Exploring the Potential of Oral Butyrate Supplementation in Metabolic Dysfunction-Associated Steatotic Liver Disease: Subgroup Insights from an Interventional Study.

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• Whilst improvements to hepatic steatosis were undetected following butyrate supplementation, biochemical markers of inflammation and liver function were improved.

• Individuals with a lower BMI, higher CRP and higher HbA1c are more likely to see benefits following butyrate supplementation, however these benefits may only be small.

Introduction -

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a disease associated with the occurrence of obesity, cardiovascular disease, and diabetes mellitus. Whilst the pathogenesis is still being investigated, it has been hypothesised that gut dysbiosis may be involved. Short chain fatty acids (SCFAs) such as butyrate associated with healthy gut bacteria have been shown to act on the liver, reducing the production of lipids and decreasing hepatic steatosis. This study aimed to determine any benefits and safety of butyrate supplementation in individuals with MASLD.

Methods -

• This was a randomised control trial (RCT) of 181 individuals with MASLD and at least one of obesity, hypertension, or dyslipidaemia.

• Participants were split into 2 groups; 121 individuals received 1000mg sodium butyrate plus diet plan and 60 received 1000mg calcium butyrate plus diet plan due to the unavailability of calcium butyrate. Both groups reached statistical power.

• Study duration was 12-weeks.

• Primary endpoint was change in liver steatosis measured using the Controlled Attenuation Parameter (CAP) via FibroScan®.

• Secondary endpoints included liver stiffness, biochemical measures, hepatic steatosis and fatty liver indices, faecal calprotectin levels, stool SCFA levels, and microbiome composition.

Results –

The results showed that:

• There were no significant changes in CAP (∆CAP: sodium butyrate, 0.84; calcium butyrate, −0.23; p = 0.70).

• Sodium butyrate did improve some biochemical indicators of liver function; serum trimethylamine N-oxide (TMAO) (P=0.021) and fatty liver index (P=0.047).

• Calcium butyrate significantly improved calprotectin levels (P=0.031).

• Subgroup analysis showed that responders to butyrate were more likely to have a lower body mass index (BMI) (26.1 ± 1.7 vs 27.8 ± 1.7; P= < 0.001), higher C-reactive protein (7.7 ± 4.2 mg/L vs 4.9 ± 4.4 mg/L; P= 0.006), higher HbA1c (6.7 ± 0.4 vs. 6.4 ± 0.5, P = 0.037) and a lower abundance of the gut microbiota Subdoligranulum and higher Catenibacterium.

Conclusion –

• Neither sodium nor calcium butyrate improved liver steatosis, as measured by CAP. However, the effects on metabolic and inflammatory markers indicates that specific individuals with MASLD may benefit.

• Butyrate supplementation may not directly affect liver steatosis, but it may be of benefit to liver function and inflammation.

• Individuals with a lower BMI, inflammation, and higher HbA1c are likely to see the greatest benefits.

• 12-weeks may be an insufficient study duration for effects to be seen on liver steatosis. Given that biochemical markers of liver function were improved, longer durations are warranted.

• CAP may be insufficient to detect small hepatic changes and more sensitive imaging may be required.