For more than one hundred years, we believed avoiding bugs or removing them from our system was the simplest way to improve our health.
But while tremendous public health advances have come from controlling dangerous pathogens, we now understand the trillions of other bacteria that live in our body – and in particular, our gut – perform a range of important functions.
So when, and how, should we try to manipulate these microorganisms, collectively referred to as our microbiome?
What we eat satisfies the nutrient demands of our microbiome – and subsequently shapes their capacity to further contribute to our health. But the modern lifestyle, particularly diet and hygiene changes, have altered our relationship with our microbes.
To have a healthy microbiome, the best advice is to include natural plant foods, including fibre, in your diet. But although diet has a major role in shaping our microbiome, it’s not a precise way to re-engineer it if things have gone wrong.
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There are two broad avenues for microbiome engineering: generic strategies that target large numbers of different microbes (bacteria) simultaneously, such as fecal transplant and antibiotics; or specific strategies that target a small group of microbes, such as probiotics.
Although changes in our microbiome are associated with many chronic diseases, and those changes almost certainly have some contribution to the disease, they are not necessarily the main cause. Microbiome manipulation is most useful when we know exactly how microbes are involved in particular diseases.
But if you don’t have a problem, you don’t need to mess with your microbiome. This is another reason why taking antibiotics when you don’t them is a bad idea.
Fecal microbial therapy, or fecal transplants, are the transfer of a fecal sample from a healthy donor to a recipient. This can be done via nasogastric tubes (inserted into the nostril, down the throat and into the stomach) or inserted directly into the colon.
Fecal transplants have had spectacular success with treating C. difficile infections. This bacterium causes severe diarrhoea and inflammation. Recurrent infections are extraordinarily debilitating and life-threatening.
Trials of fecal transplants typically show a 90% success rate in treating this condition.
But C. difficile disease is a special case. The disease has one main cause and a consequence of the infection is a greatly reduced microbiota. In the “empty” gut environment of such patients, it’s easy to introduce new organisms. The removal of one problem organism is an easy target.
Most conditions involving gut health – such as obesity, inflammatory bowel disease, and irritable bowel syndrome) – have more complex causes and the gut retains a high-density complex combination of bacteria.
For complex gut health issues, the effectiveness of fecal transplants is either much lower, or not proven. Of two published studies of fecal transplants for inflammatory bowel disease, for instance, one found a low effect and one no effect.
Although clinical trials of fecal transplants have reported few problems, we should be alert to the risk. There have been reports of patients showing unexpected weight gain after treatment, for instance. This may be attributable to the engineered microbiota, or may simply reflect that they are no longer seriously ill.
For issues of long-term safety and effectiveness, there are still far more questions than there are answers.
Modern lifestyle changes in diet and hygiene have dramatically changed what microbes we are exposed to and how successful they are in colonising us. Our microbiome has changed and we seem to have lost some benefits. Probiotics aim to restore these.
Probiotic can be a confusing term, since its use in marketing creates the perception that any product for human consumption that contains specific live bacteria is a probiotic. This contrasts with the definition used by health regulators around the world: probiotics are live bacteria that, when taken in sufficient amounts, confer a health benefit.
The issue revolves around whether the specific bacteria being ingested are what is actually delivering a particular health benefit. There is a lot of marketing hype around products containing good bacteria that “may improve” wellbeing or immune function.
Products that contain live bacteria, such as yoghurt, fermented milk drinks, or pills, contain bacteria that are considered beneficial and are generally recognised as safe. But this is not to say that consuming the product will deliver a known health benefit (the probiotic definition).
There are many examples where probiotics have been shown to be useful in controlled clinical trials. One example is the use of probiotics in preterm births. Premature babies are at high risk of developing serious illness because they lack beneficial microbes. Probiotic treatments have consistently been found to lower the risk.
Probiotics work most effectively when directly addressing the cause of a disease.
For more complex issues or general health improvement, the story with probiotics is less clear cut. Most probiotic bacterial strains do not actually permanently colonise your gut. So to get any benefit for chronic conditions, you need to continually take them.
The next generation of probiotics are starting to address these issues.
There is great cause for optimism the next generation of microbiome-based therapies will offer significant advances. You don’t restore a complex ecosystem by throwing in one species and expecting it to survive, let alone fix everything. New approaches to probiotics aim to change the ecology of the gut.
Recent studies using cocktails of probiotic species have had encouraging results in experimental studies of mice with inflammatory bowel conditions. The goal is to inoculate with networks of bacteria rather than a single strain. Such networks are more able to deliver complex functions or to displace problem bacteria.
A new generation of biotech companies is developing microbiome-based probiotic pills (crapsules) as alternatives to fecal transplants for treating C. difficile. Although early studies were very promising and hailed as a breakthrough therapy, a recent phase two trial was less successful. It’s clear there is potential here, but further work is needed.
Although we are in the early stages of the microbiome-engineering era, the future is bright.
About The Author
Andrew Holmes, Associate Professor, University of Sydney; Laurence Macia, Senior Research Fellow in Physiology, School Medical Sciences, University of Sydney, and Stephen J Simpson, Professor, ARC Laureate Fellow & Academic Director, The Charles Perkins Centre, University of Sydney