Prebiotic Xylo-oligosaccharides Targeting Faecalibacterium prausnitzii Prevent High Fat Diet-induced Hepatic Steatosis in Rats

Abstract

Understanding the importance of gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat associated with low abundance of Faecalibacterium prausnitzii in humans and further, administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed to target F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD) or low (LFD) fat-diet for 12-weeks in Wistar rats (n=10/group). XOS increased F. prausnitzii growth having only minor impact on the GM composition. When supplemented with HFD, XOS prevented hepatic steatosis. The underlying mechanisms involved enhanced hepatic β-oxidation and mitochondrial respiration. 1H-NMR analysis of caecal metabolites showed that compared to HFD, LFD group had healthier caecal short-chain fatty acid profile and the combination of HFD and XOS was associated with reduced caecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Caecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, our study identifies F. prausnitzii as a possible target to treat NAFLD with XOS. The underlying preventive mechanisms involved improved hepatic oxidative metabolism.

Gut microbiota–mitochondrial inter-talk in non-alcoholic fatty liver disease

“…Short-chain fatty acids are a primary type of bacterial metabolite produced by bacterial fermentation of otherwise indigestible fibers in the colon (46). Many previous studies have illustrated the role of aberrant levels of SCFAs in NAFLD progression (39,40,(47)(48)(49)(50). SCFAs can disrupt the functioning of the intestinal barrier impairing the translocation of LPS and increasing the level of liver endotoxemia to promote the pathogenesis of NAFLD (50).…”

“…Indeed, previous studies have indicated that gut microbiota directly regulates T-cell immunity through SCFAs (52,53). Moreover, supplementation of a high fiber diet increases the levels of SCFAs, especially butyrate, to promote hepatocyte proliferation (49,54). Butyrate, nicotinate, and 2-oxoglutarate positively regulate hepatic oxidative phosphorylation and negatively regulate TG content through oxidative metabolism.…”

“…Xylo-oligosaccharides (XOS), a potential prebiotic target of F. prausnitzii, have been explored for the treatment of NAFLD induced by HFD diet (49). Lensu et al (49) showed that XOS could increase the abundance of F. prausnitzii, which controlled hepatic fat content in humans (91).…”

“…Xylo-oligosaccharides (XOS), a potential prebiotic target of F. prausnitzii, have been explored for the treatment of NAFLD induced by HFD diet (49). Lensu et al (49) showed that XOS could increase the abundance of F. prausnitzii, which controlled hepatic fat content in humans (91). Moreover, XOS reduced intestinal inflammation by reversing the effects of HFD (92), enhanced hepatic β-HAD activity and complex I levels, and promoted oxidative phosphorylation, which improved mitochondrial respiratory capacity and elevated ATP production.…”

Data_Sheet_1.pdf

“…Energy expenditure and RER were assessed with indirect calorimetry during a 24 h metabolic cage stay as described previously (Lensu et al, 2020). Briefly, the commercial metabolic cages were equipped with Promethion ® GA3 gas analyzers (Sable Systems, Las Vegas, NV, United States) and FR8 flow generators (Sable Systems) (Lensu et al, 2020). The flow rate was set at 3,000 mL/min and the raw data were processed using ExpeData ® software (Sable Systems).…”