Hans Knöll Institute

Resistant starch is a nondigestible fiber that ferments in the large intestine, and consumption of it has previously been shown to have a positive effect on metabolism in animal studies. Now, a 4-month randomized controlled trial in people with non-alcoholic fatty liver disease (NAFLD) indicates that daily intake of resistant starch can alter gut bacteria composition and lower liver triglycerides and liver enzymes associated with liver injury and inflammation. Resistant starch is a nondigestible fiber that ferments in the large intestine, and consumption of it has previously been shown to have a positive effect on metabolism in animal studies. Now, a 4-month randomized controlled trial in people with non-alcoholic fatty liver disease (NAFLD) indicates that daily intake of resistant starch can alter gut bacteria composition and lower liver triglycerides and liver enzymes associated with liver injury and inflammation. This research appears in the journal Cell Metabolism on September 5. NAFLD, caused by a buildup of fat in the liver, affects about 30% of the population worldwide. It can lead to severe liver diseases and contribute to other conditions, such as type 2 diabetes and cardiovascular disease. Currently, there is no approved medicine available to treat NAFLD. Doctors usually recommend dietary changes and exercise to alleviate the conditions. "We think it would be very meaningful if we can find an effective approach, maybe through identifying new therapeutic targets, to manage NAFLD," says Huating Li, the paper's co-corresponding author at Shanghai Sixth People's Hospital. Previous research has suggested that NAFLD is associated with perturbed gut microbiota. For example, people with early-stage NAFLD already have an altered gut bacteria profile. So, Li and her team wanted to investigate if resistant starch -- a type of fiber known to encourage the growth of beneficial gut bacteria -- can help treat NAFLD. The team recruited 200 NAFLD patients and provided them with a balanced dietary plan designed by a nutritionist. Among them, 100 patients also received a resistant starch powder derived from maize while the other 100 received calorie-matched non-resistant corn starch as a control. They were instructed to drink 20 grams of the starch mixed with 300 mL water (1 ¼ cups) before meals twice a day for 4 months. After the 4-month experiment, participants who received the resistant starch treatment had nearly 40% lower liver triglyceride levels compared to patients in the control group. In addition, patients who had the resistant starch treatment also saw reductions in liver enzymes and inflammatory factors associated with NAFLD. Importantly, these benefits were still apparent even when statistically adjusted for weight loss. "Our study shows resistant starch's impact in improving patients' liver conditions is independent of body weight changes," says Yueqiong Ni, the paper's co-first author at Shanghai Sixth People's Hospital and Leibniz Institute for Natural Product Research and Infection Biology -- Hans-Knöll-Institute (HKI) in Germany. By analyzing patients' fecal samples, the team found the resistant starch group had a different microbiota composition and functionality compared with the control. In particular, the treatment-group patients had a lower level of Bacteroides stercoris, a key bacterial species that can affect fat metabolism in the liver through its metabolites. The reduction in B. stercoris is stronglylinked to the decrease in liver triglyceride content, liver enzymes, and metabolites observed. When the team transplanted fecal microbiota from resistant starch-treatment patients to mice fed with a high-fat high-cholesterol diet, the mice saw a significant reduction in liver weight and liver triglyceride levels and improved liver tissue grading compared with mice that received microbiota from the control group. "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," Li says.

Researchers have developed a novel approach to treating eating disorders. The scientists showed that a group of nerve cells in the hypothalamus (so-called AgRP, agouti-related peptide neurons) control the release of endogenous lysophospholipids, which in turn control the excitability of nerve cells in the cerebral cortex, which stimulates food intake. A group of researchers has developed an entirely novel approach to treating eating disorders. The scientists showed that a group of nerve cells in the hypothalamus (so-called AgRP, agouti-related peptide neurons) control the release of endogenous lysophospholipids, which in turn control the excitability of nerve cells in the cerebral cortex, which stimulates food intake. In this process, the crucial step of the signalling pathway is controlled by the enzyme autotaxin, which is responsible for the production of lysophosphatidic acid (LPA) in the brain as a modulator of network activity. The administration of autotaxin inhibitors can thereby significantly reduce both excessive food intake after fasting and obesity in animal models. The article 'AgRP neurons control food intake behaviour at cortical synapses via peripherally-derived lysophospholipids' has now appeared in Nature Metabolism. Eating disorders and especially obesity are one of the most common causes of a variety of diseases in industrialized societies worldwide, especially cardiovascular diseases with permanent disabilities or fatal outcomes such as heart attacks, diabetes, or strokes. The Robert Koch Institute reported in 2021 that 67 per cent of men and 53 percent of women in Germany are overweight. 23 per cent of adults are severely overweight (obese). Attempts to influence eating behaviour with medication have so far proved ineffective. A novel therapy that modulates the excitability of networks that control eating behaviour would be a decisive step towards controlling this widespread obesity. The research team found an increased rate of obesity and the attendant type II diabetes in people with impaired synaptic LPA signalling. A group led by Professor Johannes Vogt (Faculty of Medicine, University of Cologne), Professor Robert Nitsch (Faculty of Medicine, University of Münster) und Professor Thomas Horvath (Yale School of Medicine, New Haven, USA) has now shown that control of the excitability of neurons in the cerebral cortex by LPA plays an essential role in the control of eating behaviour: AgRP neurons regulate the amount of lysophosphatidylcholine (LPC) in the blood. Through active transport, LPC reaches the brain, where it is converted by the enzyme autotaxin (ATX) into LPA, which is active at the synapse. Synaptic LPA signals stimulate specific networks in the brain, thus leading to increased food intake. In the mouse model, after a period of fasting an increase in LPC in the blood led to an increase in stimulating LPA in the brain. These mice showed typical food-seeking behaviour. Both could be normalized by administrating autotaxin inhibitors. Obese mice, on the other hand, lost weight when these inhibitors were administered continuously. Johannes Vogt explained: 'We saw a significant reduction in excessive food intake and obesity through gene mutation and pharmacological inhibition of ATX. Our fundamental findings on the LPA-controlled excitability of the brain, which we have worked on for years, therefore also play a central role for eating behaviour.' Robert Nitsch sees the findings as an important step towards new drug development: 'The data show that people with a disturbed synaptic LPA signalling pathway are more likely to be overweight and suffer from type II diabetes. This is a strong indication of a possible therapeutic success of ATX inhibitors, which we are currently developing together with the Hans Knöll Institute in Jena for use in humans.' These findings on the excitation control of neuronal networks in eating behaviour through lysophospholipids and the new therapeutic possibilities they suggest could in future contribute not only to treating eating disorders, but also neurological and psychiatric illnesses.