Updated: Jun 17, 2020
The dynamics of the gut microbiota are clearly shown below, which while it is comparing the response in different cities, also shows a temporal effect. A large variation in abundance over time suggests an unstable gut microbiota.
Gram-positive cocci and rod-shaped bacteria are the predominant microorganisms found in the small intestine. However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the Enterobacteriaceae. The bacterial flora of the small intestine aid in a wide range of intestinal functions.
The bacterial flora provide regulatory signals that enable the development and utility of the gut. Overgrowth of bacteria in the small intestine can lead to intestinal failure. In addition the large intestine contains the largest bacterial ecosystem in the human body. About 99% of the large intestine and feces flora are made up of obligate anaerobes such as Bacteroides and Bifidobacterium.
Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.
Bacteria make up most of the flora in the colon and 60% of the dry mass of feces. This fact makes feces an ideal source of gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies. Somewhere between 300 and 1000 different species live in the gut, with most estimates at about 500.
Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship. Though people can survive with no gut flora, the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metabolism like propionate and acetate, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.
Bacteria commonly found in the human colon
Bifidobacterium bifidum 30–70
Staphylococcus aureus 30–50
Clostridium perfringens 25–35
Proteus mirabilis 5–55
Clostridium tetani1– 35
Clostridium septicum5– 25
The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram-positive
1. Improved gut microbiota with cholesterol-lowering medication
Date:June 15, 2020
Source: University of Gothenburg
Summary:There is a clear link between improved gut microbiota and one of our most common cholesterol-lowering drug groups: statins.Share:
FULL STORY There is a clear link between improved gut microbiota and one of our most common cholesterol-lowering drug groups: statins. This is evident from a European study involving researchers from the University of Gothenburg. Scientists have previously found an association between the gut microbiota and various metabolism-related and cardiovascular diseases. Now the current study, published in the journal Nature, shows improvement in gut microbiota in the participant group who were taking statins. The direct mechanisms have not been identified. Nonetheless, in this first major publication from MetaCardis (Metagenomics in Cardiometabolic Diseases), a collaborative EU-based project involving 14 research groups from six countries, the results are unequivocal. One of the authors is Fredrik Bäckhed, Professor of Molecular Medicine at Sahlgrenska Academy, University of Gothenburg, who focuses on the role of gut microbiota in metabolism. "Although the study does not provide a causal link," he says, "it's exciting to see how a well-established and clinically used drug can change the gut microbiota. Time will tell whether statins affect bacteria in the gut directly or whether these drugs affect both gut and immune cells that, in turn, help modify the microbiota."
The purpose of MetaCardis is to clarify whether and how gut microbiota may be linked to cardiovascular disease. In the project, more than 2,000 Europeans with varying degrees of metabolic and cardiovascular disease have been meticulously investigated. The gut microbiota is divided into various main groups, known as enterotypes, that vary among individuals. One of these, labeled Bact2, has fewer bacteria in terms of number and composition alike. Microbes lacking in Bact2 include anti-inflammatory bacteria like Faecalibacterium, one effect of which is to strengthen the immune system.
Bact2 is more common in patients with inflammatory bowel disease (IBD), multiple sclerosis and depression. In the current study, the scientists found this enterotype also to be significantly more prevalent in patients with obesity (18%) than people without it (4%) -- an observation verified in an independent Belgian study.
The positive and hitherto unknown effect of statins identified by the researchers was that the proportion of individuals with Bact2 decreased in the group given statin therapy, resulting in a more normal gut microbiota. Together, the various study findings open up for new forms of treatment in the future, in which drugs can be used to alter the gut microbiota.
"Perhaps drugs like statins can be used to change the ecology in the gut. But that calls for further studies," Bäckhed notes. Story Source: Materials provided by University of Gothenburg. Original written by Margareta Gustafsson Kubista. Note: Content may be edited for style and length. Journal Reference:
Sara Vieira-Silva, Gwen Falony, Eugeni Belda, Trine Nielsen, Judith Aron-Wisnewsky, Rima Chakaroun, Sofia K. Forslund, Karen Assmann, Mireia Valles-Colomer, Thi Thuy Duyen Nguyen, Sebastian Proost, Edi Prifti, Valentina Tremaroli, Nicolas Pons, Emmanuelle Le Chatelier, Fabrizio Andreelli, Jean-Phillippe Bastard, Luis Pedro Coelho, Nathalie Galleron, Tue H. Hansen, Jean-Sébastien Hulot, Christian Lewinter, Helle K. Pedersen, Benoit Quinquis, Christine Rouault, Hugo Roume, Joe-Elie Salem, Nadja B. Søndertoft, Sothea Touch, Marc-Emmanuel Dumas, Stanislav Dusko Ehrlich, Pilar Galan, Jens P. Gøtze, Torben Hansen, Jens J. Holst, Lars Køber, Ivica Letunic, Jens Nielsen, Jean-Michel Oppert, Michael Stumvoll, Henrik Vestergaard, Jean-Daniel Zucker, Peer Bork, Oluf Pedersen, Fredrik Bäckhed, Karine Clément, Jeroen Raes. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature, 2020; 581 (7808): 310 DOI: 10.1038/s41586-020-2269-x
Research articles related to the UA project
May 17, 2020
(2) Decoding the massively complex gut microbiome
Date: May 14, 2020
Source:University of California - Santa Barbara
Summary: For something that has evolved with us over millions of years, and remains part of our physiology over our entire lives, our gut microbiome, oddly, remains somewhat of a mystery. Comprised of trillions of microbes of at least a thousand different species, this community of bacteria, viruses, protozoa and fungi in our gastrointestinal tracts is unique to each individual and has been found to be intimately connected to various fundamental aspects of our fitness, from our immunity to our metabolism and mental health.
FULL STORY For something that has evolved with us over millions of years, and remains part of our physiology over our entire lives, our gut microbiome, oddly, remains somewhat of a mystery. Comprised of trillions of microbes of at least a thousand different species, this community of bacteria, viruses, protozoa and fungi in our gastrointestinal tracts is unique to each individual and has been found to be intimately connected to various fundamental aspects of our fitness, from our immunity to our metabolism and mental health.
For UC Santa Barbara researchers Eric Jones, Zipeng Wang and Joshua Mueller, the gut microbiome is a remarkable machine, full of interactions and competitions that directly impact our wellness. Tuning this machine in a favorable direction, they say, could improve our resistance to disease.
"Can medical therapies improve host health by modifying the microbiome composition? We still don't really know, so it's a huge field of research," Jones said. "This question is a great motivator."
In our daily lives, many of us hope to improve our gut microbiome by taking probiotics and eating fermented foods. In clinical situations, fecal transplants have been shown to successfully treat recurring infections of the gut bacteria Clostridium difficile, which often recur after antibiotics used to treat infections wipe out "helpful" gut bacteria as well. But outside of sweeping and heroic measures to add populations of good bacteria to the GI tract, there isn't a whole lot known about how to subtly point the system in a healthy direction.
"It's about more than just putting in the right microbes," Jones said. "You need to understand the environment that the microbes are in and you need to understand what facilitates a stable gut microbiome composition."
To tackle this problem, the researchers, under the guidance of UC Santa Barbara physics professor Jean Carlson, propose a technique for driving a mathematical gut microbiome model toward a target microbiome composition by manipulating certain parameters of the model. Called SPARC (SSR-guided parameter change), this approach reduces the complexity of the system without sacrificing it. And, according to a study published in the journal Physical Review E, it also "offers a systematic understanding of how environmental factors and species-species interactions can be manipulated to control ecological outcomes."
Old equation, new use "So basically, the goal is to find a parameter change that corresponds to a change in the microbiome environment," said lead author Zipeng Wang. It helps to envision the gut microbiome as a ball perched on the top of a hill, poised to roll down in one direction or another. In this idealization, the gut environment dictates the shape of the hill. A healthy microbiome composition lies at the base of one side of the hill, and a disease-associated composition on the other. While fecal transplants directly push the ball to the healthy side of the hill, SPARC, according to the researchers, controls the shape of the hill, effectively rolling the ball down on one side or the other.
To describe this gut ecosystem (data was collected from mouse model experiments at Memorial Sloan-Kettering Center in New York), the researchers used the generalized Lotka-Volterra (gLV) equations. Known also as predator-prey equations, the gLV equations stem from a century-old method used in traditional ecology to describe the interactions between species on Earth, such as competition and predation, as well as effects from indirect interactions.
"But, one of the difficulties is that the gut microbiome has all these different bacterial species," Wang said, "So the Lotka-Volterra equations become very high-dimensional, which means that there are a lot of parameters, and a lot of different ways for bacteria to interact with one another. It would be very hard for us to find the right parameters to achieve the desired microbiome composition."
To avoid the trial-and-error of manipulating an unwieldy number of different parameters, the team opted instead to examine a compressed but reliable 2D representation of the ecological model generated by the dimensionality reduction technique called "steady state reduction" (SSR). According to the researchers, this allowed them to zoom out and identify the key parameters that control the shape of the hill.
"What we like about our model is that it gives us a systematic strategy to identify these low-dimensional features that are really sensitive, that are the most important," Jones explained. "I was really surprised and pleased that we could, for example, find a single parameter and change it by 10% of its value and that would change the shape of the hill."
What is that parameter? Well, given the diversity of gut microbiomes, diets, co-occurring conditions and environmental influences, there is not necessarily one universal parameter change -- say, acidity, or fiber content -- that fits all. The SPARC method, the researchers say, guides thinking on how to identify the significant parameters based on data.
In addition, SPARC currently is primarily a mathematical exercise, though the researchers are eager to try it out in an experimental setting.
"There are people working on what they call gut-on-a-chip systems, which are kind of like miniature Petri dishes that replicate some of the conditions of the human gut microbiome," said Joshua Mueller. "It would be really exciting to validate SPARC in these tightly controlled experimental circumstances."
In the rather more distant future, Jones said, this method could also help pave the way for personalized microbiome management, in which real-time readouts of the state of our microbiomes -- say, from a smart toilet -- could tell us to change our dietary habits to avoid illness and improve our general well-being.
"In order to get to that point, we need mechanistic models of the microbiome," he said. "We need to understand how to control it. We need to understand how environmental feedbacks play into microbial dynamics." Story Source: Materials provided by University of California - Santa Barbara. Original written by Sonia Fernandez. Note: Content may be edited for style and length. Journal Reference:
Zipeng Wang, Eric W. Jones, Joshua M. Mueller, Jean M. Carlson. Control of ecological outcomes through deliberate parameter changes in a model of the gut microbiome. Physical Review E, 2020; 101 (5) DOI: 10.1103/PhysRevE.101.052402
(3) Dynamics of gut bacteria follow ecological laws
Date: May 13, 2020
Source: Columbia University Irving Medical Center
Summary: The fluctuations of gut microbial communities follow ecological principles developed for animals and financial markets, which may help to predict disease biomarkers and effects of unhealthy diets.
FULL STORY The seemingly chaotic bacterial soup of the gut microbiome is more organized than it first appears and follows some of the same ecological laws that apply to birds, fish, tropical rainforests, and even complex economic and financial markets, according to a new paper in Nature Microbiology by researchers at Columbia University Irving Medical Center. One of the main challenges facing researchers who study the gut microbiome is its sheer size and amazing organizational complexity. Many trillions of bacteria, representing thousands of different species, live in the human intestinal tract, interacting with each other and the environment in countless and constantly changing ways. The study's discovery of multiple principles of gut bacterial dynamics should help researchers to understand what makes a gut microbiome healthy, how it may become perturbed in disease and unhealthy diets, and also suggest ways we could alter microbiomes to improve health.
Gut microbiome dynamics remain poorly understood Although current DNA sequencing technologies make it possible to identify and track bacteria in the gut over time, "the biological processes governing the short- and long-term changes in the gut's microbiome remain very poorly understood," says the study's senior author, Dennis Vitkup, PhD, associate professor of systems biology and of biomedical informatics at Columbia University Vagelos College of Physicians and Surgeons.
As a first step in identifying the factors that describe microbial communities in the gut, Vitkup and his co-authors, graduate students Brian W. Ji and Ravi U. Sheth and research scientists Purushottam Dixit and Konstantine Tchourine, looked for mathematical relationships describing dynamical changes of the gut microbiome of four healthy people followed for a year. They also analyzed microbiome data obtained for mice fed either high fiber or high fat diets every day for several weeks.
With this data, the researchers explored statistical connections between various aspects of microbiome dynamics, such as fluctuations and abundances of various bacteria over time, or the average times different microbes continuously reside in the human gut. "Up to now, it has been an open question whether there are any natural laws describing dynamics of these complex bacterial communities," Vitkup says.
Chaotic fluctuations follow statistical laws As expected, they discovered large fluctuations in the composition and daily changes of the human and mouse gut microbiomes. But strikingly, these apparently chaotic fluctuations followed several elegant ecological laws.
"Similar to many animal ecologies and complex financial markets, a healthy gut microbiome is never truly at equilibrium," Vitkup says. "For example, the number of a particular bacterial species on day one is never the same on day two, and so on. It constantly fluctuates, like stocks in a financial market or number of animals in a valley, but these fluctuations are not arbitrary. In fact, they follow predictable patterns described by Taylor's power law, a well-established principle in animal ecology that describe how fluctuations are related to the relative number of bacteria for different species."
Other discovered laws of the gut microbiome also followed principles frequently observed in animal ecologies and economic systems, including the tendency of gut bacteria abundances to slowly but predictably drift over time and the tendency of species to appear and disappear from the gut microbiome at predictable times.
"It is amazing that microscopic biological communities -- which are about six orders of magnitude smaller than macroscopic ecosystems analyzed previously -- appear to be governed by a similar set of mathematical and statistical principles," says Vitkup.
Laws allow identification of abnormal bacterial behavior These universal principles should help researchers to better understand what processes govern the microbial dynamics in the gut. Using the statistical laws, the Columbia researchers were able to identify particular bacterial species with abnormal fluctuations. These wildly fluctuating bacteria were associated with documented periods of gut distress or travel to foreign countries in humans providing data for the study. Thus, this approach may immediately allow researchers to understand and identify which specific bacteria are out of line and behave in a potentially harmful fashion.
Using mice data, the researchers also observed that microbiomes associated with unhealthy high fat diets drift in time significantly faster compared with microbiomes feeding on healthier high fiber diets. This demonstrates that ecological laws can be applied to understand how various dietary changes may affect and perhaps alleviate persistent microbiome instabilities.
Gut microbiome as miniature ecological laboratory The study by Columbia researchers also opens an exciting opportunity to use the gut microbial communities as a model system for exploring general ecological relationships. "Ecologists have debated for years why and how these natural ecological laws arise, without any clear answers," says Vitkup. "Previous ecological research has been mostly limited to observational studies, which can take decades to perform for animals and plants. And some key experiments, such as additions or removal of particular species simply cannot be performed."
The gut microbiome, in contrast, provides an ideal miniature laboratory, where researchers could easily manipulate different variables, such as the number and composition of microorganisms, and then explore various aspects of environmental influences. "One of our next goals is to understand the origin of these general ecological laws using gut microbiota," Vitkup says. Story Source: Materials provided by Columbia University Irving Medical Center. Note: Content may be edited for style and length. Journal Reference:
Brian W. Ji, Ravi U. Sheth, Purushottam D. Dixit, Konstantine Tchourine, Dennis Vitkup. Macroecological dynamics of gut microbiota. Nature Microbiology, 2020; 5 (5): 768 DOI: 10.1038/s41564-020-0685-1
This article below is an interesting connection to our work at the UA. And, this article raises questions regarding the interaction of the enzymes and the abundance of bacteria, whether commensal or pathogens, that might show up in a fecal sample and 16s RNA analysis for coronavirus infected or not infected person.
University of Arizona Microbiome Project
As frequently happens, a personal issue can motivate an increased interest in a subject. Without going into details about this personal issue, for privacy reasons, I will say that I became acutely interested in the gut microbiota about four years ago. At the same time, I have been participating in the UA Senior Design Project for the past several years, as a judge, but also as a sponsor. Most of the sponsors are corporations, such as Raytheon, Caterpillar, IBM, and many others. But individuals can be sponsors as well.
One of the ways I have increased my understanding of the gut microbiota is by reviewing medical abstracts that are posted daily on "Top Health News -- Science Daily." I have noticed in my daily reviews that the number of abstracts related to the gut microbiome has increased fairly dramatically from one every few days to several in a day (that has now decreased as much of the near term interest is on COVID-19).
What has become increasingly obvious over the past couple of years from the gut studies is that there is a strong correlation between the gut and a wide range of diseases, from IBS and IBD to colorectal cancer, to Parkinson Disease, and atopic dermatitus. At the same time, there are a huge number of questions regarding the relationships between the gut and the diseases, including which is the cause and which is the effect?
Another factor that influenced my pursuit of this area of research is that several years ago, the American Gut Project began a service allowing anyone to purchase a fecal sample kit that would be analyzed once sent to the laboratories. "The Human Microbiome Project and other microbiome projects worldwide have laid an important foundation for understanding the trillions of microbes that inhabit our bodies and their impact on health and disease. However, opportunities for the public to get involved in such research have been limited. Now, American Gut gives you an opportunity to join this research project and learn what’s living on and inside you.
American Gut is a project built on the open-source, open-access principles of the Earth Microbiome Project. The data we collect is de-identified and then deposited into open repositories for the benefit of other researchers and scientists. By participating in our project, you can help contribute to research that will help the world understand how the microbiome affects our health. In exchange for your participation, we generate a report summarizing the types of microbes observed in your sample, and how your sample relates to other people in the study.
While American Gut mainly focuses on the gut as this is where most of our microbes reside, we will also look at areas like the oral and skin, as these areas of the body also contain microorganisms (Reference: American Gut Project website)."
I applied for and received a fecal sample kit from the AGP. I sent the sample in and waited the typical 2-3 months to receive the results. The overview of the results is shown below. This first page shown below is typically followed by 3-4 pages that lists abut 1,000 unique bacteria that are identified from the fecal sample using sequencing analysis. As I reviewed the results, I quickly came to the conclusion that I did not have a clue what I was looking at, except there were a number of names of bacteria I had come across in published articles.
Next, I received an announcement from the American Gut Project saying that they were holding a one day conference reviewing about ten publications presented by researchers from around the world. The presentations were both diverse and very insightful. I came away with the following main conclusions:
1. The National Institute for Health and others had funded about $800M to support the objective of developing a world wide database on the Microbiome.
2. Virtually all of the research funds came with a stipulation that the data collected could only be used for research and not for therapeutic use.
3. Longitudinal studies, that is data collected from multiple samples over time, were most useful and necessary to understand what was happening in the gut.
4. And most important, is that the plethora of information on the research side has very slowly been making its way over to the clinical side; few proven therapeutics validated to address specific diseases.
Figure 1. Typical American Gut Sample Results
At a meeting in 2019 of the da Vinci Group at the University of Arizona, I spoke with a department head in the Bioengineering Department. I described some of the issues and said that I wanted to fund a Senior Design Project in the gut microbiota research area. I was then introduced to the department head for Bioinformatics and we were off and running.
Next, I was introduced to Bonnie Hurwitz, a professor in the Bioinformatics Department. Together, we formulated a plan for the project and recruited five students at a Senior Projects Fair. While the subject is very broad, we have narrowed the scope to being what I hope will be a multi-year funded research effort. One of the diseases of interest is IBS, or irritable bowel syndrome. There is a strong correlation between IBS and dysbiosis, which is defined as an imbalance between the type of organisms present in a person's natural microflora, especially that of the gut, thought to contribute to a range of conditions of ill health. Also of interest are inflammatory markers, weight and or BMI (referred to as internal factors) that relate to dysbiosis, and also external factors such as diet. Much of this is included in the project overview in Figure 2.
Figure 2. Overview of the Senior Design Project -- Interpreting the Human Gut Microbiome
The procedures and analytical tools for generating large amounts of information about the gut are very well developed. But the problem and the challenge is the analysis and visualization of the data so that important external and internal factors can be identified that are associated with different conditions and or diseases. One of the guiding documents in the project is entitled, "A Physicians wish List for the Clinical Application of Intestinal Metagenomics," by I Klymiuk, CH Genauer, B Halhachs, GG Thallinger, wF Fricke, and C Steininger.
The list of priorities developed by the team are listed below:
1. translation into clinical action items with impact on patient outcome.
2. Standardization of diagnostic procedures in sample collection, preparation, and testing
3. Automation of data analysis interpretation, and communication
There is a detailed discussion of these priorities in the publication. But, I think it is fair to say that this project has focused on the third priority, rapid analysis of large amounts of data from longitudinal fecal samples, statistical analysis of the data and correlation with various factors, and a visualization approach.
There are five students in the class working on the project. The idea was to put together a tool to accomplish the third priority and then test it out on themselves. The students developed experiments that included an external factor (eating miso soup daily for x number of days), then fecal samples taken daily that were analyzed at the U of A Cancer Center, and finally, used a visualization approach to determine the effect of the miso on their gut flora. They also maintained a daily log of their activities and other factors that could be easily monitored. Unfortunately, the university protocols would not allow blood to be taken for analysis of inflammation markers.
The project is two semesters long and culminates in a Senior Design Project Day that historically has been on campus. There were about 110 teams, so a wide range of engineering disciplines are covered in the projects. With all of the requirements associated with coronavirus safety, the Design Day in 2020 will be done virtually. The output from the project will be an app that could be used by clinicians and or the public, although interpretation of the results really requires a specialist, generally a gastroenterologist with a strong understanding of the gut processes and relationships.
March 30, 2020. More to come.
This is a summary of the students project presented at the Senior Design Day Awards. This is a foundation, but much to do in the outyears to make it a useful tool. You will need to plug this utube file into a safari or google chrome to run it.