Gut microbes are the key to good health. That’s pretty much the accepted mantra these days, as the evidence for their benefits grows. They have been shown to affect everything from organ function and mood to disease risk.
Balancing the community of microorganisms (including bacteria, fungi and viruses) that live in the digestive tract helps us stay healthy, while an imbalance can cause disease.
We can influence the balance through what we consume — for example, fiber, fermented foods, and probiotic supplements are believed to boost “good” gut bacteria — but it can also be done therapeutically.
For example, fecal microbiota transplantation (FMT) is used to treat Clostridioides difficile (C. diff) infection, which can cause severe diarrhea. Last year C. div. led to 14,000 hospitalizations in England alone.
While FMT rebalances gut bacteria into a healthier mix, scientists have now gone a step further and developed therapies that target gut bacteria.
Balancing the community of microorganisms (including bacteria, fungi and viruses) that live in the digestive tract helps us stay healthy, while an imbalance can cause disease
Developed primarily as a safer and more convenient alternative to FMT for C. diff infections, these therapies contain live bacteria and are currently undergoing clinical trials, several of which have recently been approved by drug regulators in the US and Australia.
Experts say these advances pave the way for a future of drugs that target our gut microbiome directly and could one day treat a range of conditions associated with our gut bacteria, including arthritis, metabolic syndrome (a combination of diabetes , hypertension and obesity), even cancer.
‘The new drug approvals are leading to a paradigm shift,’ says Dr Tanya Monaghan, clinical associate professor and honorary advisor in gastroenterology at Nottingham University. “They show that we can now advance microbiome-based therapies, which are not standard ‘drugs’ per se, through the complex medical regulatory process to reach the bedside.”
Making the treatment of intestinal infections safer
Fecal microbiota transplantation (FMT) is very effective for intestinal infections (see main story), but the transfer of potentially harmful substances has raised concerns.
So now scientists are removing bacteria from the faeces of donors without this appearing to affect the usefulness of the treatment.
‘Research shows that the bacteria-free stool transplant still appears to be effective against C. diff infection due to the virus particles (‘phages’) and other molecules in the donor samples,’ says Dr Tanya Monaghan.
“Trials are investigating the exact mechanisms in FMT and benchmarking against this new approach – fecal filtrate transplant or FFT,” she says. “These more sophisticated treatments may reduce risks and be easier to standardize because we don’t have to transplant live microbes.”
The fact that C. diff infection is targeted is not random.
‘C. diff infection is particularly difficult to treat because it is a smart bacteria,” explains Dr Mona Bajaj-Elliott, ex-chair of the British Society of Gastroenterology Gut Microbiota for Health expert panel and associate professor at University College London.
‘In its natural state in soil, it forms inactive spores and has a coating that allows it to travel through the environment and into the human body without being damaged. Once ingested, it loses its coating and germinates into its active form.”
C. diff bacteria occur naturally in a healthy gut and do not normally cause problems.
However, if the balance of the gut microbiome is disrupted, Dr Bajaj-Elliott explains: ‘C. diff can take over and produce multiple toxins that attack the intestinal lining and cause symptoms such as cramping, fever, nausea, and diarrhea.”
Taking antibiotics can upset that balance, allowing C. diff to multiply. The infection poses a particular risk to the elderly in hospitals or care homes and to people with weakened immune systems.
‘The infection is difficult to treat because C. diff spores are resistant to antibiotics,’ says Dr Bajaj-Elliott. Ethanol and other antiseptics are also ineffective at killing the C. diff spores – allowing the infection to spread quickly through hospitals, causing thousands of deaths in the UK each year.
In a relatively new approach, FMT, stool from a healthy donor, is introduced into the patient’s gastrointestinal tract. The idea is to increase the diversity in their gut microbiome and flood it with “good bacteria” that inhibit the growth of C. diff.
It can be very effective. A study, in the New England Journal of Medicine in 2013, found that after a single infusion, 81 percent of patients with C. diff no longer experienced diarrhea, compared to 31 percent of those given the antibiotic vancomycin.
FMT is now recommended by the National Institute for Health and Care Excellence for patients who have had at least two C. diff infections that have failed to respond to antibiotics.
However, there are drawbacks to FMT. The main one is a lack of standardization, says Dr. Monaghan. “We don’t know the precise microbial composition of FMT that could come from different donors, or how best to administer it,” she says — and this could affect the outcome. For example, the success rate ranges from 60 to 90 percent depending on the method of administration: enema, nasogastric tube, colonoscopy, or oral capsules.
For example, fecal microbiota transplantation (FMT) is used to treat Clostridioides difficile (C. diff) infection, which can cause severe diarrhea. Last year C. div. led to 14,000 hospitalizations in England alone (File image)
“FMTs are inherently varied,” says Dr. Monaghan. “They could work well, but it’s really a lucky dip because you’re transferring an undefined number of microbes.
‘We also don’t know the long-term adverse effects of FMT. There is always a risk that we can transfer pathogens from donor samples.
“The idea of these prescription-only microbiome treatments (called living biotherapeutics, or LBPs) is that they are more sophisticated and contain certain types of beneficial bacteria.”
At least three new LBPs have been approved so far: Biomictra (in Australia) and Rebyota and Vowst (in the US).
Biomictra and Rebyota, approved for the prevention of recurrent C. diff infections, are manufactured from donor samples and administered rectally.
‘In my opinion, these are not huge advancements over FMT,’ says Dr Simon Goldenberg, a consulting microbiologist and infection control physician at Guy’s & St Thomas’ NHS Trust in London. ‘Moreover, the route of administration is a disadvantage: patients can be put off by an enema.’
Vowst, which was approved by the U.S. Food and Drug Administration in April, is an oral capsule containing 50 strains of Firmicutes bacteria spores from donors.
‘Firmicutes are normally abundant in a healthy microbiome and are thought to compete with C. diff for nutrients and thus restore gut health,’ says Dr Monaghan.
In a study published last year in the New England Journal of Medicine, C. diff patients were much less likely to experience recurrent infection after receiving Vowst than a placebo. “Vowst appears to be a real advancement in microbiome therapy,” says Dr. Goldenberg. “They engineered the sample to remove unnecessary bacteria and narrow it down to the most beneficial microbes that specifically target the C. diff spores.”
He says other companies are developing more promising microbiome therapies, citing Vedanta Biosciences as an example. “It appears to have developed a capsule containing a cocktail of eight live strains of bacteria that it claims are ‘selected for their ability to resist C. diff,'” he says.
In a 2021 study, this capsule, called VE303, led to more than an 80 percent reduction in the risk of recurrence compared to placebo after eight weeks.
Unlike most other products here, the bacteria in VE303 are lab grown and not based on human donations. ‘If the trial results are good, that would be a big step forward, as we would no longer have to rely on donors,’ says Dr Goldenberg.
Vedanta is also developing oral microbiome-based therapies for the treatment of IBS, solid tumors, antibiotic-resistant infections and food allergies.
But there are obstacles to these new therapies – one of them is cost. Dr. Monaghan says: ‘An antibiotic like vancomycin is relatively cheap, £200-£400 per course, while Rebyota would cost £7,000 and Vowst £14,000.
‘So exciting and pioneering as this approach may be, the cost could be prohibitive for the NHS.’
However, these therapies open the field for the development of more microbiome-based treatments for other diseases, she says.
“Initially these will be gut-focused – so inflammatory bowel disease – but then we can consider other diseases associated with an abnormal gut microbiome, such as arthritis, metabolic syndrome and neurological problems.”
The potential for this new approach seems enormous.
Dr. Chrysi Sergaki, microbiome group leader at the Medicines and Healthcare products Regulatory Agency (MHRA), told Good Health: ‘There is a significant amount of ongoing research into the wider utility of FMT and other microbiome-based therapies, including bowel disease (IBS). ulcerative colitis and Crohn’s disease), obesity, asthma, autism, psoriasis, bacterial vaginosis, cancer and autoimmune diseases.
“There is also increasing evidence for its application in the treatment of cardiovascular, neurological, respiratory, metabolic and hepatic diseases and antimicrobial resistance.”
So, given the new therapies that include live bacteria, shouldn’t we all just take probiotics?
“Very simple, no,” says Dr. Monaghan. “Probiotics usually aren’t as effective or as rigorously evaluated in robust clinical trials, and consumers can’t always count on what they’re getting.”
‘LBPs are single bacterial species or specifically selected bacteria designed to target a particular disease.
“These products will undergo stricter quality control, validation and trials to demonstrate that their specific bacteria have a clinical benefit – and on that basis they will be approved.
“It’s the next generation of microbiome research.”