Gut microbiome as an extra organ in human body

The human body harbors a large collection of microorganisms—predominantly bacteria, but also viruses, protozoa, fungi, and archaea. They are collectively known as the microbiome. Gut microbiota, gut flora, or microbiome are the microorganisms that live in the digestive tracts of humans and other animals. While some bacteria are associated with disease, others are particularly important for many aspects of health. In fact, there are more bacterial cells in the human body than human cells–roughly 40 trillion bacterial cells vs. only 30 trillion human cells. These microbes may weigh roughly as much as the brain. Together, they function as an extra organ in the human body and play a huge role in human health. The collective genome of the gut microbiome exceeds over 100 times the amount of human DNA in the body. Considering this enormous genetic potential of the microbiota, it is anticipated that it plays a role in virtually all physiological processes in the human body. Gut bacteria have been linked to several mental illnesses, and patients with various psychiatric disorders such as depression, bipolar disorder, schizophrenia, and autism have been found to have significant alterations in the composition of their gut microorganisms.

The interest in gut microbiome as related to human health, and specifically to mental health, is exponentially increasing in the years after 2000, as demonstrated by a search in CAS Content Collection^TM. Currently, there are over 7,000 publications on gut microbiome as related to mental health (Figure 1).

Babies acquire their first dose of microbes at birth. Development of the human gut microbiome

It is generally believed that the uterus is a sterile environment, and that bacterial colonization starts during birth. The microbiome of a newborn varies according to mode of delivery: the microbiome of vaginally delivered infants is like the maternal vaginal microbiome and that of infants delivered by cesarean section resembles the maternal skin microbiome. Various other factors affect the developing neonatal microbiome such as premature birth and mode of feeding. The major determinant of gut microbiome composition throughout adulthood seems to be diet. Fast changes in microbiome composition happen in response to changes in dietary intake. Characteristic patterns are noticeable in plant-based versus animal-based diets.   The development and alteration of the gut microbiome are affected by multiple other factors as well. Exposure to stress ranks as the second most important factor (after diet) affecting the gut microbiome composition, according to a search in the CAS Content Collection. Other factors include: mode of delivery and infant feeding method, environmental conditions, medications, stage and mode of lifecycle, comorbid diseases, and medical procedures (Figure 2). A disruption to the microbiota homeostasis caused by an imbalance in their functional composition and metabolic activities, or a shift in their local distribution is termed dysbiosis, indicating microbial imbalance or maladaptation.

Considering the now recognized significant role of diet on gut microbiome composition, and the vital impact of the gut microbiome on health, the million-dollar question remains: –which diet is beneficial and thus recommendable to keep our gut bacteria happy? Although there is not a definitive unambiguous answer pointing out certain food as a specific illness remedy, some major guidelines have been figured out. A high-fiber diet specifically affects the gut microbiota. Dietary fiber can only be digested and fermented by enzymes from microbiota living in the colon. Short chain fatty acids are released because of fermentation, which lowers the pH of the colon. The highly acidic environment determines the type of microbiota that would survive. The lower pH limits the growth of certain harmful bacteria such as Clostridium difficile. High-fiber foods such as inulin, starches, gums, pectins, and fructooligosaccharides have become known as prebiotics because they feed our beneficial microbiota. In general, high amounts of such prebiotic fibers are found in fruits, vegetables, beans, and whole grains like wheat, oats, and barley. Another highly beneficial class of foods contains probiotics, live bacteria that are good for the digestive system and may further amend our gut microbiome. These include fermented foods such as kefir, yogurt with live active cultures, pickled vegetables, kombucha tea, kimchi, miso, and sauerkraut.

Gut microbiota participants

The human gut microbiota is divided into many groups called phyla. The gut microbiota primarily comprises four main phyla including Firmicutes, Bacteriodetes, Actinobacteria, and Proteobacteria, with the Firmicutes and Bacteroidetes representing 90% of gut microbiota. The majority of bacteria reside within the gastrointestinal tract, with most predominantly anaerobic bacteria housed in the large intestine (Figure 3).  

The gut-brain axis – gut microbiome as the “second brain”

It is now well established that gut and brain are in constant bidirectional communication, of which the microbiota and its metabolic production are a major component. Michael Gershon called the digestive system “the second brain” in his 1999 book , at the time when scientists were beginning to realize that the gut and the brain in humans were engaged in constant dialogue and the gut microbes significantly modulate brain function. 

It is now a common belief that gut microbiota communicates with the central nervous system through neural, endocrine, and immune routes, and thereby controls brain function. Studies have demonstrated a substantial role for the gut microbiota in the regulation of anxiety, mood, cognition, and pain. Thus, the emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be an effective strategy for developing novel therapeutics for central nervous system disorders.

Gut microbiota and COVID-19

Recently, correlation has been reported between gut microbiota composition and levels of cytokines and inflammatory markers in patients with COVID-19.  It is suggested that the gut microbiome is involved in the magnitude of COVID-19 severity via modulating host immune responses. Moreover, the gut microbiota dysbiosis could contribute to persistent symptoms even after disease resolution, emphasizing a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Gut microbial neuroactive metabolites

Abnormalities in the gut microbiota-brain axis have come out as a key factor in the pathophysiology of neural disease, therefore increasing amount of research is devoted to understanding the neuroactive potential of the products of gut microbial metabolism. Thus, major neuroactive gut microbial metabolites have appeared as follows.

Neurotransmitters

Gut microbiome produces neurotransmitters, which regulate brain activity. The majority of central nervous system neurotransmitters are also present in the gastrointestinal tract, where they exercise local effects such as modulating gut motility, secretion, and cell signaling. Members of the gut microbiota can synthesize neurotransmitters, e.g., Lactobacilli and Bifidobacteria produce GABA; Escherichia coli produce serotonin and dopamine; Lactobacilli produce acetylcholine.  (Figure 4) They signal the brain via the vagus nerve.

Short-chain fatty acids

Short-chain fatty acids are small organic compounds produced in the cecum and colon by anaerobic fermentation of dietary carbohydrates that feed other bacteria and are readily absorbed in the large bowel.  Short-chain fatty acids are involved in digestive, immune and central nervous system function, though different viewpoints regarding their impact on behavior exist.  The three most abundant short-chain fatty acids produced by gut microbiome are acetate, butyrate, and propionate (Figure 5).  Their administration was demonstrated to alleviate symptoms of depression in mice.  Gram-positive, anaerobic bacteria which ferment dietary fibers to produce short-chain fatty acids are Faecalibacterium and Coprococcus bacteria.  Faecalibacteria are abundant gut microbes, with significant immunological roles and clinical relevance for a variety of diseases, including depression. 

Tryptophan metabolites 

Tryptophan is an essential amino acid participating in protein synthesis. Its metabolic breakdown by bacterial enzymes (tryptophanase) give rise to neuroactive molecules with established mood-modulating properties, including serotonin, kynurenine, and indole (Figure 6). It has been found that dietary intake of tryptophan can modulate central nervous system concentrations of serotonin in humans, and that tryptophan depletion aggravates depression.

Lactic acid

Lactic acid (Figure 6) is an organic acid developing mainly from the fermentation of dietary fibers by lactic acid bacteria (e.g., L. lactis, L. gasseri, and L. reuteri), Bifidobacteria and Proteobacteria. Lactates can be converted by several bacterial species to short-chain fatty acids contributing to the total short-chain fatty acid pool. Lactic acid is absorbed into the bloodstream and can cross the blood-brain barrier. Lactic acid has a well-recognized role in central nervous system signaling in the brain. Due to its ability to be metabolized into glutamate, it is used as an energy substrate by neurons. It also contributes to synaptic plasticity and triggers memory development.

Vitamins 

Most bacteria in the gut, such as Lactobacillus and Bifidobacterium, synthesize vitamins (particularly from the group of B-vitamins and vitamin K) as part of their metabolism in the large intestine. Humans rely on the gut microbiota for vitamin production. Vitamins are key micronutrients with ubiquitous roles in a multitude of physiological processes in the human body, including the brain. Active transporters bring them across the blood-brain barrier. In the central nervous system, their role spreads from energy homeostasis to neurotransmitter production. Vitamin deficiencies can have a significant negative effect on neurological function. Folic acid (vitamin B9) is a vitamin of microbial origin that has been extensively implicated in the pathology of depression. 

Perspective 

A recent innovative investigational treatment, fecal microbiota transplantation, has been tested in clinical trials and found extremely therapeutically promising. In the last five years, ~1,000 documents related to fecal transplants have been included each year in the CAS Content Collection. For example, it has been reported that fecal microbiota transplantation is able to resolve 80-90% of infections caused by recurrent Clostridioides difficile that does not respond to antibiotics. The unique implications for clinical trials using fecal microbiota transplants, which are increasingly investigated as potential treatments for a range of diseases, need to be promptly explored. 

At present, research into the modulation of the gut-brain axis via the gastrointestinal microbiota is an emerging innovative, frontline science. A large portion of the data available is based on either basic science or animal models that may not be adaptable to effective human interventions. Therefore, individualized prescriptions of specific prebiotic compounds and probiotic strains that would represent the ideal of personalization for nutrition and lifestyle medicine remain hopeful. Ongoing efforts to further characterize the functions of the microbiome and the mechanisms underlying host-microbe interactions will provide a better understanding of the role of the microbiome in health and disease.

For more on how emerging trends and new approaches are helping the millions of people who suffer from depression, anxiety, and PTSD see our blog on psychedelics and their progress as a therapeutic approach.

Since the start of the pandemic, more than 11.4 million children have tested positive for COVID-19 in the U.S., with children under 4 accounting for more than 1.6 million of those cases and 3.2% of total hospitalizations due to COVID-19. As the Food and Drug Administration (FDA) and Centers for Disease Control (CDC) have begun reviewing the safety data for Pfizer and BioNTech’s COMIRNATY® COVID vaccines for Emergency Use Authorization (EUA) with children under the age of 5, several key questions have emerged as parents learn more and decide whether to vaccinate their children under the age of 5. While dosage amounts are different for children under the age of 5, understanding the types of ingredients that are in COVID vaccines will enable parents to make more informed decisions.  

For children under 5, are the vaccine ingredients the same?  

Not exactly; while the active ingredients of the Pfizer and BioNTech COVID-19 vaccines are identical to the current adult vaccines, the only difference is in the buffer called tromethamine (Tris) used that allows for the children’s vaccine to remain refrigerated longer. While tromethamine may not sound like a common ingredient, from a scientific perspective, it was introduced into the world’s published literature in 1944 and is often used in cosmetics, serums, and vaccines since 1978.  

The other critical difference is in the dosage of 3 µg that will be administered in 3 doses for children under the age of 5 vs. the 10 µg dose that is given twice to children ages 5 and older and the 30 µg dose given 3 times to those ages 12 and above.   

How common are the ingredients of the COVID-19 vaccines?

To discover how common an ingredient is, CAS offers a unique perspective. For over 100 years, whenever new chemistry-related scientific research has been published, CAS has captured that information in the CAS Content Collection™, allowing us to see when a chemical compound first shows up in research and every time thereafter. As a result, the CAS Content Collection shows us how often a compound is studied or used in research since each compound is given its own Registry Number. By connecting each COVID-19 vaccine ingredient to its prevalence in scientific literature, we can gain insight as to how scientifically common it is.

In fact, ingredients that are most scientifically common also appear in our homes, primarily as ingredients in foods and sometimes skincare products. On the other hand, the vaccine ingredients which appear less in the CAS Content Collection (like lipids) are newer and have fewer and more specific applications. Nonetheless, our content helps us better understand these unique ingredients.

Everyday common household ingredients

The most common ingredients are easily found within our own pantries. Some, in singular form like salt or sugar, or within popular food and drink items like Gatorade or Jell-O. To see how prevalent an ingredient is in the CAS Content Collection, we consider the number of times its Registry number has been referenced in the world’s publications and will categorize them as:

• High >50,000
• Medium: 10,000-50,000
• Low: 0-10,000

* Includes occurrence of ingredient crystallized with one or two water molecules and occurrence without water.

Scientifically common Ingredients

In this category, we find those ingredients that are a little more specialized but still are used in a variety of applications. They are far more common in medicine and/or research than in our cupboards and have been so for several decades at least. The most common ingredient is 2-hydroxypropyl beta-cyclodextrin(HPBCD), a fascinating ring-shaped compound, derived from beta-cyclodextrin (BCD) that forms naturally from starch. Not only has BCD been studied over 50,000 times, but there are over 26,000 compounds based off it. Newer on the scene is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), a phosphatidylcholine that can occur naturally—in a mixture of phosphatidylcholines and other lecithins—in foods like soybeans. Its pure form, whether isolated or synthetic, has been studied in vaccines or lipid nanoparticles for over two decades. Tromethamine and tromethamine HCl, stabilizers in the Moderna vaccine, also make the list as established vaccine ingredients as well as cosmetics ingredients.

Unique Ingredients

Ingredients that are less common are the specialized lipids for the Moderna and Pfizer mRNA vaccines. These lipids make up the lipid nanoparticles (LPNs) that protect the spike protein mRNA and help carry it safely into our cells. LPN technology has been around for nearly 30 years, with cancer research playing a critical role in its innovation. To make mRNA vaccines a reality, the right lipids were needed to be discovered and developed. It is important to note that, while still new, these lipid ingredients still pre-date the COVID-19 pandemic.

The virus-related particles are the only truly new ingredients of vaccines, having been developed after the beginning of the pandemic. For Pfizer and Moderna, this consists of an mRNA strand encoding the viral spike protein of COVID-19. The mRNA used is based off the original variant of SARS-CoV-2; if newer vaccines are released that target later variants of the coronavirus, such as Omicron, this can be done by using a newer sequence of mRNA. The mRNA vaccines do not cause any genetic changes to our cells, because mRNA only stays in the cytosol of the cells and does not interfere with DNA in the cell nucleus. Like the mRNA vaccines, the Johnson & Johnson vaccine provides a genetic template to cells for producing the spike protein of the coronavirus, using a modified adenovirus-26 (ad26) vector virus that carries a piece of DNA. Because the mRNA and DNA are specific to COVID-19, these ingredients have been developed since the start of the pandemic. Similar mRNA vaccines using the same LPN technology have been studied since 2016, and an Ebola viral vector vaccine using ad26 was in development also as early as 2016.

Owing to the intense research surrounding the COVID-19 pandemic, the prevalence of these unique ingredients in the CAS Content Collection is growing all the time. No doubt, as time goes on, more uses for the LPNs and ad26 viral vectors will be developed.

Summary

The formulations and ingredients of the COVID-19 vaccines have been under a lot of scrutiny but as the EUA is potentially pending for Pfizer and BioNTech’s COMIRNATY^® children under the age of 5, understanding how common some of these ingredients may prove helpful in allowing parents to make educated decisions. For those who are seeking greater detail on all ingredients, download this table of all the ingredients by vaccine.

For even more on COVID-19, visit the CAS Covid-19 Resources collection for the latest data sets, bioindicator explorer, and peer-reviewed articles.