Chemistry vs. bacteria, # 55. Antibiotics and the intestinal flora

Right now, there is a lot of interest in all microorganisms in and on our bodies. Researchers have good look at the intestinal flora in particular. Recently, we wrote two articles on this subject, with the significant titles Who are we and There is no such thing as an individual. Newspapers devote many pages on articles titled for instance The close relationship between brain and belly. Are we on the verge of the era of gut feeling, with its scientific foundation (and approval)?

Project ‘100 years of antibiotics’
Episode 53. If chemistry loses
Episode 54. If chemistry and biotech join forces
Episode 55. Antibiotics and the intestinal flora
Episode 56. Bacteriophages, almost forgotten, but….
Episode 57. Phage therapy, a promising alternative to antibiotics?

intestinal flora
Low-temperature electron micrograph of a cluster of E. coli bacteria, magnified 10,000 times. Each individual bacterium is oblong shaped. Photo: Agricultural Research Service – Wikipedia.

Progressive insight, coming fast

Living guests in our bodies (our microbiome) number in the millions; varying from bacteria, moulds, phages (although phages cannot live independently) to nematodes and viruses. Most of them are single-celled organisms, in huge numbers. They number up to 100 trillion (1014 cells). Compare that number to the total number of cells in our bodies: 100,000 billion or about 1014 as well. Their number matches that of our cells. Human beings have about 21,000 genes that determine our existence from before we are born until after our death. The genome of our guests is many times larger; according to the latest calculations, it could number more than 9.9 million genes. By far outnumbering our 21,000. In short, the genetic diversity of microorganisms coexisting with us is huge. For instance, the bacterial strains in and on our bodies number 40,000. All taken together, the microbiome (all microorganisms taken together) weigh more than 1 kilo, just slightly less than the kilo and a half of the adult’s brain.

The microbiome has a major influence on our behaviour. It produces many signal substances; like the well-known serotonin. Our guts contain more nerve cells than our spine. Researchers nowadays expect relations to exist between the composition of our microbiome, the development of the new-born child and the regulation of our immune system. And there are signs that the microbiome might affect us later in life: in neurological development, behaviour and cognition. Some even suspect that hereditary characteristics may change under the influence of our microflora. Conversely, we know how fast microorganisms can change their (hereditary) properties through mutations.

The art of living together

An interesting research subject is the influence of the microbiome on our social behaviour. We know for some time now that the makeup of our intestinal flora changes considerably if we become isolated socially; or if our peers do not really accept us. But does the reverse hold as well? It probably does. We can contaminate each other with viruses and toxic bacteria. Then we should also be able to ‘infect’ each other with beneficial microorganisms for better group cohesion or better relationships – by kissing, caressing or other forms of bodily contact. The transfer of microorganisms, irrespective of their nature, will influence the immune system of the receiving party. And we should be able to transmit such an improved immune system to the next generation.

But researchers suppose much more to be possible. The exchange of elements of the microbiome will also affect the makeup of our genetic codes, like the RNA. Or put even more precisely: such an exchange will influence parts of our genetic machinery that have a major influence on the development of our brains; particularly in areas that determine group formation and social behaviour. It would therefore seem that people suffering from autism and related disorders will also have a different intestinal flora. Although we don’t know yet what is the cause and what is the effect. Experiments on germ-free mice show that they develop considerably less social behaviour than their non-sterile brothers and sisters. If we treat the sterile mice with the microbiome of their peers, normal behaviour returns, but just in part.

In short, in the creation social life and symbiosis appear to be much more the rule than the exception, contrary to what we always believed. That may make us pause and think on the (Darwinist) individualistic view on evolution.

immune system
Our immune system at work: granucolyte (yellow) deactivating an anthrax bacterium (orange). Photo: Volker Brinkmann – (November 2005). Creative Commons-licence.

Build-up and maintenance of our immune system

The foetus’s immune system gets a boost as it leaves the womb. In the birth tract it will meet a lot of microorganisms (and even more so as it plays in the sandbox, later in life). This would seem to be a matter of course. Research now shows us how subtly nature goes about, as the mother gradually transfers her immune system to the placenta and the embryo through the blood. During pregnancy, the intestinal wall becomes more permeable to the arteries for essential components of the intestinal flora. And we start to learn more about the pathway of intestinal flora to mother’s milk.

As we eat, the intestinal flora appears to become more active as well; a no-brainer, we might think. But this will activate our immune system at that very moment; because then it is more likely that uninvited guests will enter our bodies.

Antibiotics and our intestinal flora

It is well-known that antibiotics influence unfavourably the microorganisms in our bodies. That is the cause of many side effects. Serious effects may consist of chronic colitis and severe diarrhoea. But our knowledge of the arms used by our intestinal flora in their battle with microorganisms is growing fast. Therefore, we quickly learn more about responsible use of antibiotics – and particularly about the use of probiotics in order to keep the intestinal flora in shape.

Lesson number one begins with the cholera bacterium. Particularly dangerous are cholera bacteria growing on chitin. Chitin is the hard element (exoskeleton) of insects, lobsters, shrimps and spiders – and of moulds as well. The substance consists of a complicated sugar chain. On this substrate, microorganisms causing cholera develop a sharp protrusion. This allows them to kill the benevolent bacteria in our intestinal tract and start the cholera infection. But then, what happens? Some intestinal bacteria have developed an even better spear and win the battle. Others survive by covering themselves in a layer of sugars that the cholera bacteria cannot penetrate. Or the two bacteria might get involved in a battle for the sugars as their resource, with the cholera bacterium on the losing side.

This is not just a figment of our imagination. Other studies also show that the competition for resources may be one of the defence mechanisms of our intestinal flora against intruders. But the availability of such efficient defenders in our intestinal flora differs greatly among human beings. Therefore, a transplant of the intestinal contents may be an important defence mechanism. In mice, such a procedure is now performed almost routinely. We can also perform such dedicated transplants in humans now; we then substitute strong and healthy mixtures for weak or damaged ones. A healthy gut flora is in precarious balance. Therefore, it can be very nasty if this is disturbed by antibiotics. But a one-sided use of probiotics (intended to promote beneficial bacterial growth) may also end up on the wrong side of the competition with undesired guests.

Stool transplants

Such procedures are commonly called stool transplants. Their importance may even transcend their direct impact. Of course, researchers may want to know which components of the transplant are important, which are essential when dealing with a certain condition and what they can leave out. It may be important knowledge for patent experts and lawmakers to know the exact nature of the agent or preparation. And even more so for insurance companies.

But unfortunately, here the whole is more, and more important, than the constituent parts. We deal with a community here. We cannot isolate a (supposedly) important player from the team and then have the illusion that the problem has been solved. Or add one new player, and then think that development will take a beneficial course all by itself. Developers of agrochemicals (pesticides) know this for over 10 years now. It will take more than a simple product to influence the plant’s vast microbiome. We identified the best bits already over the past one hundred years (fertilizer, insecticides, pheromones). We now need to proceed more smartly; use living organisms ichneumon wasps, bacterial mixtures or moulds, in order to keep plants healthy and promote their growth. Medical science too will increasingly use such an approach. Imagine smarter transplants; from stem cells to complete organs and their components.

Intestinal flora

In order to contain the bacterium causing intestinal infection and serious diarrhoea, the infamous clostridium difficile, a bank of healthy gut contents has been founded in the USA  (About FMT — OpenBiome). The FDA has facilitated this by allowing less strict rules; the composition doesn’t need to be fully determined. As long as the application is safe. But alas, in 2020 this procedure appeared not to be entirely safe – resulting in a number of limitations. Now the corporate community has become active in this field as well. They develop products like freeze-dried bacterial mixtures from the stool, mixtures of beneficial bacteria grown in the lab or mixtures of bacterial spores.

Our knowledge of the part played by our gut flora is expanding fast. Some researchers have high expectations of prospects and future applications: treatments of many conditions, from intestinal complaints to autism and cancer. Their to-do list includes the containment of a number of multi-resistant bacteria.

Sources:
Wikipedia: all names and products mentioned
Friends with social benefits: host-microbe interactions as a driver of brain evolution and development?’ Roman M. Stilling, Seth R. Bordenstein, Timothy G. Dinan en John F. Cryan  in Frontiers in Cellular and Infection Microbiology ,29 oktober 2014
Review by Javier Suárez in Symbiosis 76(2), pg. 77-96 (2018): The importance of symbiosis in philosophy of biology: an analysis of the current debate on biological individuality and its historical roots.
https://www.ncbi.nlm.nih.gov/search/research-news/14278/
The Scientist AUGUST 1, 2021 The Role of Mom’s Microbes During Pregnancy https://www.the-scientist.com/news-opinion/how-commensal-gut-bacteria-keep-pathogens-in-check-69310 About FMT — OpenBiome
Fecal Microbiota Transplantation Is Poised for a Makeover | The Scientist Magazine® (the-scientist.com)
N0-nonsense Guide to Antibiotics, Moira Dolan, SmartMedInfo, 2015; ISBN: 978-09968860-2-4
– Entangled Life, how fungi make our worlds, change our minds and shape our futures, Merlin Sheldrake, The Bodley Head, London, 2020. ISBN 9781847925190
– Bio-stimulants for sustainable crop production.Edited by Yoessef Rouphael, Patrick du Jardin, Patrick Brown, Stefania De Pascale and Giuseppe Colla. Burleigh Dodds series in agricultural science, 2020. ISBN 9781786763365.

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