How fermented faeces could one day help in obesity treatment

When the gut microbiome becomes dangerously imbalanced – for instance, when antibiotic-resistant bacteria eat away at the lining of the colon – faecal transplants can be the last line of defence, at least for Clostridioides difficile infections for now. This unsavoury but often life-saving treatment uses material from a healthy person’s digestive tract to recolonise the person’s gut, hopefully boosting the proportion of “good” bacteria and wrangling the dangerous microbes back down to levels the body can manage.

Recent research suggests that using faecal transplants to shift the gut microbiome could also help to treat people with metabolic disorders if the animal-based results con be confirmed. Faecal transplants containing viruses (faecal virome transplant) from lean mice to obese mice seem to improve symptoms of type 2 diabetes and can even reduce weight gain.

But faecal transplants are not without risk, emphasises Torben Sølbeck Rasmussen, Assistant Professor at the Department of Food Science of the University of Copenhagen in Denmark. They also include hundreds or thousands of unidentified microbes, and any missteps in preparing the faeces can prove disastrous – in 2019, a faecal transplant recipient died after a crucial step was skipped in the screening process for dangerous bacteria.

For metabolic disorders such as obesity, the risk of using an unaltered faecal transplant is simply too high to justify. “There is a better way of reducing body weight than transplanting faeces in that manner,” Rasmussen says. To make faecal transplants safer, researchers are working to find ways to knock out as many of these unknown, wild-card microbes as possible while keeping the therapeutically active microbes alive and kicking.

A new study published in Nature Communications identifies a promising candidate – “fermenting poop,” Rasmussen says.

The active ingredient in poop

Your gut – and especially your large intestine, or colon – is home to a whole ecosystem of microbes that support digestion and influence the rest of your body, including your metabolism, in ways not fully understood.

Previous research suggests that one active ingredient in faecal transplants that has helped to treat people with metabolic disorders is bacteriophages – a type of virus that only infects bacteria and not human cells.

But untreated faeces are also brimming with eukaryotic viruses, which do attack human cells. And even the most thorough donor screening cannot identify all of them – “there will still be hundreds of viruses that could be dangerous, but we just do not know,” Rasmussen says, “like the human papillomavirus, which can lead to cervical cancer among women 5–10 years later.”

Rasmussen and his team set out to test various preparations to exclude bacteria and eukaryotic viruses in faecal transplants – while keeping the tiny bacteriophages intact. Then they assessed whether each preparation could treat a small group of mice with metabolic disorders as effectively as an unmodified faecal virome transplant.

Exploiting differences

The first tactic the researchers tried exploits how microbes structure their genomes. “Most eukaryotic viruses have RNA genomic structures, and most bacteriophages have DNA,” Rasmussen explains. The researchers used pyronin Y, a fluorescent red dye that binds to RNA, to inactivate the eukaryotic viruses by preventing them from reproducing. However, this preparation was a bust, Rasmussen says – the resulting virome transplant did not seem to improve the symptoms of diet-induced obesity in mice.

The second strategy focused on membranes. “Most eukaryotic viruses have a lipid membrane,” whereas bacteriophages are surrounded by a structure made from proteins, Rasmussen explains. “It is fairly simple, with some kind of detergent or soap, to dissolve the eukaryotic virus’s lipid membrane, and this will inactivate the virus.” This method also failed to deliver therapeutic results to the mice.

The third, and by far the most promising, option exploits a difference in how the microbes reproduce. “Just like yogurt or kombucha, you can ferment faeces,” Rasmussen says. “Sounds weird, but nevertheless.”

In large tanks, the researchers created a system to process faecal samples that simulates the environment of a mouse’s gut – but with important differences. Like in the gut, liquid was continuously drained from the tank (analogous to excretion) and added to it (analogous to ingestion). But unlike the colon, the tanks are not lined with host cells in which the eukaryotic viruses can nestle to reproduce. Bacteria and bacteriophages, in contrast, do not need the shelter of the intestinal lining to propagate themselves.

“This way we can enable the bacteria and bacteriophages to grow but dilute out the eukaryotic viruses,” Rasmussen explains.

The fermented faecal transplants showed promising results as a treatment, strongly reducing blood glucose levels in obese mice versus those that had not received the transplant. The researchers were also “quite surprised” to observe striking improvements in some mice’s liver health – some obese mice saw such dramatic decreases in fat deposits in their liver that the livers were indistinguishable from the livers of lean mice, Rasmussen says.

But what made some mice respond to the treatment while others were not as severely affected? By examining the recipient mice’s faeces, the researchers found that the gut microbiome composition of responders differed significantly from that of non-responders.

Early days but promising results

Rasmussen emphasises that the new study is preliminary – future research will be required to determine whether their findings hold up with larger sample sizes and in female mice. Nevertheless, he thinks that the results are encouraging and confirm that the faecal fermentation technique is worth exploring further. 

In fact, he says that a new study found that the fermented faecal virome was effective at treating people with another condition or disease.

However, the researchers were somewhat surprised that they did not see a hallmark of previous studies of faecal transplants and metabolic disorders – none of the transplant recipients, even those that received the unmodified faecal virome, got leaner. 

Rasmussen says that speaks to how challenging controlling the microbiome is, even in a laboratory setting – the species composition in both the donor microbiomes and the recipient microbiomes differed substantially from that in their previous study, even though the protocol was the same.

Looking ahead to the potential of fermented faecal virome transplants as a treatment, the fact that some mice were strong responders while others were not is not a non-starter. “In pharmacy, you accept that a drug will not work all the time,” Rasmussen says. “Some products work on you but not on me.”

“As long as it helps somebody, it is worth exploring,” Rasmussen says.”