Dietary Oxalate Loading Impacts Monocyte Metabolism and Inflammatory Signaling in Humans

Abstract

Diet has been associated with several metabolic diseases and may impact immunity. Increased consumption of meals with high oxalate content may stimulate urinary calcium oxalate (CaOx) crystals, which are precursors to CaOx kidney stones. We previously reported that CaOx stone formers have decreased monocyte cellular bioenergetics compared to healthy participants and oxalate reduces monocyte metabolism and redox status in vitro. The purpose of this study was to investigate whether dietary oxalate loading impacts monocyte cellular bioenergetics, mitochondrial complex activity, and inflammatory signaling in humans. Healthy participants (n = 40; 31.1 ± 1.3 years) with a BMI of 24.9 ± 0.6 kg/m2 consumed a controlled low oxalate diet for 3 days before drinking a blended preparation of fruits and vegetables containing a large amount of oxalate. Blood and urine were collected before (pre-oxalate) and for 5 h after the oxalate load to assess urinary oxalate levels, monocyte cellular bioenergetics and mitochondrial complex activity, and plasma cytokine/chemokine levels. Urinary oxalate levels significantly increased in post-oxalate samples compared to pre-oxalate samples. Monocyte cellular bioenergetics, mitochondrial complex I activity, and plasma cytokine and chemokine levels were altered to varying degrees within the study cohort. We demonstrate for the first time that dietary oxalate loading may impact monocyte metabolism and immune response in a cohort of healthy adults, but these response are variable. Further studies are warranted to understand oxalate mediated mechanisms on circulating monocytes and how this potentially influences CaOx kidney stone formation.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03877276.

Oxalate Alters Cellular Bioenergetics, Redox Homeostasis, Antibacterial Response, and Immune Response in Macrophages

“…We also determined that soluble oxalate compromises cellular bioenergetics in THP-1 monocytes ( 27 ). These observations were corroborated recently in human studies where we reported that healthy adults who consumed an oxalate enriched meal had decreased monocyte cellular bioenergetics and mitochondrial complex I activity, suggesting dietary oxalate could influence monocyte function in certain individuals ( 28 ). Oxalate has been shown to cause monocytes to differentiate into pro-inflammatory macrophages rather than anti-inflammatory macrophages ( 29 ).…”

“…Macrophages were subsequently exposed to uropathogenic E. coli (MOI 1:2) for 1 hour followed by antibiotic treatment (gentamycin, 200 µg/ml) for 1 hour to remove extracellular bacteria. Cells were washed with XF media and allowed to equilibrate prior to performing the mitochondrial stress test, which consisted of sequentially exposing macrophages to oligomycin (1.5 µg/ml), FCCP (2 µM), and Antimycin A (10 µM) to determine the oxygen consumption rate (OCR) over time ( 28 ). Additionally, the glycolytic stress test (GST) was performed to assess the extracellular acidification rate (ECAR) by exposing cells to glucose (10 mM), oligomycin (1 µg/ml), and 2-deoxyglucose (50 mM).…”

Dietary oxalate to calcium ratio and incident cardiovascular events: a 10-year follow-up among an Asian population

“…The Ox-induced oxidative stress and inflammation [ 37 , 38 ] and systemic oxalosis and deposition of Ox in cardiovascular tissues [ 39 , 40 ] have been suggested as mechanisms that may connect oxalemia and hyperoxaluria with CVD events. A rich-Ox diet impacts monocyte cellular bioenergetics, mitochondrial complex activity, and inflammatory signaling in humans [ 41 ]. At cellular levels, exposure to high-Ox concentrations reduces glutathione levels, increases reactive oxygen species (ROS) generation, induces mitochondrial permeability transition mediated cell death, and MCP-1 secretion [ 4 – 7 ], events may lead to the development of vascular dysfunction.…”

Role of Impaired Oxalate Homeostasis in Cardiovascular Disease in Patients With End-Stage Renal Disease: An Opinion Article

“…Nevertheless, despite a homogeneous patient population and a standardized dialysis regimen, the intraindividual predialysis POx concentration level varies from 1.8 mg/L (20 µmol/L) to 5.4 mg/L (60 µmol/L) in different studies (Ermer et al, 2017;Perinpam et al, 2017;Korol et al, 2021). Considering the marginal dependence of oxalate homeostasis on its dietary intake (Mitchell et al, 2019;Kumar et al, 2021) and limited renal excretion in patients with ESRD, it remains unclear why they have significant differences in POx concentration under the same treatment conditions. We hypothesized that in patients with anuria/kidney failure, the gut plays a much more significant role in oxalate handling than in healthy participants.…”

“…On the other hand, oxidative stress and chronic inflammation, which are present in all CKD stages, with the highest levels in ESRD (Cobo et al, 2018;Vasylchenko et al, 2020), might themselves contribute to the reduced SLC26A6-mediated transcellular oxalate transport and the enhanced passive paracellular intestinal oxalate absorption (Amin et al, 2018;Bashir et al, 2019;Kumar et al, 2021). In an obese mouse model, oxidative stress and systemic/intestinal inflammation were found to reduce active intestinal oxalate secretion and increase passive intestinal oxalate absorption, eventually resulting in obesity-associated hyperoxaluria (Amin et al, 2018;Bashir et al, 2019).…”