Table 3.

Studies on the efficacy of KD in SARS-CoV-2 in animal models.

	Study Design	Participants (n)/Age (year)	Evaluation	Intervention/ Measurement	Duration	Results	Bibliography
1	Random- ized clinical trial	Male C57BL mice infected with natural mouse beta coronavirus (mCoV) 6—mouse hepatitis virus strain A59 (MHV-A59) (reproducing the clinical features of COVID-19). Old mice (20–24 months) and young mice (2–6 months)	Effect of KD on the mouse defense response against MHV-A59 and identification of the underlying mechanism	Intranasal inoculation of mCoV-A59 into adult and old male mice. Feeding a standard vivarium feed (Harlan 2018s) or a ketogenic diet (Envigo, TD.190049)	5 days before infection	-protection against weight loss and hypoxemia caused by infection -improved survival of young but not old mice -significantly reduced mRNA expression of the Pro-inflammatory cytokines IL-1β, TNFα, and IL-6 in the lung, VAT, and hypothalamus -in old mice, a significant increase in cup cells, expansion of T ϒδ, and a significant decrease in subsets of proliferative cells -significant decrease in monocyte population subsets, change in monocyte compartiment, and loss of cluster with high levels of Chil3, Lmna, Il1r2, Lcn2, Cd33, and Cd24a; loss of monocyte subpopulation in cells with low interferon response -increase in T ϒδ cells, downregulation of TLR, Plk1, and aurora B signaling pathways in T ϒδ cells -in old mice, increased genes associated with reduced inflammation, increased lipoprotein remodeling -increased respiratory electron transport and complex I biogenesis in lung T ϒδ cells of old mice -reduced activation status of T ϒδ lymphocytes -decreased NLRP3 and caspase-1 mRNA in lung, visceral adipose tissue (VAT), and hypothalamus, and inflamasome activation in VAT -significantly reduced myeloid cell infiltration in the heart -BHB reduced oligomerization of ASC, which is an adaptor protein required for assembly of the inflamasome complex	Ryu et al. [42]
2	Random-ized clinical trial	Male albino rats of the Sprague strain/body weight 200–250 g	Measurements of ACE2, TMPRSS2, and RAS components and inflammatory genes in animal lungs and hearts	Chow diet (P: 27.0%, F: 13.0%, and C: 60. 0%), high-fat sucrose-enriched diet (P: 20.0%, F: 60.0%, and C:20.0%) or KD (P:20%, F: 80%, and C: 0%).	16 weeks	-reduced lung ACE2 and TMPRSS2 levels compared to a sucrose-enriched diet -KD in the lung resulted in decreased ACE1 and AT1 protein content, and a shift of the (RAS) system from the AngI/ACE1/AngII/AT1 arm towards the counter-regulatory, anti-inflammatory arm of the RAS KD induced anti-inflammatory effects—reduction of tlr4 and il6r gene expression, and a tendency to reduce tnfr1 gene expression	Eira et al. [126]
3	Random-ized clinical trial	K18-hACE2 mice aged 6–20 weeks infected intranasally with 60 PFU of SARS-CoV-2 (preclinical model of SARS-CoV-2 infection)	Assessment of T-cell metabolism and function	Supplementation with ketone ester 20 mg ml-1 (D- -hydroxybutyrate-(R)-1,3 butanediol monoester) in drinking water	8 days after infection	-decreased glucose dependence of CD4+ lymphocytes and increased the potential to oxidize amino acids and fatty acids thereby increasing their ability to produce IFNy and antiviral protection -ketone ester promoted faster recovery from weight loss and reduced lung injury, resulting in improved overall survival	Karagiannis et al. [116]

KD—ketogenic diet, P—protein, F—fat, C—carbohydrates, VAT—visceral adipose tissue, ER—endoplasmic reticulum, NLRP3—NLRP3 inflammasome, BHB—beta-hydroxybutyrate, TMPRSS2—transmembrane serine protease 2, RAS—renin-angiotensin-aldosterone system, ACE1—angiotensin-converting enzyme I protein, AT1—angiotensin receptor type 1 protein.