PTH-095 Oral carbon therapy is associated with a selective modulation of the microbiome in cirrhotic rats which is associated with a significant reduction in inflammatory activation

Introduction

The host-microbiome interaction is pathological in cirrhosis promoting a dysregulated inflammatory response resulting in organ injury and diminished survival. Yaq-001 is an oral non-absorpable carbon shown to result in improvement in hepatic haemodynamics and markers of liver injury but the mechanism of how this is achieved in unknown. The aims of this study were to determine whether the beneficial effects of Yaq-001 was related to the composition and associated functional state of the microbiome in bile-duct ligated cirrhotic animals.

Method

BDL (n = 12) or sham (n = 12) rats were randomised to treatment with Yaq-001 (Yaqrit Ltd. UK) from weeks 2–4. Analysis of urine samples was performed using ¹NMRs. Bacterial DNA from stool was extracted, amplified and sequenced. Arterial plasma was co-incubated with HEK-Blue hTLR4 and IL-1β/IL-18 reporter cell lines. Constitutive ROS and LPS-induced ROS production from circulating monocyte populations was determined using flow cytometry.

Results

BDL was associated with a significant reduction in Peptidostreptococcaceae and Clostridium XI (p < 0.05) in stool compared to sham controls. Carbon therapy was associated with significant increases in firmicutes, in particular clostridia populations in stool with significant reductions in bacteroides populations (p < 0.05). Functionally, BDL rats were found to have significantly higher urinary bile acids, Trimethylamine N-oxide, benzoate, glycine, acetate and lactate than sham controls (p < 0.05). Significantly lower levels of citrate, dimethylamine (DMA) and creatinine were observed in BDL compared to sham animals (p < 0.05). Carbon treatment results in a significant increase in urinary creatinineand bile acids and reduction in urinary glycine (p < 0.05). A significant increase in IL18/IL1B expression was observed in untreated BDL rats compared to sham which was significantly attenuated with carbon treatment (p < 0.05). Monocyte LPS-induced ROS production was significantly higher in BDL rats but attenuated with carbon treatment (p < 0.05).

Conclusion

The results of this study show that Yaq-001, which is a non-specific adsorbent has substantial effects on the composition and function of the microbiome in cirrhotic rats and positively modulates the function of monocytes regarding ROS production and inflammasome activation. These data provide compelling evidence that the gut bacterial products are important in mediating immune dysfunction in cirrhosis and is a target of therapy.

Disclosure of interest

None Declared.