A healthy microbiome is critically important
What did this podcast cover and why did I enjoy it?
This podcast with James Kinross introduced me to his new book, Dark Matter: The New Science of the Microbiome. If his book is half as good as this discussion with host Liz Tucker, I can’t wait to read it.
I’ve written before about how we are inextricably linked with our microbiome, the difference between microbiota and microbiome, and how we need to nourish our gut microbiota. I especially enjoyed James’ discussion because he describes so much in the context of broad principles and he introduced me to a number of new ideas.
James emphasizes several broad principles that I’ll describe below:
We have only superficial knowledge of the human microbiome – for me this is THE principle to keep in mind as we consider the subject
The microbiome is a communications super-highway between our environment and our body
The differences in microbiome composition between individuals is very large
There are four stages of microbiome development
Early influences may affect function profoundly
Producing safe and effective pharmaceuticals may be impossible without understanding the microbiome
The new ideas James introduced me to include:
Microbial scarring – early changes to our microbiome that may be irreversible
Orchestral signaling – the microbial chemical superhighway that we are subjected to
The ageing mosaic – each organ is uniquely affected by chronic inflammation
Maternal microbiome effects on a developing baby
Microbiome effects on human fertility
Lack of microbiome investigation in pharmaceutical drug development
Superficial Knowledge of the Human Microbiome
The field of research into the human microbiome is still in its infancy having been in existence for only about 20 years. We understand very little about the makeup of its enormous microbial density compared to us, the host. For example, most of what we know about its composition and function is derived from identifying bacteria and ignoring fungi, archaea, and viruses. Also, when we investigate the microbiome, we change its nature.
Our interpretation of the data we have collected is difficult because we don’t have standardized models of research and enquiry. Interactions within the microbiome and between the microbiome and its human host are many and very complex.
None of this should come as a surprise because we have yet to invest properly in microbiome research.
We are well served by use of the term Dark Matter in our study of the human microbiome. As with studies of our external universe, the term reminds us that there is much still to learn.
Nature and Size of the human Microbiome
We have microbes all over our bodies including our skin, lungs, genitals, urinary tract, and gut. Microbes within each of these areas can communicate with each other and with our bodies (a symbiotic crosstalk). When taken together, the genes (and potential for function) in our microbiota dwarf those of our own body. This means that our microbiota represent substantially greater potential to perform functions that keep us healthy if we take care of them.
“…our microbiota act as critical intermediaries between us and our environment”
The interactions with our microbiome and environment are much more complicated than we had realised. Traditionally we believed that our environment, be it the food we ate or the harmful things we were exposed to, simply affected our bodies. We are beginning to understand that our microbiota act as critical intermediaries between us and our environment, especially those in our gut. Microbial products (e.g., vitamins and metabolites) act as chemical messages to our bodies.
Our microbiome creates a chemical super-highway that interacts with our body through a process called orchestral signaling, whereby hundreds of thousands of chemicals are sent throughout our bodies as signals to be interpreted by different parts of us at any point in time.
Our chemical orchestra communicates with all the organs in our body and even across the placenta into a developing baby, and plays different roles through gestation and throughout our lives. If we keep our microbiota healthy, they will create a resilient microbiome that can flex and adapt to changes in our lifestyle.
“Our microbiome creates a chemical super-highway that interacts with our body through a process called orchestral signaling.”
Liz and James briefly get into an interesting discussion about the human appendix. Traditionally the appendix was wrongly considered to be a redundant organ resulting in an evolutionary dead end. In fact, the appendix has its own unique microbiome, may be involved in seeding the gut microbiota and may be a unique immune organ in its own right. Removal of the appendix may or may not be healthy (so little known, as usual) but, if removed early in life, later microbiome development and resilience may be affected. Incorrect removal has been associated with irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colorectal cancer, and harmful bowel infections.
Inter-individual Differences Are Very Large
The large differences in microbiota composition and microbiome function between each of us (inter-individual differences) strike me as an important factor to keep in mind, second only to how little we actually know generally.
James discusses inter-individual differences in the context of diseases and their treatments, including pharmaceutical drugs and fecal microbiome transplantation (FMT). The latter, as its name suggests, involves the transfer of fecal microbiome content from a healthy donor to a patient. It appears that the inter-individual differences between donors and between recipients of FMT may outweigh all other variability in a particular treatment approach. Equally, observed variations between individuals’ responses to drug treatment can be very large, and this may be related to microbiome variability.
Sources of variation in microbiota composition and microbiome function can include:
Age - old vs young
Sex - male vs female
Geographic location
Behaviours
Nutrition
Location on the body
Location along the length of the intestine
Stages of Microbiome Development and their implications
There are four stages of microbiome development, and each stage is unique in its function, resilience and health implications
The four stages are:
Gestational
Age three to five years
Age five to 60 years
Age 60-70 and older
Gestational
A mother’s microbiome plays an important signaling role during her baby’s development. The microbial orchestral signaling from the mother causes changes in her baby’s developing organs and immune system that have life-long implications. For example, metabolites such as short-chain fatty acids (SCFA) from the mother’s microbiome influence her baby’s brain development. If her microbiome is disrupted, and SCFA production is affected, brain development can be affected, sometimes irreversibly. Her disrupted microbiome may also induce obesity in her baby. A pregnant mother’s health can also be affected. A disrupted microbiome has been associated with gestational diabetes. However we look at this, a pregnant woman’s microbiome is worth protecting.
Three to five years
From birth to three-to-five years old, the infant’s microbiota composition and microbiome function develop, increase in resilience, and stabilise.
Five to 60 years
Absent significant environmental stressors, the microbiome tends to be stable and resilient during these years.
“…chronic inflammation is referred to as inflammageing. Different organs in our bodies are affected at different rates and this creates what is called an ageing mosaic.”
Age 60-70 and older
As we age, we become less able to manage the crosstalk between our microbiota and body through the immune system. The ensuing chronic inflammation is referred to as inflammageing. Different organs in our bodies are affected at different rates and this creates what is called an ageing mosaic.
James draws a distinction between our chronological age and our biological age. The implications are that we can reduce our biological age by taking care of our body and our microbiome. Conversely, we can increase our biological age by subjecting ourselves to negative environmental influences.
It should be noted that at this later stage in life, it becomes more difficult to alter our microbiome. This may represent a double-edged sword but it is worth being mindful that preventing microbiome damage beats fixing it.
Environmental factors that affect our health through life
In any discussion of the impact of the environment on our microbiome, it is important to bear in mind our large intra-individual variability. Within each of the life stages described above, great variation can occur daily and over longer time periods.
We should expect a certain amount of harmless change in our microbiome function in a life well lived. Daily changes may result from things like hormone flux, sleep/awake cycle, and work/play practices. Longer-term changes will occur with movement to a new location, exposure to pets and livestock, living with a partner and with children, nutrition and taking pharmaceutical drugs.
Environmental factors that affect the microbiome early in life are especially important because they can influence early development and the likelihood of chronic disease later in life. Aside from the gestational factors covered earlier, an infant’s microbiome can be affected by other factors like vaginal versus cesarian births or the choice to breast-feed or not.
The special case of antibiotics
There is one environmental exposure that occurs consistently in James’ discussion of negative influences on gut microbiome development. Exposure to antibiotics carries a consistent risk of damage.
The use of antibiotics rose significantly after WWII and today 38 billion doses of antibiotic drugs are administered annually. Antibiotics are also used in animal husbandry and those of us consuming intensively reared chickens and cattle products may be consuming antibiotics regularly.
Antibiotics can reduce the number of microbes in our gut by up to 20 – 30-fold, reduce diversity and function, and those changes can be permanent through a process called microbiome scarring.
The risk of antibiotic damage to the microbiome is highest early in life, and has been associated with obesity, asthma and allergies.
Irrespective of the route, I personally try to minimize my exposure to antibiotics.
Human microbiome and fertility
James spends some time describing the long-term implications of medical interventions prior to puberty such as pharmaceutical drugs and appendix removal. He associates these interventions with the worldwide drop in female and male fertility.
In women there is a strong association between changes in vaginal microbiome and fertility. There are potential links between microbiome disruption, chronic inflammation, hormone production and polycystic ovary syndrome (PCOS). Microbiome disruption has also been associated with the risk of endometriosis.
Between 1973 and 2018 a greater than 50% drop in human sperm count has been recorded. This may be associated with vitamin absorption, specifically vitamin A which affects spermatic function.
“Antibiotics can reduce the number of microbes in our gut by up to 20 – 30-fold, reduce diversity and function, and those changes can be permanent through a process called microbiome scarring.”
The effect of pharmaceutical drugs on human health
Four to five trillion doses of pharmaceutical drugs are administered worldwide every year. Many classes of pharmaceutical drugs can impact the ecology of our gut microbiome. The elderly are especially at risk because they often suffer from multiple chronic diseases (e.g., obesity, type-2 diabetes, high blood pressure, heart disease) and take many medications to treat their symptoms. These drugs can change the structure and function of the human microbiome.
Is the Production of Safe and Effective Drugs Possible Without Considering our Microbiome?
Firstly, James does make the point that some pharmaceutical drugs do not affect our microbiome, although he isn’t specific in the podcast about which.
He emphasises that there exists large inter-individual variability of microbial ecology between people. When combined with the knowledge that many different strains of microbes metabolise drugs differently, this means that one of the basic principles of modern drug development is called into question.
When investigating the safety and effectiveness of a potential new drug, one of the first things we try to understand is, when taken, where does this experimental chemical go in the human body? We investigate its absorption, distribution, metabolism, and excretion (ADME) and refer to this as its pharmacokinetics (PK).
James asks the obvious question, can we accurately predict the PK of a potential new drug without understanding how it interacts with the enormous metabolic impact of our microbiome? He makes it obvious that he believes the answer is a resounding “no”.
What Your GP Doesn’t Tell You Podcast
I like this podcast for several reasons. It tends to cover a range of topics that interest me, it includes individuals who appear knowledgeable about the big issues associated with their chosen matter, and the host asks intelligent questions related to the points made by her guests.
From the commentary on her blog site:
“This fortnightly podcast reveals the stories from the world of medicine that others don’t, won’t or only very partially report. Aimed at both doctors and the public, it’s hosted by award-winning medical journalist and former BBC producer, Liz Tucker, who reports not just on the science but on the finance and money that can impact it. Liz asks what does the medical data actually tell us and why is this often interpreted and presented very differently? How do we know what information to trust and when should we ask our GP, but what’s the evidence?”
James Kinross
“Dr Kinross is a Senior Lecturer in Colorectal Surgery and a Consultant Surgeon at Imperial College London. His clinical interest is in robotic surgery and minimally invasive surgery for colorectal cancer. He performs translational research in the fields of early colorectal cancer detection and prevention and in surgical technology transfer.
His group is studying how the gut microbiome causes colorectal cancer and how it may be engineered to improve operative outcomes. He works with the African Microbiome Institute to determine how diet/microbiome interactions cause western diseases such as cancer, and he is a Co-I on the Horizon 2020 funded GROWTH consortium studying how the microbiome influences anastomotic healing and surgical gut health. He cofounded the International Cancer Microbiome Consortium.”