More than a gut feeling

In 2008, there was huge excitement in the medical research community about the Human Microbiome Project, a five-year effort to characterise the human microbiome and analyse its role in human health and disease. Sequencing methods had been developed 20 years previously for the Human Genome Project, and with capacity left over, scientists turned their attention to the microbes that colonise various parts of the body.

Composed of vast numbers of microorganisms, mostly made up of anaerobic bacteria, the gut microbiome is responsible for multiple functions in bowel movement, digestion of food, and absorption of nutrients.

A tremendous amount of research was published, cataloguing these complex processes, after which focus turned to trying to compare the microbes present in the guts of healthy people with those in people who had certain diseases or conditions. Two main conclusions were drawn. First, there were many more different types of microbes in the gut than scientists had previously thought. The typical microbiome is comprised of thousands of microbial species and millions to trillions of microbial cells.

And second, there was evidence that the microbiome patterns were different in healthy people than they were in those with conditions such as obesity and inflammatory bowel disease. What’s often under-reported is the fact that researchers were not able to establish any causal link between the make-up of the gut microbiome and any of these conditions.

As Dr Mary Ellen Sanders, a consultant with three decades of experience in the probiotic field, explains: “The hope was that if we could identify this ideal healthy microbiota, then we could shift people with aberrant microbiota patterns to be healthier. But the excitement about the science got ahead of what the conclusions from it could legitimately be.

We don’t know whether those differences in microbiota compositions are caused by the disease or condition or whether changing those microbial patterns will have any effect on it.”

For this reason, she believes that any discussion about the microbiome needs to be approached with some level of understanding of what the limits of the current research are, recognising what we know and what we don’t.

Research challenges

There is one thing we do know at present. A faecal microbial transplant, also known as a stool transplant – whereby faecal bacteria and other microbes from a healthy individual are transferred into another individual – is an effective treatment for clostridium difficile infection (CDI). It has an efficacy rate of nearly 90% for multiple recurrent CDI. “That is something that we do have a causal relationship for,” Sanders says. “But beyond that, we don’t know.”

One field of research Sanders finds exciting is the growing body of evidence that the gut microbiome is an important factor in a number of mental health conditions, such as depression and anxiety.

In layman’s terms this revelatory yet infantile field is centred around the gut-brain connection. In short, neural pathways in the brain affect the stomach and intestines, and vice versa, which is why people feel nauseous or get “butterflies” when they’re anxious. Research on the enteric nervous system (ENS), essentially two layers of more than 100 million nerve cells lining the gastrointestinal tract, is beginning to show that the ENS can communicate with the brain in complex ways.

As a result, studies have suggested that ingesting probiotics – which comprise live microorganisms promoted with claims that they can provide health benefits – can reduce symptoms.

For example, in a 2021 meta-analysis of seven trials, Viktoriya Nikolova, a PhD student and researcher at King’s College London, and colleagues, found that probiotics can significantly reduce depressive symptoms after just eight weeks. The caveat was that the probiotics only worked when combined with an approved antidepressant.

A few years earlier in 2018, another meta-analysis also showed that probiotics, when compared with placebo, improve the mood of people with depressive symptoms, without the need for antidepressants.

On the anxiety front, there is compelling evidence from animal studies to show that ingesting probiotics can relieve anxiety, although human studies are less convincing. It’s a similar story with schizophrenia. But as Sanders stresses, the difference between an animal model and a human model is huge.

“With the gut-brain targets, there’s a clear mechanism and a clear reason to expect that you could manipulate the microbiota and that it would have an effect on the brain, but we simply don’t have rigorous end points [an event or outcome that can be measured objectively to determine whether the intervention is beneficial] in humans yet,” she says.

We’re at a similar point in the area of metabolic health. “We want to know whether or not we can administer a probiotic to help control different expressions of metabolic disease such as obesity, high blood pressure, high cholesterol or blood lipids,” Sanders explains. “There are strong mechanistic expectations, but finding the right strain, the right dose, the right subpopulation, where it’s going to be effective, that’s going to take some time.” Sanders has helped numerous food and supplement companies develop and communicate about probiotic products over the last 30 years, as well as authoring over 120 peer-reviewed publications on efficacy substantiation, microbiology and regulatory issues pertaining to probiotics. She says that the pre-clinical stage of trials can be particularly challenging.

“Researchers must ask themselves, ‘What are the traits I’m looking for in a probiotic that is going to express the right clinical endpoint in the person?’” she says. “They’re clever and take their best guess on what kinds of properties they think these microbes need to express. Then you move them into clinical trials. But you’re not necessarily right.”

Sanders says negative depictions of probiotic research in the media aren’t helping the development of the field. “A study will come out showing that a trial showed no benefit expressed and the headline is: ‘Probiotics don’t work!’ But which probiotic? Which specific endpoint was tested?” she says.

Invariably, the negative outcomes of probiotics are often overreported, undermining the huge potential these microbes have to alter and impact bodily processes in many positive ways.

“The reality is that the majority of clinical trials fail,” Sanders admits. “You go into a trial with a specific hypothesis and it’s a very specific endpoint that you’re making your best guess on. And a lot of times you’re wrong, you learn something from that trial and you have to go back. That’s the nature of research. If those negative trials weren’t published, I would say that the probiotic field is doing something wrong but the way it’s reported oftentimes in the popular press really penalises companies for trying to do the right thing.”

Are live microbes officially good for you?

Alongside her role as a consultant, Sanders is the executive science officer for the International Scientific Association for Probiotics and Prebiotics. For the past couple of years, they have been looking into whether there is sufficient evidence to develop a rationale that consuming live microbes should be a dietary recommendation. In other words, that live microbes – in the form of probiotics or fermented foods – are officially good for you.

“The whole probiotics field is very focused on specific strains for specific outcomes and we’re looking at this from a different point of view,” she explains. “If you look at aggregate information based on fermented foods that contain live microbes and probiotics, can we say in a very general sense, like they do for fibre, that there is a compelling totality of evidence that they’re good for you?” They haven’t reached any conclusions yet.

“We’re looking at what the data says and if we don’t have the evidence yet, what evidence is needed and how do we go about generating it?” Sanders explains. The work has attracted the interest of microbiota researchers, nutritionists, the fermented food industry and probiotic developers.

“Right now, there isn’t the data to say it’s necessarily good for you. The thinking is that it makes sense because we live in such a sanitised world and take antibiotics and many babies are born via C-Section. There are all these reasons why our microbiota isn’t where it should be,” she adds.

For Sanders, the most important thing is not to talk about hypothesis as if it was fact. “You’ll see a lot of people marketing fermented foods and saying that live microbes are good for you,” she explains. “But oftentimes, those claims are overstated. They’re not harmful and I would never discourage someone from consuming fermented foods. In fact, I’m happy to encourage it. But when someone asks why, you have to say, there’s a lot of thinking that this is good for you, but so far, we don’t have real data.”

Like any scrupulous researcher or scientist, Sanders doesn’t do intuition. Instead, as far as probiotics are concerned, she is steadfastly committed to rigorously testing how microbes can impact and benefit the body. In the vast, endlessly intricate minefield of the microbiome, gut feelings just aren’t enough.