Navigating the probiotics landscape

APPROXIMATELY a hundred trillion microbial cells make up our microbiota, and 95% of our microbiota is in our gut. Genomic technologies have helped facilitate characterisation and analysis of the microbiome.

The composition of our gut microbiota changes with our age. There are differences between breast-fed and bottle-fed babies, and microbial diversity increases after weaning and the intake of solids. As we grow older, there is a change in the pattern of our microbiota; the proportions of our dominant and less dominant microbes change as we advance in age. Each of us has a unique gut microbiome. Our birth mode, genetics, diet, diseases and antibiotic treatments will all have an impact on our microbiome.

What we eat shapes our gut microbiota, which produces metabolites (vitamins, amino acids, fatty acids, bile acids and sugars). Changes in the concentrations of certain groups of metabolites can help determine whether there is evidence of disease.

A disruption in the microbiota is called dysbiosis. Many diseases appear to be linked to dysbiosis. Antibiotic-associated diarrhoea is an obvious one, but several others such as asthma, allergies, autoimmune diseases, cancer (particularly colorectal cancer), dental caries, depression and anxiety, diabetes, inflammatory bowel disease, metabolic syndrome and psoriasis also appear to have some relationship with dysbiosis. Loss of diversity appears to play a key role here.

We are becoming more conscious of the fact that our gut microbiota is something we need to be looking after, and we can gauge this growing awareness by looking at some of the popular literature that is being published about the “healthy gut”. Our lifestyle (whether we smoke, drink alcohol, experience stress and use drugs) and host factors (genetic and epigenetic factors, immune function, mucosal integrity, and age) can determine the health of our microbiome.

Many patients who come to the infectious diseases clinic are worried about taking antibiotics and ask us about the effects of antibiotic treatment. Bacterial infections and sepsis need antibiotic treatment – you can’t avoid antibiotics if you have a real infection. But antibiotics do affect the gut microbiota – you may see a loss of microbial diversity and fewer healthy microbes. This can last for months or (in some cases) even years. Disruption of the metabolome (the totality of metabolites in the body) may lead to inflammation. We also know that genes associated with antibiotic resistance can transfer between bacteria, so this is another way in which the gut microbiome may be affected.

Prebiotics are non-digestible substances that act as food for healthy bacteria that live in our body. They stimulate the growth or activity of certain bacteria in the gut microbiota. Probiotics are bacteria that support our digestive system. They feed off prebiotics and can be found in some fermented foods. We now have formulations containing specific strains of probiotics being marketed as supplements. The global probiotic supplements market grew to US$4.11 billion in 2016 and is expected to grow to US$6.95 billion by 2022. One study has suggested that 1.6% of adults (3.9 million) and 0.5% of children (294 000) in the US are taking these supplements, so it is quite clear that they have a wide appeal.

Despite the prolific marketing, clinicians remain unconvinced about probiotics as the evidence is mixed. Reviews have suggested that there is little evidence supporting the use of probiotics as a preventive intervention. Additionally, after antibiotic treatment, the use of probiotics appears to impair (rather than expedite) gut microbiota reconstitution. As this is an important indication for the use of probiotics, further research on the impacts of probiotic use on the gut microbiota, and the efficacy of probiotic use for restoration or reconstitution of the gut microbiota after treatment with antibiotics, is warranted. In the next article in this series, we will address the significance of emerging research on the use of faecal microbiota transplantation.

There is, however, some evidence for probiotic use in patients who are at higher risk of developing antibiotic-associated diarrhoea and Clostridium difficile diarrhoea. Probiotics may also reduce the duration of illness and antibiotic use in patients with upper respiratory tract infections. A meta-analysis of 17 studies examining the potential impacts of probiotic use on antibiotic utilisation for children found an association between probiotic supplementation and reduced antibiotic use. Given that this meta-analysis purported to support the prophylactic use of probiotics (to prevent acute infections), reporting a lower rate of antibiotic use among children who received supplements (which implies that they experienced fewer infections), future studies may wish to explore this association further.

At the moment, we don’t have definitive, high quality information about the benefits of probiotic use, and this may simply be because we haven’t yet conducted the right trials with the right outcome measurements. No large, long term clinical trials have proved that probiotic supplements offer clinical benefits to people who are already healthy. In general, probiotic supplements appear to be safe for short term use in patients who are not immunocompromised or severely debilitated.

We don’t have enough evidence to conclude that probiotics are safe and effective for people with cancer. Probiotics may reduce the incidence of diarrhoea, sepsis and central line infection, and the duration of fever. But there are also case studies of serious bloodstream infections caused by probiotics, in which the probiotics have gone into the bloodstream and caused sepsis. For immunocompromised and immunosuppressed patients, this is a concern. The other concern is that introducing new bacteria could potentiate the risk of transfer of resistance-associated genes among bacteria.

How and when probiotics may offer a benefit is still being investigated. Studies have provided some answers, but further research may be necessary before probiotic treatment can be recommended to clinicians and patients in specific settings (and for specific indications). Particularly, questions around adverse effects, the efficacy and impact of standard formulations on heterogenous microbiota, and the safety and feasibility of restorative or prophylactic strategies need to be investigated.

Below is some information that clinicians can refer to if asked about probiotics.

Which probiotic should be chosen to prevent antibiotic-associated diarrhoea?

When you look at the formulations that are available in the market, you should look for information on the label about “colony forming units” (CFUs). Like the labels of other medicines, probiotic labels should be read carefully. Be aware that some of these capsules need to be stored in a particular way. In the future, there will hopefully be greater regulation of the manufacturing process and clarity about the claims that manufacturers can make.

A Dutch team conducted a review of the available evidence on probiotics and antibiotic-associated diarrhoea, and evaluated products sold in the Netherlands against recommended criteria. The team concluded that only one dairy product in the Dutch market met the recommended CFU count. Products containing Lactobacillus rhamnosus GG with a minimal daily dose of 2 billion CFUs were awarded the highest rating for this indication.

For how long is it okay to take probiotics?

There isn’t much evidence to show that taking probiotics has long-term benefits. The evidence suggests that microbial diversity is the key – so taking one type of probiotic long-term may not be particularly beneficial. Probiotics are considered safe overall for healthy people, but risks may be greater in immunocompromised people.

Are probiotics safe if white cell count is low?

There are some risks associated with taking probiotics, especially in people who are immunosuppressed, including bacterial translocation across the gut and into the bloodstream. It is not recommended that highly immunosuppressed people take probiotics for that reason.

Can probiotics be taken during antibiotic treatment?

There is evidence to suggest that taking probiotics at the same time as antibiotics is beneficial, and has, in fact, been recommended in France for decades.

Professor Karin Thursky is the deputy head of infectious diseases at the Peter MacCallum Cancer Centre in Melbourne; director of the National Centre for Antimicrobial Stewardship; director of the Guidance Group at the Royal Melbourne Hospital; and clinical lead of the state-wide “Think sepsis, act fast” collaboration in Victoria (Better Care Victoria).

Dr Arjun Rajkhowa is the centre manager of the National Centre for Antimicrobial Stewardship at the Department of Medicine, University of Melbourne, the Doherty Institute, and Royal Melbourne Hospital in Melbourne.

Professor Monica Slavin is the head of infectious diseases and the director of the National Centre for Infections in Cancer at the Peter MacCallum Cancer Centre in Melbourne.

Dr Megan Crane is the centre manager of the National Centre for Infections in Cancer at the Peter MacCallum Cancer Centre in Melbourne.

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.