Scientists have unveiled a new weight-loss pill that works right in the gut, all without impacting appetite or brain chemistry.
Scientists at Nanyang Technological University in Singapore have developed a novel gut-based compound that offers a fundamentally different approach to weight loss than the injectable drugs dominating the health space.
Unlike popular medications such as Ozempic and Wegovy, which work primarily by suppressing appetite and altering blood sugar regulation, the new pill acts locally within the intestines to directly reduce the amount of dietary fat that the body absorbs.
The compound blocks a receptor on intestinal cells responsible for ushering fats into the body, reducing the amount of fat that gets transferred from the gut to the liver. At the same time, it promotes the growth of beneficial gut bacteria that produce short-chain fatty acids shown to reduce inflammation and reinforce the intestinal barrier.
By focusing on the gut itself, the NTU team has created a weight management strategy that does not require patients eat less or endure the gastrointestinal slowdown, which can lead to diarrhea, constipation or stomach paralysis, associated with GLP-1 agonists, presenting an alternative drug for those who struggle with or are ineligible for existing medicines.
In a study on animal models, mice fed a high-fat diet and given the oral compound gained significantly less weight than untreated mice, all without toxic side effects or systemic exposure.
However, a major concern with GLP-1 medications is the need to remain on them indefinitely, even after achieving weight-loss goals, and it remains unclear whether this new gut-based compound requires the same lifelong commitment.
Unlike Ozempic and Wegovy, which suppress appetite and alter blood sugar, this new pill works locally in the gut, blocking dietary fat absorption directly (stock)
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Dr Andrew Tan, an expert in metabolic disorders and co-creator of the DRUG, said: ‘Our findings suggest that applying a controlled brake on fat absorption in the gut can help reduce the amount of fat reaching the liver, particularly during periods of high-fat intake or for people who are unable to exercise.’
The urgency of developing such alternatives is underscored by the scale of the obesity epidemic. With more than 40 percent of Americans fitting the obese designation, obesity has become one of the most critical public health concerns of the 21st century, fueling increases in type 2 diabetes, fatty liver disease and heart disease.
Despite widespread awareness of dietary guidelines, modern food environments high in saturated fats and refined sugars continue to drive caloric excess. Most Americans get roughly half of their calories from ultra-processed food.
The scientists built a repository of 52 different artificial compounds meant to mimic natural fats that the body already makes to determine whether their gut-based weight loss pill actually worked, as reported in the study published in the journal Pharmaceutical Research.
They then edited the compounds to make them more likely to remain intact when they come in contact with stomach acid during digestion.
They then took these candidates into the lab and tested them on human liver and colon cells. Using fluorescent dyes that glow under microscopes, they watched in real time as fat molecules tried to slip through receptors on intestinal cells.
In cells not treated with the compounds, the fat glided right in, a process that, in a living body, would result in weight gain and increased fat delivery to the liver. But in cells exposed to the best-performing compounds, the entrance was effectively blocked.
They created compounds that kept fat out of intestinal cells but still let sugar in, which ensured they would not interfere with blood sugar metabolism. They discovered three promising compounds: 12-TAASA, 12-SAASA and 12-HDTZSA. All three survived a simulated stomach environment with nearly all their structure intact.
Then the researchers tested the compounds in animals. They fed mice a high-fat, high-calorie diet designed to mimic a human diet replete with fast and ultra-processed foods. Within weeks, the rodents were obese and their livers were fatty, a condition that, in humans, drives inflammation, scarring, and can eventually progress to cirrhosis or liver cancer.
Mice on a high-fat diet (LIDPAD) treated with oral 12-TAASA or 12-HDTZSA gained significantly less weight, matching the effect of semaglutide injections (Sema)
Some of these mice received daily oral doses of the experimental compounds, WHILE others got injections of semaglutide, the active ingredient in Ozempic and Wegovy.
To track where the compounds went after swallowing, the researchers analyzed blood and stool samples. Compounds showed up in feces but were undetectable in blood plasma.
That told researchers that the pills were staying in the gut rather than circulating throughout the body.
After four weeks of daily doses, mice on a high-fat diet that received 12-TAASA gained significantly less weight than untreated mice even while eating the same food. Their livers were lighter, less fatty and showed less scarring.
On glucose tolerance tests, the pill-treated mice performed just as well as those getting semaglutide injections.
The gut microbiome also shifted. Harmful, inflammation-linked bacteria like Romboutsia receded. Beneficial strains including Blautia and Roseburia flourished. Blood levels of acetate, proponiate and butyrate, metabolites that improve the body’s response to insulin and reduce inflammation, rose significantly.
The most vivid proof came from fluorescent fat tracking. Untreated mice swallowed a glowing lipid shake concoction two hours later, which turned their portal veins and livers green. In 12-TAASA-treated mice, the signal was faint and delayed. Less fat escaped the gut and reached the liver, meaning the block on receptors worked.
In a direct comparison, daily oral doses of 12-TAASA matched twice-weekly semaglutide injections for weight loss and glucose tolerance improvement despite the new compound never leaving the gut
If these results were to hold up in humans in a later-phase trial, the impact could be significant. Most weight-loss drugs tamper with brain chemistry, suppressing appetite, slowing the rate at which the stomach empties or tinkering with hormone signals.
This approach has been proven effective but it also comes with a myriad of side effects including nausea, muscle loss and vomiting.
The experimental compound does not adjust brain chemistry and thus did not show any of these side effects in the animal trials.
For the millions of Americans contending with obesity but who would like to steer clear of needles or avoid gastrointestinal symptoms, a novel pill with an entirely new mechanism of action would be particularly appealing.
For patients with fatty liver disease, the benefits could be even more significant. Less fat reaching the liver means less fat remaining in the liver. In clinical terms, that constitutes full reversal.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), drives inflammation, scarring, and progression toward scarring in the liver itself, but it also silently amplifies risk throughout the body.
Patients with MASLD are more likely to suffer heart attacks, strokes and certain cancers, even if their liver never fails. For many people, the end result is liver failure or cancer.
The findings, while compelling, are still in mice. Human biology is very different from mouse biology, and what is produced in the lab might fail in human studies, which are on the horizon.
The NTU team partnered with a biotech firm to advance the technology to human trials for safety and efficacy. But that is a lengthy process that requires investment and regulatory approval.
Even under ideal conditions, it would likely take several years for the new pill to hit pharmacy shelves.
