Overview
The human microbiome, also known as gut flora, is a hot scientific topic as of late. This post examines recent findings from primary scientific literature to explain how microorganisms can raise or lower our risk of disease. Microorganisms can be bacteria, protists, fungi, or viruses. Since most of them are smaller than the cells in our body, they can travel throughout the blood and tissues easily. The gastrointestinal (GI) tract is where most of them reside – about 95% of the microbes in your body are located there. Almost all species in the GI tract are anaerobic which means that they don’t use oxygen for respiration. Many organisms in the human microbiome (HM) co-evolved with our species, so they often consume the same amino acids or produce compounds that we use biologically. Gut microbes can influence the types of food you crave and how efficiently you digest them. They also mediate some inflammation and immune response processes [1].
Since there are millions of species in the bacteria kingdom, it’s no surprise that hundreds or thousands of individual species are expected in the GI tract at any time [2]. Scientists have collected HM data from thousands of individuals and that aggregated data tells us which species are normal – thus expected in the GI tract – and which species are unusual. Understanding which species are unusual when compared to the average HM aids physicians in diagnosing unknown ailments if rare species are present. We know that our individual microbe communities are established within a few days of birth and there are about 100 trillion living inside our bodies at any given time [2].
Figure 1: Relationships among each level of taxonomy
So, how exactly do scientists count them all? The answer draws on their genetic codes. You’re probably familiar with the idea that we have a unique chemical fingerprint called DNA. The whole code can be broken into a collection of smaller parts called sequences. Some sequences are the same for every member of a species. Others, however, differ because of the probabilities of inheriting a particular copy from each parent. You may also be familiar with genetic mutations – these are small changes in DNA that don’t affect the overall integrity of the structure, but do affect the protein products that result from it.
We can track the evolution of mutations over time and genetic sequencing helps us do that. For example, did you know that blue eyes in humans are said to be the result of a single mutation thousands of years ago? It follows that everyone with blue eyes is descended from the same person who carried the first mutation. Genetic sequencing can identify unique pieces of code that belong to only one species – often the result of a mutation. Even though people with blue eyes are not a unique species (since they can reproduce with other humans no matter their eye color), we can use sequencing to determine whether the donor of some DNA had blue eyes. This is how we can take tissue from fossilized bones or a crime scene and generate an image of the person who owned it. We do the same thing for gut flora by matching the sequences found in stool samples to a library of genetic material from known organisms.
Figure 2: Bi-directional nature of communication between the gut microbioma and anatomic systems[2]
Key players and their contributions
About 70-75% of the HM consists of just two phyla. You can think of a phyla as the level of taxonomy just below kingdoms. The bacterial phyla that make up 70-75% of the HM are Firmicutes and Bacteroides. The bulk of the remaining HM phyla consist of Proteobacteria, Actinobacteria, Fusobacteria, and Verrumicrobia. We’ve learned that the proportion of these phyla differs predictably among ethic groups – a phenomena known as enterotypes. Since the HM co-evolved with world cultures, it might be possible to learn what our ancestors ate based on the gut flora of their descendants [2].
DNA is not the only genetic coding language. RNA is a similar code interpreted by the ribosomes in prokaryotic cells. Ribosomes are like tiny factories that read the RNA blueprint and create proteins from the instructions. Each 3-character sequence corresponds to an amino acid. Amino acids are always floating freely in the cellular fluid so the ribosome helps to retrieve whichever one the code calls for, assembles it and affixes it to a chain called a protein. In a way, the RNA sequences that bacterial ribosomes interpret are a part of our own genetic code because the process takes place in our body [1].
Mitochondria are organelles (miniature organs in cells) that produce energy for our cells. They’re interesting from an evolutionary perspective because evidence suggests that they used to be independent organisms. At some point, mitochondria formed a symbiotic relationship with eukaryotic cells. This explains why they can exchange cellular signals with bacteria – and therefore our gut flora.
You may be familiar with Streptococcus bacteria because of the havoc they can wreak on your throat. But did you know that these bacteria in the Firmicutes phylum can exist dormant in our bodies without causing sickness? This characteristic explains why people who suffer a strep infection may not develop symptoms until much later, usually when their immune system is weakened for some reason. Sydenham’s chorea and rheumatic fever are two examples of serious problems caused by Streptococcus.
Germ-free mice are a special kind of mouse designed to live without gut flora. They are kept in isolation, breathing filtered air, and eating food that has been sterilized to kill any microbes in it. Scientists bred these animals to see what happens when someone doesn’t have a microbiome at all. What we learned from them explains a lot about how the ENS communicates with the brain, and how our bodies absorb food. Germ-free mice taught us that a microbiome is absolutely essential for passing food particles through intestinal walls, transmitting nerve signals in the ENS, and activating sensory neurons [1].
Microbes can produce neurotransmitters. These are compounds that activate receptors on neurons and either excite or subdue their activity. GABA is an inhibitory neurotransmitter that can be produced by our own bodies or by some species of bacteria. Lactobacillus is one such species in the Firmicutes phylum; Bifidobacteria is in the Actinobacteria phylum but it can also produce GABA. Imbalances in the amount of GABA in the brain can cause anxiety, problems growing new connections between neurons, and even depression [1].
Ways to support your microbiome
- Take a probiotic supplement
- Have your gut flora analyzed to see if the species present or their proportions differ from expected guidelines
- Consume pre-biotics – these are foods are compounds that act as a precursor to a healthy microbial community
- Avoid eating too much bread or sugar. These foods support Candida overgrowth – which causes problems ranging from indigestion to thrush, a painful yeast infection in the mouth and throat.
- Don’t overuse antibiotics. If you’ve ever experienced diarrhea while taking a course of amoxicillin, then you’ve experienced firsthand the result of killing your “good” bacteria. This isn’t to say that you should eschew modern medicine for the sake of avoiding this problem, just that you should be aware of overusing antibiotics. Aside from harming your natural microbial balance, overusing antibiotics can cause bacteria to acclimate and evolve into antibiotic-resistant strains called superbugs.
Disease and gut flora interactions
Alzheimer’s disease is associated with marked decreases in several phyla of bacteria, and increases in three. Bacteroidetes, Tenericutes, and Rikenellaceae are found at higher levels than expected in the bowels of mice with a genetic mutation that accelerates Alzheimer’s-like cognitive decline. In particular, they have a mutation in the amyloid precursor protein (APP) gene. Alzheimer’s disease is caused by the mis-folded protein products of this gene. They clump together inside neurons and injure them over time. There appears to be an association with the presence of microbiota overall and the severity of Amyloid plaque formation. Researchers in Switzerland discovered that the APP transgenic mice that were also raised in a germ-free environment exhibited less cognitive decline then their transgenic peers with a microbiome [3].
Cardiovascular disease is the leading risk factor for developing vascular dementia later in life. What’s more, there are 5 biomarkers that can be used to assess both cardiovascular health and Alzheimer’s disease risk. That’s one of many findings that supports a link between the two conditions. Scientists wanted to know whether these common biomarkers are associated with any particular bacteria in the gut – and it turns out, they are. The biomarkers of interest are triglycerides, hs-CRP (c-reactive protein), LDL cholesterol, HDL cholesterol, and total cholesterol. Organisms that have an overall negative association with the biomarkers are Roseburia, Parabacteroides, Clostridium, Peptostreptococcus, Clostridiates, and Eubacterium [4]. Anaerotruncus, Akkemansia, and Acidaminococcus tend to be positively correlated. These associations are complex; for example, the presence of Odoribacter is associated with increased HDL cholesterol and decreased LDL cholesterol.
Findings regarding the direction of correlation between these biomarkers and microbes are conflicting. One one hand, Karlsson et al. found that Erysipelotrichaseae were negatively correlated with LDL and total cholesterol levels. In other words, higher levels of Erysipelotrichaseae are associated with lowered cholesterol. However, Koren et al. found a positive association between Erysipelotrichaceae levels and these biomarkers. Recall that most microbes are in the GI tract but not all of them. For example, Zhang and Zhang discovered that high levels of oral Legionella and Streptococcus microbes are associated with atherosclerosis.
Type 2 diabetes symptoms may be managed using Lactobacillus supplements. This microorganism is typically present in dairy products and helps lower blood glucose levels [5]. In addition, its presence is associated with increased HDL or “good cholesterol” levels in the bloodstream. Other microbes are found in higher concentrations when someone is living with metabolic dysfunction. Firmicutes and Bacteroidetes seem to increase when glucose isn’t processed properly.
References
[1] Bhattacharjee, S. & Lukiw, W. J. Alzheimer’s disease and the microbiome. Front Cell Neurosci 7, 153, doi: 10.3389/fncel.2013.00153 (2013).
[2] Foster, J. A & Neufeld, K. M. Gut-brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences 5, 36, doi: 10.1016/j.tins.2013.01.005 (2013).
[3] Harach, T., Marungruang, N., Duthilleul, N., Cheatham, V., McCoy, K. D., Frisoni, G., Neher, J. J., Fåk, F., Jucker, M., Lasser, T., Bolmont, T. Reduction of Abeta amyloid pathology in APP transgenic mice in the absence of gut microbiota. Scientific Reports 7, 41802, doi: 10.1038/srep41802 (2017).
[4] Karlsson F. H., Fåk, F., Nookaew, I., Tremaroli, V., Fagerberg, B., Petranovic, D., Backhed, F., Nielsen, J. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nature Communications 3, 1245, doi: 10.1038/ncomms2266 (2012).
[5] Zhang, Y. & Zhang, H. Microbiota associated with type 2 diabetes and its related complications. Food Science and Human Wellness 2, 3-4, doi: doi.org/10.1016/j.fshw.2013.09.002