Ketogenic foods (KF) limit digestible carbohydrate but contain high fat, and have antioxidant and anti‐inflammatory effects as well as improving mitochondrial function. Beta hydroxybutyrate (BHB), one of the ketone bodies, has been reported to reduce pro‐inflammatory NLRP3 inflammasome, as well chemokines including CXCL2 and CCL5 in cultures. We assessed the immune‐modulating effects of two low carbohydrate (LoCHO) foods varying in protein and fat, and compared their effects to a food replete with carbohydrate (CON) in healthy canines. This study was approved by IACUC and the Animal Welfare Committee, Hills PNC. Macronutrients (P/F/C; % energy) for the foods were: CON (23/34/35), LoCHO1 (53/39/8) and LoCHO2 (27/67/5). We previously reported that LoCHO2 significantly increased circulating BHB compared to both CON and LoCHO1 although LoCHO1 did not increase BHB above that found when dogs consumed CON food. In the present study, dogs were fed control food (CON; ketogenic ratio (KR 0.46) followed by LoCHO1 (KR: 0.97), then LoCHO2 (KR: 1.63) or LoCHO2 followed by LoCHO1. Each food was fed for 5 weeks, with collections in the 5th week; 15 weeks feeding total. Gene expression for inflammatory cytokines and receptors from whole blood collected in PAXgene RNA tubes from 10 dogs was assessed using Canine RT2 Profiler PCR array. When compared to CON there was a significant decrease in several pro‐inflammatory cytokines/chemokines in both LoCHO1 and LoCHO2 groups including CCL1, CCL8, CCL13, CCL17,CCL24, CX3CL1, CXCR1, IL‐10RA, IL‐17A, IL‐1RN, IL‐5, IL‐9, and SPP1 (all p<0.05). Interestingly, a subset of inflammatory proteins that decreased in LoCHO1, but not in LoCHO2, included IL‐33, IL‐6R, Il‐7, IL‐8, NAMPT, and TNFRSF11B. In contrast, the decrease in inflammatory markers in LoCHO2, but not in LoCHO1, included C5, CSF3, IFN‐γ, IL‐3, IL‐10RB, IL‐17C, TNFSF13, TNFSF13B, and TNFSF14. Decreased levels of selected cytokines indicate the ability of both low‐carbohydrate foods to exert an anti‐inflammatory effect and provide a strong rationale for testing its efficacy in dogs with inflammatory conditions. For instance, cytokines including IL‐7 and IL‐8 are increased in chronic inflammatory conditions such as colitis, dermatitis, as well as in autoimmune conditions. Increased IL‐33 is also associated with chronic lesional skin of atopic dermatitis in canines and these conditions might benefit from LoCHO1 food. LoCHO2 food decreased complement component 5 (C5) and blockade of C5 attenuates renal dysfunction including glomerulopathy. LoCHO2 also decreased TNFSF13, a member of the tumor necrosis factor superfamily, highly expressed in tumors, and associated with poor prognosis, indicating its potential as a nutritional intervention strategy for cancer. Taken together, our results indicate that both LoCHO1 and LoCHO2 foods might be important as part of immune‐modulating therapeutic nutritional strategies to reduce inflammation or inflammatory pathways to maintain health in canines.
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