Gut microbiota‐derived nicotinamide mononucleotide alleviates acute pancreatitis by activating pancreatic SIRT3 signalling

Abstract

Background and Purpose: Gut microbiota dysbiosis induced by acute pancreatitis (AP) exacerbates pancreatic injury and systemic inflammatory responses. The alleviation of gut microbiota dysbiosis through faecal microbiota transplantation (FMT) is considered a potential strategy to reduce tissue damage and inflammation in many clinical disorders. Here, we aim to investigate the effect of gut microbiota and microbiota-derived metabolites on AP and further clarify the mechanisms associated with pancreatic damage and inflammation. Experimental Approach: AP rat and mouse models were established by administration of caerulein or sodium taurocholate in vivo. Pancreatic acinar cells were exposed to caerulein and lipopolysaccharide in vitro to simulate AP. Key Results: Normobiotic FMT alleviated AP-induced gut microbiota dysbiosis and ameliorated the severity of AP, including mitochondrial dysfunction, oxidative damage and inflammation. Normobiotic FMT induced higher levels of NAD + (nicotinamide adenine dinucleotide)-associated metabolites, particularly nicotinamide mononucleotide (NMN). NMN administration mitigated AP-mediated mitochondrial dysfunction, oxidative damage and inflammation by increasing pancreatic NAD + levels. Similarly, overexpression of the NAD + -dependent mitochondrial deacetylase sirtuin 3 (SIRT3) alleviated the severity of AP. Furthermore, SIRT3 deacetylated peroxiredoxin 5 (PRDX5) and enhanced PRDX5 protein expression, thereby promoting its antioxidant and anti-inflammatory activities in AP. Importantly, normobiotic FMTmediated NMN metabolism induced SIRT3-PRDX5 pathway activation during AP. Conclusion and Implications: Gut microbiota-derived NMN alleviates the severity of AP by activating the SIRT3-PRDX5 pathway. Normobiotic FMT could be served as a potential strategy for AP treatment.

Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

“…Contrastingly, normal gut microbiota variation produces NMN, enhancing pancreatic NAD + biosynthesis and mitochondrial deacetylase SIRT3 activity. Thus, gut microbiota-derived NMN protects against acute pancreatitis [ 120 ]. These results suggest that the gut microbiota, the gut microbiota-derived NMN, and the intestinal NAMPT–NAD + –SIRT axis collaborate to regulate intestinal homeostasis and systemic metabolic functions (Figure.…”

“…These findings suggest that the uptake of orally administered NAD + precursors requires microflora. Consistently, normal gut microbiota variation is required to produce NMN, enhancing NAD + biosynthesis in remote organs [ 120 ]. Therefore, the Slc12a8 NMN transporter and microbiota in the small intestine might work synergistically to regulate intestinal and whole-body NAD + biosynthesis.…”

“… Vicious cycles of metabolic disorders by disrupting intestinal AMPK–NAMPT–NAD–SIRT1–gut microbiota–Wnt signaling–GLP-1 axis [ 98 , 101 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. NMN—nicotinamide mononucleotide; NR—nicotinamide riboside; Wnt—wingless-related integration site; GLP-1—glucagon-like peptide-1.…”

The role of gut microbiota in acute pancreatitis: new perspectives in pathogenesis and therapeutic approaches

“…[30] In turn, several gut bacterial metabolites including hydrogen sulfide, indole-3-acetic acid, and lipopolysaccharides may contribute to mitochondrial dysfunction and ROS production, whereas beneficial microbiota-derived NMN could reduce mitochondrial oxidative injury via promoting the activation of mitochondrial deacetylase SIRT3. [10] Therefore, regulating microbial metabolites may represent a promising strategy to protect AP-mediated oxidative damage.…”

“…[7] Recent studies have demonstrated the shift in the proportion of commensal and pathogenic microbiota during pancreatitis, [8] however, it is still uncertain whether the change of gut microbiota is a driving force in AP, or merely a collateral response to inflammatory states. Meanwhile, intestinal microbiota-associated metabolites such as short chain fatty acids (SCFAs) [9] and nicotinamide mononucleotide (NMN) [10] present the promising avenue for drug or dietary intervention tactics in AP treatment. [11] In this review, we will provide an overview of recent progress in comprehending the correlation between gut microbiota and the pathogenesis of AP, and speculate potential therapeutic strategies (Fig.…”