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The Microbiome Otago Blog
A multidisciplinary human health research collaboration

A new evaluation of probiotics – two articles in the journal “Cell”.

Probiotics (products containing live bacteria that upon consumption are believed to confer a heath benefit) have been available commercially for more than a century. Despite widespread use of these ‘food supplements’, evidence of universal efficacy of this generic group of products has not been obtained. The misuse of the word ‘colonisation’ (inferring a state of permanent residence) of the bowel in relation to probiotic products is widespread, despite evidence from almost 20 years ago that, for most people, viable probiotic bacteria are only detected in faeces during the period in which the probiotic product is consumed. The authors of a Cell article (Zmora et al. Cell (2018), https://doi.org/10.1016/j.cell.2018.08.041) extend research into the reason why probiotic bacteria do not colonise the human bowel by describing the bacterial collections associated with the gut lining in various locations within the digestive tract. They concluded that it is these bacterial collections that direct whether probiotic bacteria persist for longer or shorter periods in the human bowel. Their overall conclusion is that, given differences in mucosal bacterial populations between humans, probiotics are unlikely to be universally efficacious and that ‘tailor-made’ probiotics designed for specific diseases and even for specific people (personalised medicine) could be investigated. It will be interesting to see whether this latter option could be available to more than an affluent few.

In an accompanying article, the same group of authors describe an investigation into whether a probiotic helps re-establish the bowel microbiota after its composition has been disturbed by antibiotic administration. Concerns about the potential of orally administered, life-saving, broad-spectrum antibiotics to disturb the composition (collateral damage) of the normal bacterial community (microbiota) of the human bowel have been expressed. This ‘dysbiosis’ of the microbiota might have long term consequences on human health, especially if occurring in early life when the developing immune system and other aspects of physiology could be influenced by environmental factors. The reconstitution of the composition of the microbiota is of interest medically and commercially – especially the use of probiotic products during or after antibiotic treatment. Most antibiotic treatments are for no more than a week or so, but long-term treatment for chronic conditions can lead to the proliferation of toxin-producing bacteria in the bowel that results in serious disease (see a previous blog on this site). The authors of the second Cell article (Suez et al. Cell (2018), https://doi.org/10.1016/j.cell.2018.08.047) investigated the effect of probiotic consumption on recovery of the microbiota after a period of broad-spectrum antibiotic treatment. The experiment was not conducted in a clinical context – the people involved were healthy volunteers given a mixture of antibiotics. Surprisingly, the authors report that recovery of the microbiota was impaired by probiotic consumption (only one probiotic product was tested). Unexpected to me, because bacteria in probiotic products do not belong to the numerically predominant members of the human bowel microbiota and are not expected to persist long-term once administration has ceased. This result therefore needs confirmation in further studies. What was expected, and which did occur, was that administration of preparations of the volunteers own stool (faecal microbiota transfer/transplant) hastened the recovery of microbiota composition. The necessity of such procedures needs to be evaluated in the medical context of whether they confer sufficiently convincing benefits on patient well-being while outweighing any potential risks associated with dosing patients with an undefined mixture of faecal bacteria.

Faecal microbiota (microbiome) transplant – Getting a new collection of bowel bacteria.

It’s a funny old world. Humans have spent centuries developing ways of avoiding contact with excreta because of the dangers of transmitting gut infections from one person to another. Safely removing faeces to the sewer, even if the sewage was for decades emptied untreated into waterways and the sea, was one of the triumphs of public health medicine. Yet enormous interest in transferring faeces from one human to another – intentionally – is now topical in microbiome circles and the readership of newspapers and magazines. This transformation of ideas has come about because of a particular kind of infection, most common in elderly people who frequently take antibiotics, often long term, who have chronic infections such as of the urinary tract. They are usually living in hospitals or residential care facilities. This kind of usage of antibiotics can alter the balance of bacterial groups that constitute the collection of microbes that lives in the large bowel (colon) of humans. This collection, known as the microbiota (or microbiome if you include their genomes) is normally self-regulating, but some antibiotics administered long term can upset the usual in-built regulatory systems. When this happens, a particular species of bacteria, which is normally kept at low numbers in the colon, can multiply unchecked and produce enough toxins to cause inflammation and malfunction of the colon. The result is a disease called antibiotic-associated colitis, which causes diarrhoea and in severe cases is extremely debilitating and even life threatening in the elderly. The bacterial species that proliferates to cause the problem was called Clostridium difficile (it now has a new name Peptoclostridum difficile) so the disease is also known as Cdiff infection. Cdiff is a normal member of the colon microbiota of about 3% of people, but held at low levels by other bacterial groups. In some cases, transmission of spores (resistant structures), produced by Cdiff, are transmitted between patients in the hospital environment. The spores can germinate in the colon, leading to Cdiff multiplication if the microbiota has been disturbed. Curiously, other antibiotics are used to treat Cdiff infection. It is usually successful, but once the antibiotic treatment stops, Cdiff multiplies again and causes a relapse of the disease. So, that’s why doctors proposed, as long ago as the 1980s, to transplant healthy microbiotas, by means of enemas or naso-gastric tubes, to patients suffering from Cdiff infection. This could result to the restoration of an intact microbiota that would suppress Cdiff, resulting in a cure for the patient with a much lower risk of relapse. Indeed, many trials have shown that faecal microbiota transplant works in curing most severe cases of Cdiff infection. However, inoculating humans with a crude suspension of faeces could be risky – what unknown, dangerous agents might be transferred in the preparation? Careful screening and selection of donors is needed. Scientists think that a defined therapy would be better so as to remove the risks, real or imagined, of faecal microbiota transplant. To do this, we need to know which bacterial species normally suppress Cdiff in the colon. Some progress is being made – already we can start to recognize which species are more likely to actually persist in the colon after transfer and which are more likely to be lost relatively quickly. Faecal suspensions that are currently used are prepared by blending faeces without protecting the suspensions from air. Most of the members of the microbiota are quickly killed by exposure to oxygen, but faecal microbiota transplant does work. Maybe it’s spores – yes spores again – that are important because they are not killed by oxygen. So maybe the secret is to select spore-producing bacteria that inhibit Cdiff from the microbiota, grow them in the laboratory, purify their spores and use the spore preparations to inoculate the patients? Now you would have a defined mixture to transplant. Some people think that you don’t need bacteria at all, and that bacterial viruses (bacteriophages) that infect and kill Cdiff are the useful agents that are being transferred by faecal microbiota transplant! This raises the interesting question as to whether Cdiff infection could be a target for ‘bacteriophage therapy’. This would rely on finding bacterial viruses that target Cdiff, an even more defined approach. Anyway, getting away from faeces would be a good idea.