Short‐term reduction of dietary gluten improves metabolic‐dysfunction associated steatotic liver disease: A randomised, controlled proof‐of‐concept study

Summary Background The current management of metabolic dysfunction‐associated steatotic liver disease (MASLD) relies on lifestyle intervention. Prior studies have shown that nutritional wheat amylase trypsin inhibitors (ATI) activate toll‐like receptor 4 on intestinal myeloid cells to enhance intestinal and extra‐intestinal inflammation, including the promotion of murine MASLD, insulin resistance and liver fibrosis. Aims We aimed to assess the impact of ATI (gluten)‐free diet in liver as well as metabolic parameters of biopsy‐proven MASLD patients. Methods We performed a 6‐week, proof‐of‐concept 1:1 randomised controlled trial of an ATI‐free diet. The controls followed a balanced diet recommended by the German Nutrition Society. We assessed changes in controlled attenuation parameter (CAP), body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA‐IR). Patient‐reported outcomes were assessed by the CLDQ‐NASH questionnaire. Forty‐five patients were consecutively enrolled (21 in the intervention arm and 24 in the control arm). Results Three patients from each arm discontinued the study. In the ATI‐free diet group, a significant decrease in BMI ( p = 0.018), CAP ( p = 0.018) and HOMA‐IR ( p = 0.042) was observed at 6 weeks. The mean difference in CAP between the two arms at week 6 was 30.5 dB/m ( p = 0.039), with a delta significantly higher in the ATI‐free diet group ( p = 0.043). Only an ATI‐free diet could achieve a significant improvement in CLDQ‐NASH domains ( p value for total scoring: 0.013). Conclusions A short‐term ATI‐free diet leads to significant improvements in liver and metabolic parameters, as well as patient‐reported outcomes with good tolerability. A larger follow‐up study is justified to corroborate these findings. Clinical trial number: NCT04066400.