Nearly one in three adults worldwide develop metabolic dysfunction–associated steatotic liver disease (MASLD), making it one of the most common and most rapidly growing chronic health problems. Frustratingly for both healthcare providers and patients, the only recommended treatment plan is a familiar refrain: eat better and exercise more. Although lifestyle changes improve liver condition for some, diet and exercise do not seem to have the same impact for others, for reasons that are not clear to scientists.
A new treatment aims to level the playing field by taking advantage of the gut-liver axis, a connection between the liver and the host of bacteria that live in the digestive tract. Researchers at the University of Eastern Finland used genetically engineered bacteria to manufacture medications inside the gut, boosting the effect of diet in mice with MASLD. Their findings have been published in the Journal of Agricultural and Food Chemistry.
“The results are promising and offer new hope for a widespread disease that currently has no approved medical treatment,” says co-author Carlos Gómez Gallego, a food scientist at the University of Eastern Finland in Kuopio.
How the gut sends signals to the liver
When fat builds up in the liver – a condition called steatosis – it can trigger inflammation, cause internal scarring and eventually lead to liver failure if not treated.
Today, we understand that “lifestyle factors, such as a Western diet and a sedentary lifestyle, are the main contributors.” This led to renaming non-alcoholic fatty liver disease as MASLD.
But scientists have also found that steatosis is affected by things like genetics, hormones, and an unhealthy gut microbiome – a condition known as dysbiosis, where good and bad bacteria fall out of balance.
The gut and liver are directly linked by a major blood vessel – the hepatic portal vein – which carries not just nutrients but also bacterial and chemical signals between the two organs. “The hepatic portal vein carries nutrients from the gut to the liver, but the gut microbiota metabolites are swept along too,” co-author Johnson Lok from the University of Eastern Finland explains. Basically, the liver is always affected by what is inside the gut.”
Planting bacteria inside the gut could be an ideal way to deliver therapy to the liver. In a collaborative project called BestTreat, researchers at the University of Eastern Finland teamed up with Ruben Vazquez-Uribe and Morten Sommer at the Technical University of Denmark – two microbiologists who study ways to manipulate microbes to improve human health as part of the Novo Nordisk Foundation Center for Biosustainability. And Congjia Chen, a bioinformatician and food scientist at the University of Hong Kong, helped integrate the complex microbial and metabolic signals to reveal how the engineered bacteria influenced the gut-liver axis.
These researchers from Technical University of Denmark offered a menu of genetically engineered strains of Escherichia coli, a species of bacteria commonly found in the human gut. In addition to their normal bacterial business (such as helping us digest food and producing vitamin K), E. coli can act like tiny living factories – genetically reprogrammed to make helpful medicines right inside your gut. Scientists call this approach “advanced microbiome therapeutics, and this is a step beyond the probiotics you might find at the grocery store or the pharmacy, which contain naturally occurring bacteria,” Johnson Lok says.
How hormone-making bacteria helped mice recover
The researchers investigated two strains that produce hormones called aldafermin and insulin-like growth factor 1 – both of which seem to be low among people with MASLD. Previous studies have also indicated that these hormones might help to improve MASLD symptoms when delivered as a traditional injection, Johnson Lok adds.
“These hormones are normally injected with a needle once or twice a day, but the new bacteria-based method enables them to be taken in orally,” he says. “The advantage of using advanced microbiome therapeutics is that you can take them as a pill or, in this case, gelatin cubes, and the microbes are able to produce these hormones locally in the gut.”
To determine whether this gut-based therapy could one day work in humans, the researchers first had to test it in mice with MASLD.
For 14 weeks, the researchers fed 24 mice a decadent diet, high enough in fat and sugar that the rodents developed steatosis comparable to MASLD. Then, the mice were switched to a “standard low-fat diet” for seven weeks – but some mice received an extra boost.
“Every day, we gave six mice this little gelatin cube that contains our bacteria,” Johnson Lok says, adding that the mice seemed to enjoy the gelatin cubes, which had artificial sweetener and vanilla flavouring.
The rest of the mice were sorted into three control groups: one that received no gelatin cubes at all, one that ate gelatin cubes without bacteria and another that was served gelatin cubes with a different strain of E. coli that does not produce hormones.
At the end of the diet period, the researchers assessed the mice’s liver health through magnetic resonance imaging and dissection, also analysing the content of their gut and faeces.
Modified microbes boosted liver health in mice
First, the faecal samples confirmed that the bacteria had survived the trip through the mice’s digestive tract. But did they affect the liver steatosis and overall health?
The diet was a mixed bag for mice that had not received the advanced microbiome therapy, the researchers found. Some of these mice lost weight and their liver condition improved, whereas others still had a lot of fat in the liver. “It means that the dietary intervention alone is not strong enough,” explains Johnson Lok.
In contrast, the mice that had received advanced microbiome therapy along with their improved diet had much more reliable results – they lost more body weight and ended up with less fat in their livers, the researchers found. Under the microscope, “their livers are very clean – you can see that there are not a lot of these little red droplets of fat,” Johnson Lok notes.
“Mice that received the engineered bacteria along with diet changes showed more reliable improvements, suggesting that the treatment helps where diet alone may not be enough,” Johnson Lok says. No luck for those of us hoping a delicious squishy treat would do the trick – the mice served just the gelatin cube or gelatin cubes with normal E. coli did not receive the same boost.
What’s next for gut-based treatments?
Do not look for advanced microbiome therapy in your local pharmacy just yet – the researchers say that years of testing will be necessary before it is approved for human use.
“Even if we find that this treatment is useful, it does not replace the normal, recommended therapy – adopting a more healthy diet,” Johnson Lok says. While researchers suspect that manipulating the microbiome alone is likely insufficient to overcome the impact of a poor diet, Johnson Lok has another study in progress examining the effects of advanced microbiome therapy without changing the diet.
For aldafermin and insulin-like growth factor 1, exploring whether they affect men and women differently will be important. Only male mice were used in this study because estrogen appears to protect against MASLD, meaning that the results in female mice might differ. (After menopause, women have rates of MASLD comparable to men. But before menopause, women are significantly less likely than men to develop MASLD.)
“Addressing these sex differences in the future is really important,” Carlos Gómez Gallego explains. “Patients deserve an approach that is able to mitigate this disease more effectively.”
