What do you think you are? (post 2 of 2)

To continue fromwhere we left off in the previous post (you may want to go back and read that if you haven’t) let’s look at another evolutionary arguments for the importance of our microbiome. Bacteria have been colonising humans since we first existed. Human eating habits have changed a lot within a very short period. Throughout much of our evolutionary time we have eaten a diet ripe in bacteria – meat caught and slaughtered outside, vegetables grown naturally in fields and so on. However, within recent times our food production (and consumption) has changed. Processed foods have become increasingly common, and these are largely sterile. Additionally, antibiotics are heavily used in the animal farming industry; reducing the amount of bacteria we receive from our food. Some claim that this may be disrupting our microbiome, as we are not getting the same level and diversity of bacteria. Furthermore, this disruption caused by out eating habits may be playing a role in the development of obesity in the Western world. Obviously the diet itself plays a major role in obesity, but the microbiome may also contribute. Consider the fact that if we have a gut full of bacterial cells all needing energy, they are going to take what they need from the food we ingest, before we absorb it for ourselves. If we have less microbes, in the gut, and less coming in with our food, then less energy will be taken out of the system, potentially allowing more to enter into our bodies; this excess of energy may well be play a significant role in obesity.

The use of antibiotics by farmers also argues for a role of the microbiome in obesity. The reason antibiotics are used by farmers is from the observation that this practice caused a gain of weight in the animals. For a long time this was not understood, but now with the evidence emerging from humans and other animal studies it appears that this affect could be down to the depletion of the microbiome caused by the antibiotics. A further example comes from studies in mice which have shown that transplanting the microbiome from an obese mouse into a thin mouse leads to weight gain. The reverse has also been seen. If this holds true in humans then targeting the microbiome may be a feasible way to tackle the obesity epidemic of the Western world.

Changing tack slightly, as you may be aware, antibiotics have been overused for a long time, leading to major worries over antibiotic resistance and reversion to a pre-antibiotic era. This is a huge worry, however the overuse of antibiotics may have additional consequences that we are only just starting to realise. It has been found that people in the Western world are now largely devoid of the bacterium Helicobacter pylori, which is common in the guts of people in areas of the world less rife in the use of antibiotics. Removal of H. pylori isn't a bad thing per se; this bacterium is known to cause peptic ulcers and stomach cancer. However, the importance of H. pylori is a nice shade of grey and we have only noticed the beneficial effects now it’s gone.

H. pylori plays an important role in controlling stomach acid production and people devoid of it are at a much higher risk of developing acid reflux. Acid reflux can lead to a condition known as Barrett's oesophagus and eventually certain forms of oesophageal cancer if left untreated. Coincidently with the loss of H. pylori from the gut microbiome in the West, rates of oesophageal cancer have soared. Furthermore, H. pylori is able to control inflammatory responses. This control may be important for regulating allergies, which are caused by an inappropriate inflammatory response against something harmless (such as pollen). Similarly to the rates of oesophageal cancer, it is well documented that there are an increasing number of people with allergies in the Western world. Finally, H. pylori may also be important in obesity, as it is known to regulate the hormone ghrelin, which regulates our appetite. All of this has led to some suggestions that we should inoculate babies with H. pylori. Obviously this raises ethical issues because of the potential for peptic ulcers and stomach cancer, but these are largely only seen later in life. The current idea is that we should inoculate at a young age and then give antibiotics to kill the bacteria later in life, getting the best of both worlds.

A mentioned, H. pylori may be playing a role in the inflammatory response and development of allergies. However, the link between resident bacteria and the immune system doesn’t end there. It appears that our whole microbiome is essential for the development of a proper immune system that doesn't attack the wrong things. Without the bacteria in our guts it is thought that the immune system may become hypersensitive and attack everything, leading to allergies.

Histological section of intestine lining

Sticking with the immune system, many chronic diseases have inflammation as an underlying cause. Inflammation is an essential part of our immune response, but is only beneficial if it is transient; sustained inflammation leads to damage around the body. It has been found that Bifidobacteria and Lactobacilus species in the gut are essential for maintenance of the epithelial lining in this organ (the cells that make up the walls of our gut). A proper epithelial lining plays an essential role in the passage of nutrients out of our digestive system into our blood. The lining needs to be ‘selectively permeable’ so that only certain, useful, things get through. If the lining becomes ‘leaky’, then unwanted molecules can get through such as bacteria and their toxins or whole protein molecules (instead of just the amino acids we normally absorb from the gut), all of which could trigger an inappropriate immune response. Since Bifidobacteria and Lactobacilus are needed for maintenance of the epithelial lining, any disruption to these bacteria will have an impact on the integrity of the barrier. Indeed, it has been shown that mice fed on a "junk food" diet have a disruption of these bacteria and develop a ‘leaky epithelia’. This caused a low level systemic inflammatory response, which eventually causes metabolic diseases. It is therefore highly possible that many disease with inflammation as an underlying cause could originate from issues with out internal bacterial species.

The final thing I'd like to discuss is that the notion of thinking with your gut may hold more truth than you know. It has been found that microbes in the gut are important for the generation of neurotransmitter molecules such as serotonin and thus may be playing an important role in regulating mood. Furthermore, there is evidence suggesting a link between the gut microbiome and the hypothalamic-pituitary axis (HPA), a region of the brain that shows disruption during clinical depressive episodes. Mice bred to have no microbiome show an enhanced stress response that can be curtailed by the introduction of a microbiome - this response, to a large extent, is generated from the HPA. Additionally, it been shown in mice that if the microbiome of adventurous mice is transplanted into the guts of timid mice they lose their inhibitions and become more adventurous, further supporting the notion that our gut bacteria may be influencing our brains.

It may be scary to think that we are only 10% human with the remainder being made up by microbes, the majority of which are bacteria. What may be even scarier to consider is that these bacteria may have an influence on our most evolutionarily important organ, the brain. Bacteria could be controlling our response to stress; they could also potentially have even broader and larger effects on our behaviours and mood. Additionally to affecting our brains, there is increasing evidence that the gut microbiome plays essential roles in our immune system and may even play a huge role in obesity. Obesity is one of the biggest issues in the Western world and any methods to tackle it are rightly gaining much attention. Since we can alter our gut microbiome through the foods we eat and the drugs we take it stands to reason that with increased research in the area we may be able to shape our microbiomes to tackle disease. Since the microbiome seems to affect so many different aspects of our physiology, altering it will be fraught with potential pit-falls. But to look at it in a more positive light, we may be able to tackle a plethora of diseases in a very simple and affordable manner. Bacteria tend to get a bad reputation, but without them we probably wouldn’t be here.

What do you think you are? (post 1 of 2)

You may consider yourself human, made up of human cells doing their human thing. However, this isn't the complete story. An average human adult is made up of roughly 10 to the power 13 cells (that's 1 followed by 13 zeros). While this is a fairly large number, it only accounts for 10% of the cells that make up a human body. A remarkable 10 to the power 14 bacterial cells and other microbial cells account for the remaining 90% of the cells that make us what we are. It may be better to consider humans as a super-organism, an ecosystem made up of human cells, bacterial cells, and many other forms of cellular life (and viruses). 99% of the genetic material within the human super-organism is microbial, not human, which some refer to as our "second genome." These microbial co-habitants aren't simply freeloaders either; it is becoming increasingly apparent that this "second genome" may be playing just as much, if not a greater, role in human health and disease. Additionally, while our genome is fixed, we may be able to shape the microbiome (all of the microbes that call us home) in a therapeutic guise, giving new avenues for treatment of diseases as diverse as obesity, immune-related and mental. Over the next couple of blog posts (there’s a lot to say so I’ve divided it into two) I'd like to discuss with you some of the evidence for how important the microbiome is and the importance it may be playing in a handful of diseases. 

The human digestive tract

While bacteria can be found all over humans, one of the largest concentrations of our microbial tenants can be found in the gut. To start with the most graphic of examples for how important the microbiome is let us look at fecal transplants. A reoccurring theme through this set of blog posts will be the fact that antibiotic use damages our bacterial inhabitants. Obviously we need antibiotics to treat dangerous bacterial infections, but they do have the side effect of depleting the beneficial bacteria, especially when broad-spectrum antibiotics are used. It has been observed that infection with antibiotic resistant C. difficile is common following courses of broad-spectrum antibiotic treatment for other diseases. C. dif. infection is largely a hospital acquired infection and can lead to death. Recently fecal transplants have been successfully used in C. dif. patients and these have been shown to lead to recovery from the infection which antibiotics can do very little for. The fecal transplant, or fecal bacteriotherapy as some refer to it, introduces a whole range of new bacterial species into the patients gut to replace those damaged by the original antibiotic treatment. These new species are able to grow and outcompete the harmful C. dif., allowing recovery. Clearly having an intact microbiome is important in this disease.

A clump of E. coli in the gut imaged
by scanning electron microscopy

The importance of our bacterial self can be seen in less graphic ways also. One good way to study the microbiome is to look at babies, and much of our understanding has come in this manner. Prior to birth, babies have essentially no microbiome. At birth however they are inoculated with numerous bacterial species and continue to develop their microbial populations until about the age of 3, when the microbiome becomes largely set. Natural birth is a very good way to inoculate a newborn with the necessary bacteria, as it's a fairly messy process. A far cleaner birth is achieved through caesarian section, a procedure done in a largely sterile manner. Studies of babies born through the two different methods have shown that there is, as you may expect, a large difference in their microbiomes. Babies born through C-section have a microbiome that, to a large extent, resembles the skin bacterial populations of the mother, where as babies born naturally have microbial populations resembling that of the mothers gut and vaginal bacteria. Having these different populations seems to have some consequences with certain studies suggesting that C-section babies have a higher incidence of asthma, allergy and autoimmune disease. These diseases are thought to be down to the altered microbiome. There is in fact an on going trial in which C-section babies are being inoculated with vaginal secretions to ascertain the true importance that the altered microbiome is having to health and disease. 

Bifidobacterium imaged by scanning electron microscopy

Infants have also provided further insights into the importance of our microbiome, this time from an evolutionary point of view. Breast milk is the only food source that is shaped by evolution, so the fact that it contains complex carbohydrates that babies are unable to digest, and therefore make use of, was for a long time a mystery. Why would resources be wasted putting sugars into milk that provide no benefit for the baby? Or alternatively, why have we not evolved a mechanism to digest and use these sugars? It was eventually discovered that even though we humans lack the ability to use the carbohydrates, a bacterial species in the gut known as Bifidobacterium are very capable of putting them to good use. Providing these bacteria with the sugars they need allows them to rapidly grow and become one the major constituents of our gut microbiome. Filling the gut with harmless Bifidobacterium means there is a reduced chance for other bacteria to grow, protecting us from colonization by pathogenic bacteria. Bifidobacterium are also important in another respect that I will get to in the next post. Mother's milk has been shaped by evolution and this process has resulted in the inclusion of sugars that are there simply for the benefit of a bacterial species found in the gut of babies. Clearly evolution has favoured the growth of the microbiome in this manner, once again showing how important our bacterial inhabitants are.

I shall end this post here so as not to take up too much of your time. The second half will continue on a similar theme looking at another partly evolutionary based argument for the importance of our microbiome before moving on to look at diseases linked to disruption of the microbiome. Be sure to come back for the concluding part…