Year: 2026
Type: article
Abstract: The transition from energy sufficiency to deficiency triggers complex metabolic and immune adaptations that have traditionally been viewed through a pathological perspective. This review introduces the Keto-Inflammatory Network (KIN), a novel framework positioning ketosis as an evolutionarily conserved adaptive response rather than metabolic dysfunction. The KIN integrates β-hydroxybutyrate (BHB) signaling with immune modulation, epigenetic regulation, circadian rhythms, and microbiota interactions. Through mechanisms including NLRP3 inflammasome inhibition, HDAC-mediated epigenetic modifications, and HCAR2 receptor activation, ketone bodies orchestrate anti-inflammatory responses while maintaining metabolic flexibility. The framework encompasses calcium-ketone integration through the Calci-Keto-Inflammatory Code (CKOC), temporal regulation via the Ketoinflammatory Clock, and trans-kingdom signaling through microbiota interactions. In dairy cattle, this perspective reframes periparturient ketosis as potentially adaptive, supporting lactogenesis and immune tolerance during reproductive transition. The CKOC paradigm suggests therapeutic applications leveraging ketone signaling for inflammatory diseases, autoimmune conditions, and metabolic disorders while challenging traditional ketosis management strategies. This systems-level understanding opens new avenues for precision interventions that work with, rather than against, ancient adaptive mechanisms refined through evolution.
Source: Dairy
DOI: 10.3390/dairy7010019
Author: Burim N. Ametaj
Institution: University of Alberta
Language: English
Topic: Diet and metabolism studies
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,448
OpenAlex ID: W7129069503