Probiotics: Flora Et Labora

12. July 2016
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For years marketing experts from the food industry have been promising intestinal health by way of probiotic yoghurt cultures. A new generation of probiotics seems to be capable of doing much more: They displace pathogenic antibiotic-resistant bacteria from the digestive tract.

Native bacteria from the gut appear to be true all-rounders. Alongside digestive tasks, they affect the immune system and many metabolic processes of their host. Yet those who fight unwanted intruders in the digestive tract using antibiotics often achieve the exact opposite of the desired effect. Beneficial intestinal inhabitants fall victim to the bacterial poison and pathogenic resistant attackers have a chance to spread from there. So what is there to do? Might there possibly be an alternative to the use of antibiotics?

Next-generation probiotics

With ever-improving knowledge of the human microbiome, such an alternative could reveal itself. If one fills the void left after antibiotic treatment by using the same bacterial flora, one not only restores a healthy digestive environment, but also sees to it that pathogenic visitors have much more difficulty in becoming residents there. The newly discovered potent intestinal inhabitants do not have much in common with the previously promoted live cultures found in the supermarket refrigerated section. The “next generation probiotics” are much more effective and could therefore become the weapon in the hospital for use against multi-resistant pathogens.

As much as antibiotics play a crucial role in defending the body against these bacteria, to the same extent they harbour big risks through their effects on the normal flora. According to a recent study by Brett Finlay and his colleagues from Vancouver, there is a tendency for children to develop asthma if their gut microbes are disturbed during the first 100 days of life. Strictly anaerobic bacteria of the digestive tract end up being one attack point of many antibiotics – a finding that is already over fifty years old. Vibrio cholerae and Salmonella typhimurium then have an easier time after that. Especially with bone marrow transplant patients, antibiotics enable domination of VRE (vancomycin-resistant enterococci) in the gut, which is in turn associated with an increased risk of bacteremia.

Bouncers prevent unauthorised entry

A faeces transplantation of healthy microbiome into antibiotic-naive mice in which the animals’ intestine had been colonised by AVRE and Klebsiella pneumoniae had the effect of altering the intestinal flora decisively. Thus, the pathogenic bacteria colonies were able to be expelled from the intestine. How effective this so-called colonisation resistance is still depends heavily on the design of the relevant study. In the last two years however, more reports have appeared showing that in humans as well various species of healthy intestinal flora hinder colonisation by VRE and pathogenic Escherichia coli species. A linchpin of important support in this colonisation resistance seems to be bacteria belonging to the genus Barnesiella.

Already 30 years ago scientists showed that a cocktail of ten kinds of healthy intestinal flora, including obligate anaerobic species, can cure infections of the dreaded pathogen Clostridium difficile. Among these ‘bouncers’ of the intestinal world, which probably act as a deterrent to pathogenic bacteria by their mere presence, is also Clostridium scindens. This microbe is one of only a few types of bacteria with an ability to convert primary bile salts into secondary salts, a capacity that is closely tied to protection against Clostridium difficile. Metabolisation of sialic acids – a popular source of energy for Cl. difficile and other unwanted pathogens – might be another mechanism of resistance to colonisation.

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Antibiotics displace commensal bacterial species from the gut and weaken the defence against pathogens © Pamer et al. / Science (2016)

Cooperation with the immune system

Commensal anaerobic intestinal bacteria produce short chain acids such as acetic acid, butyric acid and propionic acid, which together with the lactate from lactic acid bacteria produce an environment that makes it even more difficult for intruders to gain a foothold. The list of further weapons belonging to intestinal indigenous dwellers includes direct antibacterial factors such as regIIIγ. This lectin kills targeted gram-positive bacteria such as VRE. Using this, Bacteroides thetaiotaomicron for instance earns its place in the digestive tract. Bacteroides thuringiensis in contrast produces a poison against spore-forming bacteria such as Clostridium difficile and bacilli. Indirect actions also lead to success in colonisation resistance: segmented filamentous bacteria occur in close contact with the intestinal epithelium which ensures immune system enhancement by IgA, or they induce the production of antimicrobial peptides there which antagonise potential competition from outside.

Overall, as experiments have shown, the colonisation of unwanted germs can be rather well obstructed through the transfer of gut commensals. Available data indicates a reduction of pathogenic species by an order of magnitude six, which matches the effect of a very strong vaccine. Although the newly identified bacterial species with strong resistance to colonisation only account for a relatively small proportion of the entire flora in the intestine, they still appear to be much more effective than those acquired at huge marketing expenses as additives in dairy products. The increasing number of meaningful studies will soon provide further evidence here.

Logistical and regulatory issues

The challenge associated with regeneration of the intestinal flora infiltrated by antibiotics lies in the implementation of research into practice. Anaerobe bacteria cannot simply be mixed into food. Furthermore their cultivation involves much greater demands. A stool transplantation from healthy donors after each use of antibiotics also does not seem to be the appropriate means of delivery. Comprehensive studies of this relatively new treatment in human beings has so far only involved Clostridium difficile infections. Perhaps success may also be found by packaging the respective cultures so that they can be taken orally and made to survive the passage through the stomach and the upper digestive tract.

It’s entirely unclear how such intestinal regeneration is to be regulated. Should the gut commensals be compared to the already commercially fully successful probiotics or food additives that, putting aside the degree of veracity of their promises, can hardly be checked for their effect? What’s more, homeopathic active ingredients are – even though they are considered a therapeutic product – hardly controlled. Studies will need to take into consideration whether such resistance to colonisation by gut commensals from bred sources is intended for preventive or for therapeutic purposes. In being “normal intestinal inhabitants”, there are few serious side effects to be expected from using these fellows. Nevertheless, changes made to the intestinal flora have over the longer term hardly been studied.

500 million dollars is being handed out by the US government in order to work out the human microbiome and the consequences of alteration in its composition. “We need the ability to change dysfunctional microbiome”, Jo Handelsman, science director at the White House, says, “and we want to make them operational again”. A tool that does away with the blunt weapon that has come about from the overly frequent use of antibiotics, one that penetrates the armoury of pathogenic bacteria which have become resistant, would become a mighty step forward in the fight against infectious diseases some hundred years after the discovery of penicillin.

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