Ketogenesis acts as an endogenous protective programme to restrain inflammatory macrophage activation during acute pancreatitis

Zhang, Li; Shi, Juanjuan; Du, Dan; Niu, Ningning; Liu, Shiyu; Yang, Xingwu; Lü, Ping; Shen, Xuqing; Shi, Na; Yao, Linbo; Zhang, Ruling; Hu, Guoyong; Lu, Guotao; Zhu, Qingtian; Zeng, Tao; Liu, Tingting; Xia, Qing; Huang, Wei; Xue, Jing

doi:10.1016/j.ebiom.2022.103959

Cited by 38 publications

(19 citation statements)

References 67 publications

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“…While for species less abundant in NP patients, positive correlation to microbial gene functions related to restriction enzyme, protein digestion and absorption was observed, as well as negative correlation with benzoate degradation. A study observed that β-hydroxybutyrate (βOHB), a type of ketone body in circulation, was elevated in patient with non-SAP, but not in SAP ( 62 ). Then the researchers used mild or severe form of AP mice to demonstrate that βOHB weakened the pancreatic and systemic proinflammatory macrophages activation by means of class I histone deacetylases.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis

et al. 2022

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BackgroundAcute necrotizing pancreatitis (NP), a severe form of acute pancreatitis (AP), has higher mortality and worse outcome than non-necrotizing pancreatitis (non-NP). Infected NP is a devastating subgroup of NP. To date neither NP nor infected NP has robust prediction strategies, which may delay early recognition and timely intervention. Recent studies revealed correlations between disturbed gut microbiota and AP severity. Some features of intestinal microbiota have the potential to become biomarkers for NP prediction.MethodsWe performed 16S rRNA sequencing to analyze gut microbiota features in 20 healthy controls (HC), and 58 AP patients on hospital admission. The AP patients were later classified into NP and non-NP groups based on subsequent diagnostic imaging features. Random forest regression model and ROC curve were applied for NP and infected NP prediction. PIRCUSt2 was used for bacterial functional pathway prediction analysis.ResultsWe found that the three groups (HC, NP, and non-NP) had distinct microorganism composition. NP patients had reduced microbial diversity, higher abundance of Enterobacteriales, but lower abundance of Clostridiales and Bacteroidales compared with the non-NP group. Correlation analyses displayed that intestine bacterial taxonomic alterations were related to severity, ICU admission, and prognosis. By pathway prediction, species more abundant in NP patients had positive correlation with synthesis and degradation of ketone bodies, and benzoate degradation. Enterococcus faecium (ASV2) performed best in discriminating NP and non-NP patients. Finegoldia magna (ASV3) showed the maximal prediction capacity among all ASVs and had comparable accuracy with Balthazar CT to detect patients with infected NP.ConclusionsOur study suggests that NP patients have distinct intestinal microbiota on admission compared to non-NP patients. Dysbiosis of intestinal microbiota might influence NP progression through ketone body or benzoate metabolism. Enterococcus faecium and Finegoldia magna are potential predictors for NP and infected NP. Our findings explore biomarkers which may inform clinical decision-making in AP and shed light on further studies on NP pathophysiology and management.

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Section: Discussionmentioning

confidence: 99%

Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis

et al. 2022

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“…A study by Rahman et al showed that KD or βOHB induced a neuroprotective phenotype in monocytes and/or macrophages through HCA2 [ 24 ]. Zhang et al demonstrated that ketogenesis can inhibit inflammatory macrophage activation, indicating its potential therapeutic effect in acute pancreatitis [ 25 ]. In addition, the ketone body βOHB downregulates LPS-induced iNOS, COX-2, TNF-α, IL-1β, and IL-6 expression by GPR109A in murine microglial BV-2 cells [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis

Kong

Wang

et al. 2022

Arthritis Res Ther

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Background The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to be involved in the pathological process of osteoarthritis (OA) inflammation. Here, we investigated the ketogenic diet (KD), which has been previously demonstrated to inhibit NLRP3 inflammasome activation, to elucidate its protective mechanism against OA in rats. Methods Anterior cruciate ligament transaction (ACLT) together with partial medial meniscectomy was used to create a rat knee joint OA model. After treatment with KD or standard diet (SD) for 8 weeks, the knee specimens were obtained for testing. Results The KD significantly increased the content of β-hydroxybutyrate (βOHB) in rats. Compared to the SD group, the KD significantly reduced the damage caused by OA in the articular cartilage and subchondral bone. The NLRP3 inflammasome and inflammatory cytokines interleukin-1 β (IL-1β) and IL-18 were significantly increased in the SD group compared with the sham group, while their expression was significantly decreased in rats treated with the KD. In addition, MMP13 was significantly decreased in the KD group compared to that in the SD group, while COL2 was significantly increased. Conclusions KD can protect the articular cartilage and subchondral bone in a rat OA model by inhibiting NLRP3 inflammasome activation and reducing the OA inflammatory response.

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“…The protein encoded by HMGCS2 belongs to the HMG-CoA synthase family of mitochondrial enzymes that catalyze the first reaction of ketogenesis, which is a crucial alternative metabolic pathway and is involved in the regulation of the body's immune function ( 25 ). Restoration of ketogenesis enhances immune cell effects ( 26 ) and attenuates the activation of pro-inflammatory macrophages ( 27 ). The protein levels of HMGCS2 in the intestinal epithelium of UC patients were reported to be sharply decreased compared to healthy samples ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Revealing immune infiltrate characteristics and potential diagnostic value of immune-related genes in ulcerative colitis: An integrative genomic analysis

Huang

Zhang²,

Wang³

et al. 2022

Front. Public Health

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ObjectivesUlcerative colitis (UC) is an autoimmune disease of the colon. The aim of this study was to explore the characteristics of immune infiltrates in UC patients and identify immune-related diagnostic biomarkers for UC.MethodsThree gene expression profiles were acquired from the GEO database, followed by identification of differentially expressed genes (DEGs) by Linear Modeling of Microarray Data. Enrichment analysis of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Disease Ontology (DO) were performed to analyze the biological functions of DEGs. Subsequently, the single sample gene set enrichment analysis (ssGSEA) was performed to identify immune infiltration characteristics of UC. Correlations between diagnostic genes and immune infiltration were explored to identify markers with the greatest diagnostic potential, and a UC diagnostic model was subsequently constructed. Finally, the prediction performance of the model was quantified by nomogram, non-correlated nomogram, and ROC curve.ResultsA total of 3111 DEGs (1,608 up-regulated and 1,503 down-regulated genes) were identified. DEGs were significantly involved in the immune system and UC-related pathways. Immune infiltration profiles of colonic tissue were significantly different between healthy individuals and UC patients. High proportions of resting of aDCs, B cells, CD8+ T cells, DCs, iDCs, Macrophages, Neutrophils, pDCs, T helper cells, Tfh, Th1 cells, Th2 cells, TIL and Treg were found in UC samples. A 5-gene based diagnostic prediction model was constructed and the results of nomogram, non-correlated nomogram and ROC curve suggested the powerful diagnostic value of the model.ConclusionsThis study identified the immune infiltrate characteristics and 5 immune-related genes for UC. The model based on the immune-related genes facilitates the early diagnosis of UC and provides a basis for the evaluation of the prognosis of UC.

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Ketogenesis acts as an endogenous protective programme to restrain inflammatory macrophage activation during acute pancreatitis

Cited by 38 publications

References 67 publications

Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis

Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis

Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis

Revealing immune infiltrate characteristics and potential diagnostic value of immune-related genes in ulcerative colitis: An integrative genomic analysis

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