal disease. Despite strict dietary constraints and compliance, phosphate binders such as calcium acetate and/or sevelamer carbonate are also needed to treat secondary hyperparathyroidism. This case vignette describes an underrecognized adverse effect of a phosphate binder, sevelamer carbonate, inducing colitis in a 47-year-old male with insulin-dependent diabetes complicated by end-stage renal disease. He presented for recurrent abdominal pain with associated nausea and was found to have multiple circumferential lesions on computed tomography including distal ascending, transverse, and proximal descending colon. Colonoscopy demonstrated nearly obstructing lesions worrisome for colonic ischemia or inflammatory bowel disease. Pathological review of histology demonstrated ragged colonic mucosa with ulcerative debris and nonpolarizing crystalline material at the sites of ulceration, morphologically consistent with the phosphate binder, sevelamer carbonate. Sevelamer carbonate was discontinued, and the patient was transitioned to calcium carbonate with strict dietary restrictions. His symptoms improved with the cessation of sevelamer, and he was subsequently discharged home. He eventually underwent renal transplant without redevelopment of symptoms. Recognition of this underreported complication of sevelamer carbonate, phosphate binder, is of utmost importance in directing appropriate therapy with cessation of this medication in the setting of gastrointestinal complaints or more specifically enteritis and colitis. Clinicians providing care to end-stage renal patients taking either sevelamer and/or sodium polystyrene sulfonate should have increased awareness of the possible gastrointestinal side effects.

scholarly journals Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Olivier Phan ◽  
Marc Maillard ◽  
Hartmut H. Malluche ◽  
Jean-Christophe Stehle ◽  
Felix Funk ◽  
...  
Keyword(s):  
Phosphate Binder ◽  
Chronic Renal Disease ◽  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Chronic Kidney Failure ◽  
Lanthanum Carbonate ◽  
Phosphate Binders ◽  
Vascular Calcifications ◽  
Serum Ipth ◽  
Sevelamer Carbonate

Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed.

scholarly journals Comparative Gut Microbiome Differences between Ferric Citrate and Calcium Carbonate Phosphate Binders in Patients with End-Stage Kidney Disease

2020 ◽  
Vol 8 (12) ◽  
pp. 2040
Author(s):  
Ping-Hsun Wu ◽  
Po-Yu Liu ◽  
Yi-Wen Chiu ◽  
Wei-Chun Hung ◽  
Yi-Ting Lin ◽  
...  
Keyword(s):  
Calcium Carbonate ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Phosphate Binder ◽  
Hemodialysis Patients ◽  
Ferric Citrate ◽  
Phosphate Binders ◽  
Rrna Gene ◽  
Phosphate Binding ◽  
Linear Discriminant

Gut dysbiosis in patients with chronic kidney disease (CKD) may induce chronic inflammation and increase morbidity. Phosphate-binding agents, generally used in patients with CKD, may potentially change the composition of the gut microbiota. This study aimed to compare the microbiota composition in hemodialysis patients treated with ferric citrate or calcium carbonate. The stool microbiota was investigated in hemodialysis patients treated with ferric citrate (n = 8) and calcium carbonate (n = 46) using 16S rRNA gene amplicon sequencing profiling using linear discriminant analysis of effect size. Further predictive functional profiling of microbial communities was obtained with Tax4Fun in R. Hemodialysis patients treated with calcium carbonate had a significantly reduced microbial species diversity (Shannon index and Simpson index) and an increased microbial alteration ratio compared with patients treated with ferric citrate. A distinct microbial community structure was found in patients treated with ferric citrate, with an increased abundance of the Bacteroidetes phylum and a decreased abundance of the phylum Firmicutes. Members of the order Lactobacillales were enriched in patients treated with calcium carbonate, whereas taxa of the genera Ruminococcaceae UCG-004, Flavonifractor, and Cronobacter were enriched in patients treated with ferric citrate phosphate binder. In conclusion, Ferric citrate therapy results in a more diverse microbiome community compared to calcium carbonate therapy in hemodialysis patients with phosphate binder treatment. The gut microbiome reflects the phosphate binder choice in hemodialysis patients, further affecting the physiological environment in the gastrointestinal tract.

scholarly journals Clinical and pharmacoeconomic profile of lanthanum carbonate treatment of hyperphosphataemia in chronic renal dialysis patients

2010 ◽  
Vol 11 (1) ◽  
pp. 13-26
Author(s):  
Mario Eandi
Keyword(s):  
Calcium Carbonate ◽  
Phosphate Binder ◽  
Cost Effective ◽  
Lanthanum Carbonate ◽  
The Body ◽  
Serum Phosphorus ◽  
Recent Analysis ◽  
Phosphate Binders ◽  
Phosphate Binding ◽  
Metastatic Calcification

Hyperphosphatemia is recognized as a principal mineral disorder in chronic kidney disease (CKD) that leads to the development of secondary hyperparathyroidism. Approximately 70% of patients with end-stage renal disease (ESRD) and dialysis have hyperphosphataemia, which is associated with renal osteodystrophy, metastatic calcification and increased mortality and morbidity. Despite dietary restriction and dialysis, most patients will require a phosphate-binding agent to treat this condition.Lanthanum carbonate is an new, potent, selective, no-resin, non-calcium phosphate binder that retains high affinity for phosphate over a wide pH range, does not bind bile acids or contribute to metabolic acidosis. Taken with food, it is well tolerated. It is poorly absorbed and does not require functioning kidneys to be removed from the body. There is no evidence from current studies that it accumulates to biologically significant levels in tissues. Lanthanum carbonate has been shown in clinical studies of up to 6 years to be an effective, well-tolerated phosphate binder. Lanthanum carbonate controls hyperphosphataemia without increasing calcium intake above guideline targets and has the potential to reduce pill burden and increase patient compliance compared with other phosphate binders. Reported adverse effects are mainly gastrointestinal, and do not differ from those of calcium carbonate. The new phosphate binders, lanthanum carbonate and sevelamer, have increased the possibilities for serum phosphate control, at the expenses of significant increases in costs. The cost-effectiveness of lanthanum carbonate has been assessed by three different studies. A recent analysis, conducted on the perspective of the UK NHS, shows it is cost-effective to follow current treatment guidelines and treat all patients who are not adequately maintained on calcium carbonate (serum phosphorus above 5.6 mg/dl) with second-line lanthanum carbonate. This is particularly the case for patients with serum phosphorus above 6.6 mg/dl. A retrospective analysis, performed on IHCSI data base (USA), and a prospective study conducted in Spain show that lanthanum carbonate is cost-effective as compared with sevelamer, requiring less number of tablets, a fact that might improve adherence, and that probably explains better results with lower costs.

scholarly journals Implementation and effectiveness of an intensive education program on phosphate control among hemodialysis patients: a non-randomized, single-arm, single-center trial

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jinmei Yin ◽  
Jun Yin ◽  
Rongli Lian ◽  
Peiqiu Li ◽  
Jing Zheng
Keyword(s):  
Education Program ◽  
Hemodialysis Patients ◽  
Serum Phosphorus ◽  
Phosphate Binders ◽  
Maintenance Hemodialysis ◽  
Single Center ◽  
Clinical Trial Registry ◽  
Before And After ◽  
Intensive Education ◽  
Phosphate Control

Abstract Background Hyperphosphatemia is a common complication in patients on maintenance hemodialysis. Patients’ adherence to phosphorus control can be improved by consistent education. However, few studies have focused on the model construction and effects of health education on phosphate control for hemodialysis patients. Objective To develop an intensive education program focusing on phosphate control among hemodialysis patients and to analyze the effectiveness of this program. Design A non-randomized, single-arm, single-center trial lasting for 6 months. Setting This program was conducted in a hemodialysis center in a teaching hospital in Zhuhai, China. Participants Patients on maintenance hemodialysis with hyperphosphatemia. Methods An intensive hyperphosphatemia control education program lasting for 6 months was conducted among 366 hemodialysis patients applying the First Principles of Instruction model, which focused on mastering four stages: (a) activation of prior experience, (b) demonstration of skills, (c) application of skills and (d) integration of these skills into real-world activities. The controlled percentage of serum phosphorus, knowledge of hyperphosphatemia, and adherence to phosphate binders before and after the education program were assessed. Results The proportion of controlled serum phosphorus was significantly increased from 43.5 to 54.9% (P<0.001). The scores on the knowledge of phosphate control were improved significantly from 59.0 ± 18.9 to 80.6 ± 12.4 (P < 0.001). The proportion of high adherence to phosphate binders was increased dramatically from 21.9 to 44.5% (P < 0.001). Conclusion The intensive education program can effectively improve serum phosphorus, knowledge of hyperphosphatemia, and adherence to phosphate binders among hemodialysis patients. Trial registration Chinese Clinical Trial Registry, ChiCTR2100042017. Retrospectively registered January 12th, 2021.

scholarly journals Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort

2021 ◽  
Author(s):  
Amedeo Minichino ◽  
Matthew A. Jackson ◽  
Marta Francesconi ◽  
Claire J. Steves ◽  
Cristina Menni ◽  
...  
Keyword(s):  
General Population ◽  
Microbial Diversity ◽  
Gut Microbiome ◽  
Endocannabinoid System ◽  
Alpha Diversity ◽  
Serum Levels ◽  
Population Cohort ◽  
Random Intercept ◽  
General Population Cohort ◽  
Antidepressant Use

AbstractAnhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (β = −0.37; 95%CI: −0.71 to −0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (β = −0.13; 95%CI: −0.24 to −0.01; P = 0.03), as was the total effect (β = −0.38; 95%CI: −0.72 to −0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (β = −0.25; 95%CI: −0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.

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