Microbiome

Over thousands of years of evolution, microbes were present in our bodies. Without them, a living organism could not survive because of lack of the immune system. In Passio Human Microbiome we are programming microorganisms to perform the desired task such as intensifying actions, dulling or even self-eliminating. Our research proves that those manipulations can provide a solid answer not only for gastrointestinal diseases but also asthma, autoimmune conditions, autism or even cancer. Passio Human Microbiome is a part of a big change within medicine.

THE ROLE OF GUT MICROBIOTA IN RESPONSE TO A DRUG

The oral administration of therapeutic drugs is an easy and preferred route over other administration routes, however, there are certain aspects that need special attention. Bioavailability of oral drugs primarily depends on well-functioning digestive system and microbiota that colonize the digestive system. It has been proved that human microbiome composition plays an important role in drug and xenobiotic metabolism by means of various enzymatic reactions mediated by microbiota produced enzymes.

The occurrence of such interactions may have a complementary or opposite effect on the host’s enzymatic system ultimately affecting on pharmacological effects of administrated drugs. Some of the administrated drugs may be activated to its active form (in eg. Sulfasalazine can be transformed into 5-amino-5-salicylic acid in the course of gut inflammation disorders treating) or metabolically reactivated via bacterially expressed enzymes (like irinotecan by bacterial β-glucuronidase in cancer chemotherapy), whereas others may be inactivated (like digoxin) as a result of gut microbiota enzyme expression. While analyzing these connections, the scientist has also noticed the occurrence of various enzyme competition. The most recognizable is the one between microbial p-cresol and host metabolites of the administrated drug, like acetaminophen, for sulfotransferase 1A1 (SULT1 A1) that catalyze the conjugation of many hormones, drugs, and neurotransmitters.

The number of known interplays between gut microbiota and pharmaceutically active compounds has been described for more than 50 widely used drugs, and due to the extended research, the total number continues to grow. Gaining knowledge about these microbial enzymes and understanding the molecular mechanism that undergoes in the intestine is essential for better control of the pharmacokinetic action of commonly prescribed pharmaceuticals, and thus improving the efficiency of pharmaceutical treatment.

IMPROVED ABSORPTION OF ACTIVE SUBSTANCE vs. IMPROVING THE EFFECTIVENESS OF PHARMACOTHERAPY

Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. The primary goal of clinical pharmacokinetics includes enhancing efficiency and decreasing toxicity of drug therapy.

The development of significant correlations between drug concentration and their pharmacologic responses has enabled clinicians to apply pharmacokinetic principles to actual patient situations. Before achieving a desired therapeutic action of the oral drug, it needs to be administrated and distributed in the human body to finally reach tissue and be taken up by the target place to exert its therapeutic effect. The process of drug absorption relies on taking it into the bloodstream via digestive tract usually by passive diffusion across membranes. However, it should be emphasized that there are plenty of factors altering drug absorption.

DOES IT MATTER?

We need to remember that drug absorption is the first disposition step of a pharmaceutical compound within a human organism. In other words, absorption is one of the criteria, which influences the drug kinetics, and its concentration in the human plasma. Therefore, it affects the compound’s bioavailability and what is more important – a pharmacological activity of the drug. To the factors, which modify the degree of absorption, there should be included: drug solubility, drug dose, gastric emptying time, intestinal transit time, gut inflammation, state of mucous surfaces and much more.

HOWEVER, WHAT IF WE ARE ABLE TO INCREASE DRUG ABSORPTION, BY ALTERING THE COMPOSITION OF GUT MICROBIOME?

In theory, the better drug absorption is, the higher drug can be concentrated in human plasma. Then, why do we take so great amount of chemical compounds, which after all needs to be eliminated from our body? It is stated in numerous studies, that process of absorption critically determines the compound bioavailability. The gastrointestinal disease may also alter oral dose requirements by producing variation in both the amount and rate of drug absorption. Does it mean that we are able to control and to increase the efficiency of pharmacotherapy by altering the microbiome? How does the process of absorption function while dysbiosis? Should patients with confirmed dysbiosis take the same dose of drugs as usual? Maybe, instead of constantly increasing the drug dose, we should take a look at the microbiome condition?

Once again. The principle of our mission is still the same – to better understand microbiome-host interactions and to provide new solutions with proven efficiency of treating method and routine use in clinical practice.

THE EFFECT OF MICROBIOME ON A METABOLISM IN LIFESTYLE DISEASES

Interactions between the microbiota and the host are very complex and play the crucial role not only in basic physiological processes but also in development (and healing!) of a number of chronic diseases: metabolic disorders like obesity and diabetes, gastrointestinal and cardiovascular diseases, mental disorders and even cancer, to name only a few. It is widely accepted now that human genotype and dietary habits aren’t the only factors contributing to the development of metabolic diseases. It is all about the interplay between these two and host-microbiome composition. Obesity itself has been proven to be directly associated with gut microbiome dysbiosis resulting in damaged gut epithelial barrier and impaired metabolism overall.

WHAT IF WE COULD REVERSE IT?

It is already known that it works for obese mice that had their intestinal microbiome substituted with one collected from lean individuals. Their adiposity was greatly reduced and so the outcome was shortly named a miracle. Are these tiny microbes so powerful for real? Quite recently it has been shown, that gut microbiome may play a role in type 2 diabetes development as well. There is growing evidence that lowering microbial diversity in guts results in chronic inflammation, insulin resistance, and impaired amino acid metabolism – all of these being well-established diabetes symptoms. On the other hand, an abundance of certain species of Enterobacteriaceae family is known to be linked to cardiovascular disease (CVC). What is more, CVD patients often show low levels of healthy gut microbiome bacteria and it seems to be a promising and non-invasive biomarker for CVD diagnostics.

SO DO WE HEAD FOR A BREAKTHROUGH?

Gut-brain axis that plays the main role in proper gastrointestinal and brain functions is a well-known concept for over a half a century now. Thanks to some recent research, we know that microbiome is another player there. Its role in protecting the intestinal barrier and tight junction integrity in enterocytes is obvious. It is also known to modulate enteric sensory neurons and regulate the mucosal immune system. The abundance of certain genera or quite the contrary – their deficiency, may lead to a shortage of some metabolites present in the healthy organism and induce intestinal defects typical of irritable bowel disease or inflammatory bowel disease. But that is not all. Absence of some microbial genera is linked to altered production, expression and turnover of neurotransmitters, mainly due to reduced gene expression and impaired synthesis of serotonin, GABA etc.. As a result, microbiota present in the intestine directly influences brain neurological functions. What we talk about here is also inducing various mental disorders like anxiety, depression or maybe even autism.

Microbial influence on immune cell functions and metabolic pathways is also associated with tumorigenesis as revealed by some studies. The extent and clear interactions are still not fully understood but what we know now is that not only pathogenic bacteria presence but also lack of commensals may lead to changing human cancer susceptibility and progression. What if modulating the microbiome led to considerable improvement in cancer treatment and care?

We do ask questions. We do test hypotheses. Our mission is quite straight – to better understand microbiome-host interactions and provide new solutions with proven effectiveness for treatment and routine use in clinical practice.

MAPPING GUT MICROBIOME

During the past century, noncommunicable diseases were the greatest reason for human deaths, even if we would compare it to infectious diseases. Trillions of commensal bacteria live in the human body and create as a whole the human microbiome. The great part of these microbes are located within the human gut (but not only) and have a significant impact on human health and survivor, including digesting food,  activation of a certain class of medicines, producing metabolites like short-chain fatty acids and anti-inflammatory substances, as well as stimulating the immune system.

WHAT EXACTLY IS GUT MICROBIOME?

The gut microbiome is a complex system consisting of plenty number of microbes, which metabolically interacts with the host. There are four dominant phyla in the human gut: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Gut microbiome fights against disadvantageous effects of exposure onto the external environment, therefore it acts as some kind of biotic shield between the inside and the outside of a human body. The link between the host and gut microbiome is existing by metabolites produced by bacteria colonizing the human gut. Apart from some biological effects, these metabolites could also have a great impact on altering the composition of the microbiome. The knowledge of interactions between microbiota and host metabolism, as well as modification of microbial ecology, is really crucial for effective therapeutic treatments for many diet-related diseases in the near future. Nevertheless, there is still a lack of knowledge about the exact metabolic paths, molecular mechanism and the role of microbes in human health.

WHAT ARE THE MAIN FUNCTIONS OF GUT MICROBIOME?

• Fermenting unused energy;
• Training the immune system;
• Preventing the growth of pathogenic bacteria;
• Regulating the development of the gut;
• Producing vitamins, such as biotin and Vit K;
• Producing hormones to direct the host to store fats;
• Repress microbial growth through the barrier effect.

WHY DO WE WANT TO DISCOVER HUMAN GUT MICROBIOME? WHAT IS THE AIM?

The main aim of mapping gut microbiome is to identify and characterize microbes living in the gut. Why? The microbes are partially responsible for human illness and health. Additionally, it is extremely important to evaluate the common part of microbes, which is available in individuals. Furthermore, it is necessary to understand if some changes in the human gut microbiome could be correlated with human health, and how these changes affect the homeostasis of the human body.