Invited: Longitudinal Assessment of Diets with Varying Carbohydrate-to-Fat Ratios and Fiber Supplementation on Immunometabolic Markers, Liver Function, and Gut Microbiome

Background: The proportions of macronutrients and fiber in the diet influence host metabolism and the development of metabolic and fatty liver disease. Objectives: We aimed to investigate the temporal changes in metabolic and liver function markers that occur in response to diets with markedly different proportions of carbohydrates and fats, such as the ketogenic diet (KD) and a high-carbohydrate diet (HCD). We further examined whether these diets exert differential effects on immunometabolic markers under obese physiological conditions. Additionally, we evaluated whether the incorporation of prebiotic fiber modifies the metabolic effects of the KD. Methods: This study conducted longitudinal assessments of immunometabolic and liver function markers in both lean and obese C57BL/6 mice. Results: Assessments at 2, 4, 8, and 16 wks post-intervention in lean mice revealed that diets rich in fat (high fat (HFD) and KD) induced obesity and hyperglycemia compared to the baseline chow diet. KD instigated nutritional ketosis as early as two-wk post-feeding; however, it impaired metabolic and liver function starting from wk 2. Following the 16-wk intervention, we observed that the fat-rich diets (HFD and KD), but not the HCD, promoted hepatic steatosis, inflammation, and fibrosis, as assessed by ¹H-NMR, quantitative PCR, and histology, respectively. Next, we found that incorporating inulin into the KD (KD-F) partly mitigated the adverse immunometabolic effects of the KD. In the HFD-induced obesity cohort, intervention with chow, HCD and KD-F improved immunometabolic and liver function markers. The chow and HCD showed the most pronounced benefits as early as two wk following the diet switch. Microbiome analysis revealed reduced bacterial richness across all experimental diets (HCD, KD, and KD-F) compared to chow. Conclusions: Our findings demonstrate that KD affects metabolic and liver health differently in lean versus obese states. While the whole-grain-based diet and HCD were the most effective overall, the fiber-enriched KD (KD-F) outperformed the standard KD in promoting recovery from HFD-induced metabolic and hepatic dysfunctions. This suggests that incorporating fiber enhances the therapeutic potential of KD while preserving the metabolic benefits of ketogenesis.