It has long been thought the type and amount of microbes using the human body as a home shape the way we live and behave. The microbiome as it is known is shown to have a greater and greater impact in our daily lives.
A new study published in Nature (paywall) provides evidence demonstrating the artificial sweeteners we all love and consume to control weight leads to increased blood glucose levels. How can something used to replace sugar in consumables raise the amount of sugar in the blood?
Like many other answers regarding human health, look no further than the microbiome. Consuming artificial sweeteners alters the composition of the intestinal microbes leading to a growing glucose intolerance. The researchers linked artificial sweetener use to altering metabolic pathways within the microbiome that leads to increased susceptibility to metabolic disease.
To verify their findings, researchers gave antibiotics to the mice used as models thus reversing the effects of artificial sweeteners. Results were also verified by using fecal transplantation in the mice to reverse glucose intolerance.
The Human Microbiome: Our Ecosystem
We already knew the microbes outnumbered our human cells 10 to 1 and that the microgenome outnumbered our human genome 100 to 1. The evidence is growing suggesting our normal flora govern more of our lives than we naively assumed for decades. We are not individuals but individual incubators for the microbial overlords that we could not live without. Just like other ecosystems, changing our lifestyles have a complicated effect on system as a whole. Small alterations to the microbiome can have major impacts and be the difference between health and disease.
Future posts will hopefully provide evidence demonstrating how we are shaped into individual ecosystems. Thank you, microbiome.
I have sat on this long enough. It’s not like a have anything else going on right now (except the birth of a son in a month, syllabus to write, classes to prepare, evaluations to do, data to journal, …). Introducing:
Here are the details presently. I and anyone willing to help will scour the journals of our respective fields and choose those we feel need to be disseminated to the larger public. In a short synopsis (abstract if you will), an overview of the article and why it is important will be written and deposited here. Details will be worked out on how to submit the abstracts in the near future.
Now is the time to act (or later if now is not convenient)!
I was recently approached about developing a children’s book to educate about bacteria in hopes of clarifying misconceptions many have about ‘nasty germs’. I must say how amazed and honored by the invitation I am. The company is small without a lot of capital to produce such a book at will. So, I was asked if I had contacts that would graciously sponsor the production of the book. This to me is bittersweet. I would love to be a part of something that would be so helpful for the public regarding the reality of microbes (they tend to get bad press in general). However, I’m not one to ask for money…ever.
This has sparked questions in my head about the state of educational media production. S.T.E.M. is all the rage these days and rightly so. As our society progresses, the need for a workforce trained for technical and scientific positions is essential. One example…billboard signs. Growing up, I used to get excited and amazed when I saw a person putting up a new billboard sign. Taking the old one off, applying the new one in its place. However, now these signs are replaced by digital billboards. Who is going to change the billboard advertisement? Someone trained to tear down the old and glue the new one on? Someone with a background in electrical engineering? If there is a problem with the billboard, who will fix it? A carpenter or an engineer? This is just one example.
The STEM push is necessary and welcome in my opinion. However, a quite fitting phrase comes to mind: show me the money. We are throwing money into public school systems that are fueled by bureaucracy and inefficiency. Yet we still have to cut out box tops to support local schools and have several fundraisers a year for a new gym floor. Anyone see the irony?
Put the money where it can be useful. Put it in projects that will encourage our children to pursue a career that will promote curiosity and critical thinking. This has been my soapbox, today sponsored by the letters S, T, E, and M.
Many do not place ‘bacteria’ and ‘memory’ in the same sentence. Normal human perception does not connect the two concepts. However, Mother Nature seems to have a more profound perception. The past 50 years or so of scientific investigation has shown how our uniqueness as humans is actually commonplace across all forms of life on Earth. Case in point, how closely associated molecular memory is between bacteria and human.
Bacteria use adaptation to signals as memory
Swimming bacteria do not move randomly in their environment. This behavior would be futile and counterproductive. Instead, bacteria are constantly monitoring their environment in search of food and poisons. Moving towards the former and away from the latter. This observation was first published in the late 19th century. Bacteria, like the famous and infamous E. coli, use molecular antennae to receive these important ‘signals’ as the basis in the decision of which direction to swim. What if the bacteria find a great place to reside with lots of food but still need to receive signals to ensure they remain there? The antennae have sections that can be modified easily and reversibly. These modifications, in the form of methylation, alter the sensitivity of the antenna protein to subsequent signals. Methylation allows these antennae not to receive the number of absolute signals but relative signals. In other words, the antenna protein through fine-tuned methylation detects changes in the number of signals now versus some time in the past. This is the basis of molecular memory.
These antennae are proteins called methyl-accepting chemotaxis proteins, or MCPs. MCPs accept methyl groups from the essential cofactor S-adenosylmethionine (aka SAM or AdoMet). AdoMet is essential to both prokaryotes and eukaryotes like humans. The methyl groups are added by a protein called CheR (pronounced ‘key R’) which transfers the methyl from AdoMet to very specific amino acid side groups of glutamate. The process, called O-methylation adds the methyl group to the single-bonded oxygen on the carboxyl.
The length of a bacterium’s molecular memory is very short in comparison to how we perceive memory at only a few seconds. But, to bacteria it is long enough to successfully navigate the environment with similar precision when concentrations of food or poison vary (up to several orders of magnitude, or ~1000x).
Does the basis of molecular memory in humans mimic bacteria?
Eukaryotes, including humans, use a very similar mechanism in signal transduction to bacteria. Phosphorylation (transferring a phosphate group from ATP or GTP to a protein amino acid) is the basis of all signal transduction and cell regulation. Bacteria use histidine kinases and response regulators, as do plants to some degree. However, the majority of regulation through signal transduction in eukaryotes is through two types of proteins, RAS proteins and the heterotrimeric G-proteins. G-proteins interact with membrane receptors that regulate their activity. What determines which surface receptors G-proteins interact with? Isoprenylcysteine methyltransferase, or ICMT, is one of two methyltransferases that regulate signal transduction activity. ICMT is a membrane protein that uses AdoMet to add methyl groups to isoprenylcysteine, a post-translationally modified cysteine residue on both heterotrimeric and RAS-related G proteins. Methylation regulates which receptors the G-proteins interact with, thus playing a major role in connecting the initial signal to downstream regulatory pathways. The carboxyl methylation essentially modulates G-protein signalling globally.
G-protein carboxyl methylation is regulated by GPCR signaling and, as seen above, GPCR signaling is regulated by G-protein carboxyl methylation. This feedback/feed forward loop could be seen as a form of molecular memory stored in methylation patterns. Within the brain, ICMT activity is almost exclusively found in the region controlling coordination of movement. Thus, methylation could be used to modulate certain neuronal signaling pathways which result in learned patterns of sensory-motor skills.
The only other major methyltransferase is from a protein known as PPMT. PPMT interacts with a major enzyme in signal termination, the protein phosphatase PP2A. PPMT adds methyl groups to the backbone carboxyl of a specific leucine in PP2A. This carboxyl methylation helps determine which B subunit PP2A interacts with and where in the cell PP2A can be found. PPMT structurally resembles CheR in bacterial memory. Moreover, the enzyme that removes the methyl group from PP2A, PME, structurally resembles the bacterial enzyme that removes methyls from MCPs, CheB.
PP2A is one of the major regulators of pathway coordination to maintain synaptic plasticity in the brain. Interestingly, methylation defects and PP2A-PME complexes are suggested to play a role in the cause of Alzheimer’s Disease and memory loss. Methylation defects leading to defective phosphatase activity of PP2A leads to accumulation of a phosphorylated subunit of the structural protein microtubule. In this phosphorylated form, the filaments used to keep axons structurally sound collapse and lead to loss of normal synapses. Therefore, molecular memory in the form of methylation plays a vital role in promoting normal brain activity and its disruption can ultimately lead to dementia.
Chicken, meet egg. Egg, meet chicken.
So, from bacteria to human, carboxyl methylation is necessary for memory. Did these pathways evolve individually in parallel, or did the memory we have today originate in the predominant lifeforms found within us?
Li and Stock. (2009) Biol. Chem. 390: 1067-1096. DOI 10.1515/BC.2009.133
Patrons: metabolites/compounds/substrates and products
Managers: two-component proteins to regulate gene transcription
Employee list: genome
Copy machine: DNA replication machinery
So, in the last part our restaurant was going great and we opened up a new restaurant with the same employee list among other things. The two restaurants are now independent of each other and are free to act accordingly.
What if things change and times are not going as well? The overall number of patrons drastically decreases, not enough electricity (ATP) to run the restaurant or running water (redox potential)? What if disaster is about to strike? How can the restaurant prepare all the managers, employees, the building, the doors, the patrons for it?
Luckily the restaurant has a monitoring system that can quickly make sure the restaurant will be ready for anything that comes its way. The monitoring system can take snapshots of all data generated by the restaurant: power supply, water supply, patron count, employee count, conditions outside the restaurant like weather or competing restaurants. The monitoring system is the bacterial second messenger systems. With the support of the managers, the monitoring system can instantaneously keep track of all variables and make changes as needed.
The system is detecting the start of a drought. This drought will lower the number of patrons coming and going from the restaurant. The drought will also change the available electricity and water supply of the restaurant. The monitoring system sounds the alarm, a message is sent over the intercom for all the managers and employees to hear and react to. The intercom message alerts some managers to call in additional employees while telling others to stop their work. Some employees take on a new job in preparation for the drought. The intercom message is the bacterial second messenger cyclic-di-GMP. The entire restaurant begins preparations for the drought so it can survive until better times are present. Other than changes to managers and employees, some new employees are called in to prepare the building itself. Perhaps to change the number of doors. The employees may also change the exterior of the building to better withstand the drought like changing a wood exterior to a brick or stucco one. The brick or stucco are the exopolysaccharides, complex sugars on the exterior of the cell that can serve as protection or to help cells adhere to each other to ride out the hard times together.
When times change, the restaurant has to be able to change with them. That is why these restaurants have been in business for ~3 billion years and still going strong.
My family and I recently went to a circus. It had one ring, and that was manageable. We have also been to a traditional three ring circus in the past. Personally, I felt there was too much going on at one time to enjoy all three rings at once. Each ring had skillfully trained performers doing their job for the enjoyment of the audience simultaneously. That is how a circus functions. Now imagine if you were able to observe a circus with more than 1000 rings. Imagine the complexity and the majestic choreography unfolding before your eyes. This is essentially what bacteria have been doing f0r millions of years with ease Instead of rings, these little circuses have pathways, a group of proteins/enzymes that all function together to perform a task. Like a circus, these pathways are not in isolation but instead many are performing at the same time. Even the “simplest” bacteria have over 500 pathways. Imagine trying to watch a 500 ring circus and understanding what is going on or being in charge of all 500 rings as they perform. Just because we don’t understand microbes does not make them simple, it makes us naive.
When sequencing a bacterial genome, computers and researchers try to connect all the dots. That is, they try to predict the role each gene/protein plays within that circus. For a bacterial circus with 5000 members (genes), only about one third of those can be assigned to a particular ring (pathway). This means a majority of members from a genome have a role we haven’t observe enough to classify its context. Now, imagine two thirds of KNOWN genes in KNOWN bacteria and the fact we approximately know 1% (or less) of the total number of bacterial species on, or in or above, earth. It doesn’t take long to discover that there is much more to discover in microbiology.
We as humans are beginning to utilize bacteria, or their pathways, to advance our civilization. Whether it is to clean up our polluted, toxic land or to advance medicine through fecal transplants, bacteria will play a much bigger role in the near future. Not bad for such small species. 500 rings or 2000 rings, these circuses are truly the greatest shows on earth!
A 1500 ring circus from a typical bacterium.
Continuing on the theme that bacteria are Nature’s smallest circus, I want to highlight the most glaring problem with our knowledge of these 2000 ring circuses. We have discussed how proteins encoded by genes within a microbe’s genome often work together to carry out their function, i.e. pathways (or rings). To date, according to the NCBI genome site 4019 bacterial genomes have been sequenced to the point that we know the number of genes and proteins each organism contains. Moreover, this equates to 7,309,205 genes total or roughly 1818 genes per genome. These are astonishing numbers. To show our futility as experts of all things natural, over 30% of these genes are considered hypothetical or uncharacterized. In some genomes, these genes make up 60% of the total genes. These terms are a technical way of saying “hell if we know what they do”. Computers have recognized them as genes or open reading frames, however, the gene itself isn’t similar enough to known or characterized genes for scientists or computers to call it “the same”. If these gene products (proteins) functions are unknown, they cannot be assigned to a ring in the circus therefore making the largest ring by far in any bacterial circus the “unknown” ring.
Many say storytelling in science is a great way to describe complex material in an understandable way for the masses. In this post, I will try to use an analogy to illustrate the complexity of a typical motile bacterial cell.
Microbial Physiology through Storytelling
If there is anything Americans know, it’s food. We are a nation obsessed with food and frequent restaurants on a regular basis.
Imagine your favorite restaurant as one huge bacterial cell.
When I travel to another city, I can’t rely on habit to guide me to a restaurant for dinner. I have to search for it while driving down the road. In order to know when I have found the restaurant I am searching for, I must rely on signs telling everyone what the restaurant is. The sign is a way to recognize and identify the building as i) a restaurant and ii) the specific type of restaurant. Bacteria do the same. They have ‘signs’ (proteins and other molecules) attached to the outside of the cell that lets other cells around identify what the cell is. I go into the restaurant through a door that allows patrons to move in and out of the building like bacteria have gates or channels that allow molecules to move in and out of the cell. Almost always, patrons are different leaving than they were when entering the restaurant; filled with yummy food they consumed and perhaps stopping to make a deposit in the waste room before leaving. Many molecules that leave a cell are different than those that enter. The workers of the restaurant have to keep track of the number of patrons entering and leaving the building to efficiently serve the patrons. Each employee has a specific job to do for very specific patrons. The employees have to identify their patrons and serve them as described by the bosses. Bacteria have an array of workers (proteins and protein complexes) that have very specific job descriptions depending on the patrons (substrates and product molecules) present in the cell. The restaurant survives by serving as many patrons as possible efficiently and correctly just as a cell must survive by responding correctly and quickly to everything in its environment.