Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: role of melatonin and lipid peroxidation

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide with universally accepted treatments still lacking. Oral supplementation of sodium butyrate (SoB) has been suggested to attenuate liver damage of various aetiologies. Our study aimed to further delineate mechanisms involved in the SoB-dependent hepatic protection using a mouse model of fructose-induced NAFLD and in in vitro models. C57BL/6J mice were either pair-fed a fructose-enriched liquid diet ±0·6 g/kg body weight per d SoB or standard chow for 6 weeks. Markers of liver damage, intestinal barrier function, glucose metabolism, toll-like receptor-4 (TLR-4) and melatonin signalling were determined in mice. Differentiated human carcinoma colon-2 (Caco-2) and J774A.1 cells were used to determine molecular mechanisms involved in the effects of SoB. Despite having no effects on markers of intestinal barrier function and glucose metabolism or body weight gain, SoB supplementation significantly attenuated fructose-induced hepatic TAG accumulation and inflammation. The protective effects of SoB were associated with significantly lower expression of markers of the TLR-4-dependent signalling cascade, concentrations of inducible nitric oxide synthase (iNOS) protein and 4-hydroxynonenal protein adducts in liver. Treatment with SoB increased melatonin levels and expression of enzymes involved in melatonin synthesis in duodenal tissue and Caco-2 cells. Moreover, treatment with melatonin significantly attenuated lipopolysaccharide-induced expression of iNOS and nitrate levels in J774A.1 cells. Taken together, our results indicated that the protective effects of SoB on the development of fructose-induced NAFLD in mice are associated with an increased duodenal melatonin synthesis and attenuation of iNOS induction in liver.

Impact of Melatonin on Skeletal Muscle and Exercise

“…The authors hypothesized that melatonin might act as a local Zeitgeber in the gut. Moreover, there is evidence that butyrate supplementation stimulated melatonin secretion in the duodenal tissue and in human colon carcinoma Caco 2 cells [225].…”

Melatonin: Roles in influenza, Covid‐19, and other viral infections

“…17 It seems not unlikey that butyrate therefore acts on the mitochondrial melatonergic pathway to increase melatonin production, as suggested by its induction of the melatonergic pathway in intestinal epithelial cells. 49 Dysregulating the gut microbiome and decreasing gut-derived butyrate may therefore be another mechanism whereby viruses can act to modulate mitochondrial and immune cell function. Butyrate is also a histone deacetylase (HDAC) inhibitor, thereby allowing it have epigenetic regulatory effects that are relevant to viral infections.…”

“…As the alterations in butyrate and LPS can impact mitochondrial function and immune system responses, including from changes in the regulation of immune cell mitochondria, such changes in gut processes provide another focus for viral interactions with wider body systems.Gut dysbiosis and increased gut permeability are intimately linked. Butyrate acts to maintain the gut barrier, at least in part via an increase in the melatonergic pathway in intestinal epithelial cells 49. …”

The role of the microbiome in NAFLD and NASH

“…Zhou et al (2017a) reported that FMT attenuated high-fat diet-induced NASH in mice via beneficial regulation of gut microbiota. The administration of butyrate, a SCFA, effectively ameliorates lipid accumulation and liver inflammation in animal NAFLD models, through modulation of gut microbiota and gut barrier function (Zhou et al, 2017b), attenuation of inducible nitric oxide synthase (iNOS) induction (Jin et al, 2016), and suppression of inflammatory pathways (Sun et al, 2018). The effect of FMT on NAFLD/NASH is just beginning to be investigated and requires more animal and human clinical studies.…”

“…Pharmaceuticals targeting bile acid dysregulation in NAFLD, including FXR agonists, PPARa agonists, ursodeoxycholic acid (UDCA), and its derivatives, have entered different phases of clinical trials, and some of them have shown promising therapeutic effects (Yu et al, 2018). The administration of butyrate, a SCFA, effectively ameliorates lipid accumulation and liver inflammation in animal NAFLD models, through modulation of gut microbiota and gut barrier function (Zhou et al, 2017b), attenuation of inducible nitric oxide synthase (iNOS) induction (Jin et al, 2016), and suppression of inflammatory pathways (Sun et al, 2018).…”