Immune-Modulating Effects of Low-Carbohydrate Ketogenic Foods in Healthy Canines.

Background: Ketogenic foods limit digestible carbohydrates but contain high fat, and have antioxidant and anti-inflammatory effects as well as improving mitochondrial function. ß-Hydroxybutyrate (BHB), 1 of the ketone bodies, reduces the proinflammatory NLR family pyrin domain containing 3 inflammasomes, as well as chemokines in cultures. Objectives: We assessed the immune-modulating effects of 2 low-carbohydrate (LoCHO) foods varying in protein and fat and compared their effects with a food replete with high-carbohydrate (HiCHO) in healthy canines. Methods: Dogs were fed control food [HiCHO; ketogenic ratio (KR: 0.46) followed by LoCHO_PROT (KR: 0.97), then LoCHO_FAT (KR: 1.63) or LoCHO_FAT followed by LoCHO_PROT. Each food was fed for 5 wk, with collections in the 5th wk; 15 wk feeding total. Gene expression for circulating inflammatory cytokines from 10 dogs was assessed using the Canine RT2 Profiler polymerase chain reaction array, and fold changes were calculated using the ΔΔCt method. Results: LoCHO_FAT significantly increased circulating ß-hydroxybutyrate compared with both HiCHO and LoCHO_PROT. When compared with HiCHO, there was a significant decrease in several proinflammatory cytokines/chemokines in LoCHO_PROT and LoCHO_FAT groups, including chemokine (C-C motif) ligand (CCL)1, CCL8, CCL13, CCL17, CCL24, chemokine (C-X3-C motif) ligand 1, chemokine (C-X-C motif) receptor 1, Interleukin-10 receptor alpha ((IL)-10RA), IL-1 receptor antagonist, IL-5, and secreted phosphoprotein 1 (all P < 0.05). Interestingly, a subset of inflammatory proteins that decreased in LoCHO_PROT but not in LoCHO_FAT included IL-33, IL-6 receptor, IL-7, IL-8, Nicotinamide phosphoribosyltransferase, and tumor necrosis factor (TNF) receptor superfamily member 11B. In contrast, the decrease in inflammatory markers in LoCHO_FAT, but not in LoCHO_PROT, included complement component 5, granulocyte colony-stimulating factor or G-CSF, interferon-γ, IL-3, IL-10RB, IL-17C, Tumor necrosis factor superfamily (TNFSF)13, TNFSF13B, and TNFSF14. Decreased concentrations of selected cytokines indicate that both low-carbohydrate foods exert an anti-inflammatory effect and provide a strong rationale for testing their efficacy in dogs with inflammatory conditions. Conclusions: Both LoCHO_PROT and LoCHO_FAT foods might be important as part of immune-modulating therapeutic nutritional strategies to reduce inflammation to maintain health in canines. Our study identifies several inflammatory genes that are reduced when fed ketogenic food that were not previously reported.

Betaine and L-Carnitine Synergistically Influence the Metabolome and Immune Response in Dogs.

This study used thirty-two dogs, which were assigned to a preferred period of 14 days and then assigned to one of the four treatment foods: control (containing no added betaine, no added L-carnitine), control with 0.5% added betaine (Treatment 2), control with no added betaine and 300 ppm added L-carnitine (Treatment 3), or control with 0.5% added betaine and 300 ppm added L-carnitine (Treatment 4). All treatment foods were fed for ninety days. Untargeted blood metabolomic analysis and immune response were measured at the beginning and end of the 90-day feeding trial. Feeding betaine increased single-carbon metabolites while decreasing many carnitine-containing metabolites. Feeding L-carnitine increased many carnitine metabolites, while the combination synergistically influenced the metabolome. The combination of betaine and L-carnitine increased the cytokines released in a Tru-culture system in response to stimulation while numerically decreasing their release when unstimulated. Therefore, the combination of dietary betaine and L-carnitine could have the dual positive effects of reducing cytokine stimulation, controlling inflammation during health, and providing a robust response to bacterial infection.

Metabolomic changes in cats with renal disease and calcium oxalate uroliths.

INTRODUCTION: There is a significant incidence of cats with renal disease (RD) and calcium oxalate (CaOx) kidney uroliths in domesticated cats. Foods which aid in the management of these diseases may be enhanced through understanding the underlying metabolomic changes. OBJECTIVE: Assess the metabolomic profile with a view to identifying metabolomic targets which could aid in the management of renal disease and CaOx uroliths. METHOD: This is a retrospective investigation of 42 cats: 19 healthy kidney controls, 11 with RD, and 12 that formed CaOx nephroliths. Cats were evaluated as adults (2 through 7 years) and at the end of life for plasma metabolomics, body composition, and markers of renal dysfunction. Kidney sections were assessed by Pizzolato stain at the end of life for detection of CaOx crystals. CaOx stone presence was also assessed by analysis of stones removed from the kidney at the end of life. RESULTS: There were 791 metabolites identified with 91 having significant (p < 0.05, q < 0.1) changes between groups. Many changes in metabolite concentrations could be explained by the loss of renal function being most acute in the cats with RD while the cats with CaOx stones were intermediate between control and RD (e.g., urea, creatinine, pseudouridine, dimethylarginines). However, the concentrations of some metabolites differentiated RD from CaOx stone forming cats. These were either increased in the RD cats (e.g., cystathionine, dodecanedioate, 3-(3-amino-3-carboxypropyl) uridine, 5-methyl-2'-deoxycytidine) or comparatively increased in the CaOx stone forming cats (phenylpyruvate, 4-hydroxyphenylpyruvate, alpha-ketobutyrate, retinal). CONCLUSIONS: The metabolomic changes show specific metabolites which respond generally to both renal diseases while the metabolomic profile still differentiates cats with RD and cats with CaOx uroliths.

The Increase in Circulating Levels of Pro-Inflammatory Chemokines, Cytokines, and Complement C5 in Canines with Impaired Kidney Function.

Chronic low-grade inflammation is a key contributor to the progression of kidney disease. The release of cytokines and other pro-inflammatory proteins may further contribute to detrimental kidney health by increasing interstitial edema and renal fibrosis. The aim of the present study was to investigate the inflammatory markers in canines who developed renal disease naturally and were diagnosed with renal disease either during life or following necropsy, as assessed by a veterinarian. RNA was isolated from canine blood obtained at necropsy and stored as bioarchived samples from ten canines with renal disease (9.6−14.7 yr) and ten controls (10.1−14.8 yr). At the time of death, the mean blood creatinine concentration and BUN were elevated in dogs with renal disease compared to control (both p < 0.01). Samples were assessed for changes in gene expression using the Canine cytokine RT2 Profiler PCR Array for inflammation. There was a significant increase in C-C Motif Chemokine Ligand 16 (CCL16), C-X-C Motif Chemokine Ligand 5 (CXCL5), Interleukin 16 (IL-16), and Complement Component 5 (C5) (all p < 0.05 vs. con). In addition, there was also a statistically non-significant increase in 49 genes and a down-regulation in 35 genes from a panel of total 84 genes. Pro-inflammatory genes including CCL16, CXCL5, IL-16, and C5 can all contribute to renal inflammation and fibrosis through different signaling pathways and may lead to a progressive impairment of kidney function. Blockade of their activation may be important in ameliorating the initiation and/or the progression of renal disease.