Microbiota-Targeted Intervention Decreases IHTC in Patients With NAFLD


The clinical trial compared outcomes in patients with NAFLD on a resistant starch diet to a control group over a 4-month period, with results suggesting microbiota dietary supplements may improve liver conditions.

Huating Li | Credit: Shanghai Jiao Tong University School of Medicine

Huating Li

Credit: Shanghai Jiao Tong University School of Medicine

Findings from a recent study suggest the use of resistant starch as a microbiota-directed dietary supplement may be an effective intervention for patients with non-alcoholic fatty liver disease (NAFLD).

Investigators noted a 5.89% net absolute change of intrahepatic triglyceride content (IHTC) in the resistant starch group relative to the control group after adjusting for weight loss, corresponding to a relative change of 24.30%.1

“We are able to identify a new intervention for NAFLD, and the approach is effective, affordable and sustainable. Compared with strenuous exercise or weight loss treatment, adding resistant starch to a normal and balanced diet is much easier for people to follow through,” said Huating Li, doctoral supervisor at Shanghai Sixth People’s Hospital.2

The American College of Gastroenterology recommends weight loss, increased exercise, a balanced diet, and alcohol avoidance to treat NAFLD, citing a lack of US Food and Drug Administration approved medications for treatment.3 However, microbiota play a role in stimulating the immune system and breaking down food compounds that may help treat patients with chronic bowel disorders like NAFLD if properly supplemented.4

To evaluate the effects of resistant starch as a microbiota-targeted intervention for NAFLD, investigators conducted a 4-month dietary randomized, double-blinded, placebo-controlled clinical trial of 200 patients with NAFLD in Shanghai, China. Participants were recruited and randomized with a 1:1 allocation to the 4-month administration of resistant starch type 2 from high-amylose maize (HAM-RS2, 40 g/day) or control starch with equal energy supply, with groups balanced based on baseline anthropometric and clinical characteristics of participants.1

The primary outcome of interest was change in IHTC at the end of the 4-month intervention period. Secondary outcomes of interest included change in body weight, BMI, fat percentage, and fat mass. Investigators used comprehensive clinical measurements to evaluate changes in metabolic phenotypes of NAFLD during the intervention. Multi-omics profiling was used to assess how RS and associated alterations in the gut microbiota or metabolites contributed to NAFLD improvement, with findings validated in mice and cell lines for causal insights.1

Investigators noted there was no statistical difference between the groups for adherence to starch intake, adherence to diet, and dietary intake of energy and macronutrients except fiber during the trial. After the 4-month intervention, investigators found IHTC was significantly decreased in the resistant starch group (9.08%; 95% Confidence Interval [CI], 11.91%-6.26%) compared with the control group (39.42%; 95% CI, 56.13%-22.72%) (p < 0.0001). Participants in the resistant starch group also experienced significant reductions of body weight, BMI, fat percentage, and fat mass.1

After adjusting for weight loss, investigators found the net absolute change of IHTC in the resistant starch group relative to the control group was 5.89% (95% CI, 8.87%-2.91%), corresponding to a relative change of 24.30% (95% CI, 42.42%-6.18%) (p = 0.0001). Further regression analysis suggested the resistant starch effect was only partially mediated by weight loss (R2 = 23%).1

Investigators also noted significant reductions of liver enzymes indicative of liver injury after resistant starch intervention, including alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase. Fibroblast growth factor 21 (FGF21), a biomarker of NAFLD, was also reduced after resistant starch consumption.1

Investigators pointed out serum branched-chain amino acids (BCAAs) and gut microbial species, in particular B. stercoris, were significantly correlated with IHTC and liver enzymes, which were reduced by resistant starch. Further investigation revealed the transference of resistant starch-altered microbiota into mice alleviated NAFLD and decreased the colonic levels of BCAAs, which investigators suggest supports the causality of gut microbiota changes, BCAA availability, and hepatic steatosis.1

“Our study shows resistant starch’s impact in improving patients’ liver conditions is independent of body weight changes,” said Yueqiong Ni, of Shanghai Sixth People’s Hospital and Leibniz Institute for Natural Product Research and Infection Biology at Hans-Knöll-Institute in Germany.2


1. Ni Y, Qian L, Siliceo SL, et al. Resistant starch decreases intrahepatic triglycerides in patients with NAFLD via gut microbiome alterations. Cell Metabolism (2023). https://doi.org/10.1016/j.cmet.2023.08.002Cell Press.

2. Resistant starch supplement reduces liver triglycerides in people with fatty liver disease. EurekAlert! September 5, 2023. Accessed September 5, 2023. https://www.eurekalert.org/news-releases/1000032?3.

3. American College of Gastroenterology. Non-alcoholic Fatty Liver Disease (NAFLD) Overview. Accessed September 5, 2023. https://gi.org/topics/fatty-liver-disease-nafld/

4. Harvard T.H. Chan School of Public Health. The microbiome. The nutrition source. Accessed September 5, 2023. https://www.hsph.harvard.edu/nutritionsource/microbiome/

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