The term gut microbiota refers to the massive collection of microorganisms that inhabit our gastrointestinal tract. And “massive” is far from hyperbole: an estimated 30-100 trillion bacteria (along with fungi, viruses, and archaea) comprise the microbiota, collectively weighing around 4.5 pounds and containing over 150 times more genes than our own human genome! These microbes include a mixture of commensal (neutrally existing), symbiotic (mutually beneficial), and pathogenic (harmful to us) organisms, and can consist of any of 35,000 species known to inhabit the human gut.  Every person’s gut contains approximately 400 to 1,500 different species of the possible 35,000 different microorganisms that are well adapted to survive in the gastrointestinal tract, although about 99 percent of those microorganisms come from thirty to forty species of bacteria. Our guts are inhabited by other microorganisms besides bacteria, including archaea (similar to bacteria), viruses, and single-cell eukaryotes (like yeast).

The term gut microbiome is often used a catch-all term to describe the gut microbiota plus its metabolome (the collection of biologically active molecules within and produced by our gut microbes), but microbiome technically refers to the amazing collection of genes that our gut microbiota have. The contribute 3.3 million genes whereas humans only have  about 23,000 genes.  This is important because our gut microbiota regulate many aspect of human health via their genetic contribution.  While gut microbiome, microbiota and metabolome are often used interchangeably, it’s important to note that these three terms all describe different aspects of the microbial community in our guts.  For the sake of clarity, I will use the term microbiota when referring to the collection of microbes in our guts and the term microbiome when referring to the ecosystem as a whole.

Amazingly, the gut microbiome wasn’t even widely recognized to exist until the late 1990s!

The Diverse Roles of Our Gut Microbiota

Our gut microbiota help us digest food, produce chemicals that improve the health of the cells that form the gut barrier, and directly regulate the immune system, and they can even influence brain health by producing neuroactive chemicals that are absorbed into the bloodstream and travel to the brain. A healthy diversity of the right kinds of microorganisms in the gut is one of the most fundamental aspects of good health.

The gut microbiome performs diverse functions essential to our health. Perhaps best understood is their role in digestion. Our gut microbiota have enzymes that break down certain types of sugars, starches, and fiber from foods so that we can digest them and absorb their nutrients. Bacteria also ferment fiber in our digestive tracts, producing short-chain fatty acids—such as acetic acid, propionic acid, and butyric acid—which are extremely beneficial energy sources for the body and are essential for regulating metabolism. These short-chain fatty acids also aid in the absorption of minerals such as calcium, magnesium, copper, zinc, and iron. Our gut bacteria aid in the absorption of minerals in other ways too. They degrade minerals complexing with phytate (an “antinutrient” present to varying degrees in all plant-based foods that binds minerals and makes them less absorbable; see for example Is Oxalate Sensitivity Real? and Nuts and the Paleo Diet: Moderation is Key), making those minerals available for absorption. Our gut bacteria also synthesize vitamins, B and K vitamins in particular, which our bodies then absorb (and which provide us with important micronutrients that we may not get enough of otherwise). Gut bacteria may also play a key role in facilitating absorption of dietary fatty acids, thereby also increasing absorption of important fat-soluble vitamins like A, E, D, and K (although the results of this cutting-edge research have yet to be confirmed in humans).  Gut bacteria can also ferment proteins, producing branched-chain amino acids, well known to be important for muscle recovery and athletic performance.

Our gut bacteria also directly control the integrity of the gut barrier by regulating important tight junction proteins (claudin-2, occludin, cingulin, ZO-1, ZO-2) between the gut epithelial cells (see What Is A Leaky Gut? (And How Can It Cause So Many Health Issues?)). These effects aren’t limited to the gut either: recent studies have shown that our gut bacteria can regulate the permeability of epithelial barriers elsewhere in the body , including the blood-brain barrier.  Yes, our gut bacteria control how leaky the blood-brain barrier is, again through regulating important tight junction proteins ( in this case, claudins, tricellulin, and occludin).  There’s also an indirect effect on gut barrier integrity via modulation of serotonin (which regulates gastric motility) and Toll-like receptors (TLRs) which are important for antigen presentation by dendritic cells and macrophages to the adaptive immune system.

The microorganisms in our guts help to maintain the delicate balance required by our immune systems, keeping the various populations of immune cells in check and modulating their activity. Achieving a healthy balance in the immune system is therefore reliant on having a healthy population of gut microbiota, growing in the correct numbers in the correct locations and with appropriate diversity.  In fact, let’s dig into the details on this role…

Our Gut Microbiome  and the Immune System

Let’s first review the key players of the adaptive immune system, so we can understand just how vital a healthy, diverse gut microbiota is for immune function. (For more details, see The Paleo Approach)

The adaptive immune system is the part of the immune system that attacks on invading organisms (pathogens) with specificity, meaning its attacks are targeted for exactly that specific virus, bacteria, fugus or parasite that is infecting us.  It also remembers invaders (this is called immunological memory) so that it responds more intensely and quickly for subsequent infections. The adaptive immune system is why vaccines protect us against infection and why we get chicken pox only once.  The adaptive immune system also tailors responses to eliminate specific pathogens or pathogen-infected cells in the most effective and efficient way possible. (Contrast this to the innate immune system which is like our immune system’s first-responders; they’re fast to mobilize but can’t attack with much specificity.  The innate immune system is responsible for detecting a foreign invader in the first place and then recruiting the adaptive immune system to help fight them off.)

There are two main cell types that drive adaptive immune responses: B cells (which produce antibodies) and T cells (many of which act like the middle management of the immune system).

There are a variety of different subtypes of T cells, each with it’s own function in the adaptive immune system.  Among these are the helper T cells, whose job it is to control the actions of most other cell types in the immune system (hence the middle management metaphor). Some drive the immune system and inflammation, and some suppress and regulate the immune system, effectively turning off inflammation when the pathogen is vanquished. The important helper T cells for driving the immune system and inflammation are Th1, Th2, Th9, Th17, and Th22 cells). Th1 cells recruit and regulate nonspecific immune cells, such as macrophages, and secrete cytokines that stimulate T cells to mature into cytotoxic T cells. Th2 cells activate B cells (which then divide rapidly and secrete antibodies). Th9 cells are similar to Th2 cells (they are activated by different cytokines) and are important for host defense against parasitic infections (specifically helminth worms), but are also implicated in the development of chronic allergic inflammation, airway remodeling such as in asthma, and autoimmune disease. Th17 cells are similar to Th1 cells (they secrete different cytokines), are highly inflammatory, and are activated in response to certain bacteria and parasites. Excessive numbers of activated Th17 cells are present and probably responsible for tissue damage in some autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disorders. There is also some evidence that Th17 cells may have a regulatory function similar to Th3 cells or Tr1 cells (see below), but the research on this isn’t conclusive. Th22 cells are also similar to Th1 cells (they secrete different cytokines than Th1 and Th17 cells) and have been implicated in inflammatory skin disorders such as psoriasis, atopic eczema, and allergic contact dermatitis.

There are also helper T cells that are immune modulators: their job it is to help suppress the immune system. Th3 cells (also known as adaptive regulatory T cells or induced regulatory T cells) protect the lining of the gut (the gut mucosa, or mucosal barrier of the gut) from nonpathogenic antigens (foreign substances other than viruses, bacteria, fungi, and parasites). Th3 cells also suppress Th1 and Th2 cells, making Th3 cells important immune modulators. Tr1 cells (also called type 1 regulatory T cells), which are similar to Th3 cells (they secrete different cytokines than Th3 cells), control the activation of memory T cells  and suppress Th1- and Th2-mediated immune responses to pathogens, tumors, and to “self.”

Regulatory T cells are another type of T cell (not a helper T cell) that are crucial for regulating the adaptive immune system. These cells suppress the activity of immune and inflammatory cells to shut down T-cell-mediated immunity toward the end of an immune reaction. Their immune modulating activity extends to the innate immune system as regulatory T cells can also suppress activation of dendritic cells. Regulatory T cells maintain “immune tolerance,” or the process by which the immune system tolerates and chooses not to attack an antigen (which is important during pregnancy, for example). Beyond this, regulatory T cells have the critical job of suppressing the activity of any T cells that recognize self and therefore might attack healthy cells in the body. A lack (or perhaps reduced ability) of regulatory T cells is thought to be crucial the development of autoimmune disease. Cytokines produced by Th3 cells may be important in the activation of regulatory T cells.

Summary: there are many types of immune cells that work together like instruments in an orchestra to fight off an invading pathogen.  When the immune system isn’t balanced (as in cancer, autoimmune disease, allergic diseases, and all situations in which systemic (bodywide) inflammation is present which really just means all chronic diseases), it’s as though the instruments aren’t in tune and are all playing different pieces. That cacophony results in an immune system that both fails at its primary role and also damages us in a variety of different ways.  The gut microbiome acts as a conductor, helping to tune each instrument and making sure that the entire orchestra is playing the right piece.

A healthy gut microbiome is critical for the development and maturation of the immune system, modulating nearly every aspect of the adaptive immune system and even some of the innate immune system. For example, a complete lack of gut microbiota is known to result in severe deficiencies of most helper T cell subsets, but an increase of Th2 cells. Some bacterial components are known to balance Th1, Th2, and Th3 cell populations through regulation of dendritic cell activation (increasing or decreasing dendritic cell activation depending on the circumstance). Some bacterial components stimulate the production of Th17 cells, some modulate the activation of natural killer cells (innate immune system cells), some influence the interaction between antigen receptors on the immune cell surfaces and the antigens themselves. Probiotic bacteria not only keep the immune system in check during times of health, but also help control the immune defense against invading pathogens, for example, by stimulating the production of antibodies against the foreign microorganism.

Different bacterial components modulate different aspects of the immune system, including modulating/regulating all of the following:

• gene expression of cytokines (chemical messengers of inflammation, including IL-10, IL-22, IL-1β, IFN-γ, TGF-β1)
• production and activity of regulatory T cells
• number and activity of IgA-secreting plasma cells in the gut lining
• the balance between  Th1, Th2, and Th3 cell populations via regulation of dendritic cell activation
• production of Th17 cells
• activation of natural killer cells
• the interaction between antigen receptors on the immune cell surfaces and the antigens themselves (via Toll-like receptors, TLRs)
• the production of antibodies against foreign microorganisms

For those of you who nerd out on the details of immune function like I do, you’re reading that list and thinking “woah, our gut microbiome is basically the managers of our entire immune system!”.  For those of you who read that list and start going cross-eyed, the take-home message is that our gut microbiome controls virtually every aspect of how our immune system functions.  Given that inflammation is part of the pathogenesis of all chronic illness, it’s no wonder we now have conclusive links between all chronic illness and irregularities in our gut bacteria.

Gut Dysbiosis and Chronic Disease

Gut dysbiosis is a general term that refers to any abnormality in our gut microbiota. This includes too many or too few microorganisms growing in the various sections of the gastrointestinal tract, the wrong kinds of microorganisms or the wrong balance between the different populations of microorganisms, and microorganisms in the wrong place. Any of these situations can have profound impacts on our digestion, gut barrier health, and the modulation of our immune systems.

One common form of gut dysbiosis is overgrowth of bacteria or yeast in the small intestine. This is referred to as small intestinal bacterial overgrowth, or SIBO, (this term does apply to yeast overgrowth) and it is now believed to be the cause of irritable bowel syndrome (or at least some forms of IBS, which is probably a collection of disorders that have yet to be sorted out).

Importantly, gut dysbiosis is strongly linked to chronic disease.  In fact, a link has been found in every chronic disease in which a connection to gut bacteria has been investigated.

What Does a Healthy Gut Microbiome Look Like?

Diversity is considered the number one hallmark of a healthy gut microbiome.

When the microbiota of people living in Western cultures were analyzed in comparison with those of people living in rural settings who had hunter-gatherer lifestyles and with those of wild primates like chimpanzees, Western-culture gut microbiota were found to be significantly lacking in both richness and biodiversity. This is directly attributable to diets high in industrially processed foods (which are also low in fiber), which don’t supply enough nutrition for our microbiota to thrive. Interestingly, there is even less diversity of gut bacteria in obese people than in lean people: more food does not equal more nutrition, and the worse our diet, the more our gut microbiota suffer.

In the adult human gut, two phyla (the taxonomic category right below “kingdom”) dominate: Bacteroidetes and Firmicutes. These are present in every human gut, and much smaller proportions of the phyla Actinobacteria, Proteobacteria, Verrucomicrobia, and Fusobacteria can also be present. While there are literally thousands of species of bacteria belonging to each of these phyla (including ones that are probiotic, commensal and pathogenic), it’s useful to look at some of the broad strokes when it comes to this birds-eye look at the gut microbiom.

Bacteroidetes Phylum: Bacteroidetes is one of the two most abundant phyla in the human gut microbiome (the other being Firmicutes). This phyla is relatively less susceptible to perturbations than Firmicutes and Proteobacteria, and all of its members are Gram-negative and nonsporeforming. Bacteroidetes appear strongly implicated in weight maintenance and obesity, with a higher predominance (relative to Firmicutes) being associated with significant weight loss, and a lower predominance found in obese individuals. (The obesity link is potentially due to more efficient energy extraction from carbohydrates when the Firmicutes/Bacteroidetes ratio is high, leading to an increased energy balance.) Due to its dominance in the gut microbiome, as well as its extensive positive interactions with other taxa, Bacteroidetes fits the criteria for “foundational taxon.”

Firmicutes Phylum: Along with Bacteroidetes, Firmicutes are one of the two most abundant phyla in humans, and compared to Bacteroidetes is relatively susceptible to perturbations. This phyla is represented mostly by lactic acid bacteria (such as Lactobacillus and Enterococcus, as well as Clostridium). Relatively lower levels are found in diabetics compared to nondiabetics, and lower levels are also found in patients with Crohn’s disease or IBD. A higher proportion of Firmicutes is associated with obesity, possibly due to the bacteria in this phylum increasing the efficiency of energy extraction from carbohydrates. The story here is complex though, because the gut microbiota of hunter-gatherers are dominated by Firmicutes and these bacteria dominate when diets are rich in vegetables.

Actinobacteria Phylum: Although this phylum comprises a very small proportion of the gut microbiome, it fits the criteria for “keystone taxon” due to its positive association with microbial diversity and high level of ecological connectedness. All Actinobacteria members are gram-positive, nonmotile, nonsporulating, and non-gas-producing anaerobes, and the phyla as a whole is relatively stable and resistant to perturbations.

Proteobacteria Phylum: The Proteobacteria phylum is gram negative and relatively less stable than Bacteroidetes and Actinobacteria. Most of the known pathogenic bacteria in humans belong to this phylum, and some evidence suggests that Proteobacteria members may play a key role in IBD. Proteobacteria members reside within the mucus layer in the colon and can use mucus as an energy source.

Verrucomicrobia Phylum: This phylum contains only a handful of described species, but some of those species are extremely important—namely Akkermansia muciniphilia, a major player in immune signaling and chronic disease.

How to Support a Healthy Gut Microbiome

Diet is the single biggest influence on microbiota composition. In fact, diet is directly responsible for more than 60% of the variation in bacterial species in the gut.

We know that inadequate fiber intake, high intake of omega-6 polyunsaturated fats (relative to omega-3s), high intake of saturated fat and low levels of vitamin D all cause a shift in the gut microbiota from probiotic to commensal, opportunitistic and pathogenic strains. In particular, inadequate fiber tends to shift the population of gut bacteria from majority Gram-positive strains (mainly those in the Firmucutes phylum) to more Gram-negative strains (mainly those in the Bacteroidetes phylum).  High omega-6 fat intake depletes growth of both Firmicutes and Bacteroidetes phyla.  And, high saturated fat intake skews microbiota unfavorably towards more Bilophila, Turicibacter, and Bacteroides. Vitamin D deficiency leads to shift toward pathogenic bacteria (Helicobacter, Veillonella and Erysipelotrichaceae), whereas supplementation restores levels of probiotic bacteria (Lactococcus, Akkermansia).

Some individual food compounds can also promote the growth of the wrong kinds of bacteria. Grains, dairy, legumes, nightshades, and alcohol are all known to contain compounds that can hinder the growth of beneficial strains of bacteria while supporting the growth of undesirable strains, like E. coli.  These include agglutinins, prolamins, digestive enzyme inhibitors and alochols (including sugar alcohols).  See Are all lectins bad? (and what are lectins, anyway?), Why Grains Are Bad-Part 1, Lectins and the Gut, Wheat and Innate Immunity, Is It Paleo? Splenda, Erythritol, Stevia and other low-calorie sweeteners and The WHYs behind the Autoimmune Protocol: Alcohol.  Some emulsifiers also preferentially feed undesirable strains of bacteria (see Is It Paleo? Guar Gum, Xanthan Gum and Lecithin, Oh My!).

It’s not just a question of which kinds of bacteria our diet nourishes but also a question of bacterial metabolism (yep, the metabolome). Just as a high-sugar diet causes oxidative stress in our bodies (see Why Is Sugar Bad?), a high-sugar diet causes oxidative stress in our gut bacteria. Those bacteria adapt by altering their metabolism, which greatly affects our health.

The good news here is that the population of microbes in the gut (types, total and relative quantities, and location) adapts quite rapidly to changes in diet, in a matter of a few days to a few weeks.

• Dramatically increasing intake of fresh vegetables and fruit restores levels and diversity of probiotic species in as little as 3 to 4 days.
• Fish oil supplementation can restore levels of probiotic bacteria in about two weeks.

In fact, these are the two most important dietary factors for supporting healthy and diverse gut microbiota: eat plenty of whole vegetables and fruits, eat plenty of seafood, don’t go crazy on saturated fat. (Also see Saturated Fat: Healthful, Harmful, or Somewhere In Between?)

Lifestyle also plays a role here.  Inadequate sleep, high chronic stress, living a sedentary lifestyle, and overtraining all negatively impact the microbial diversity and proportion of probiotic species in the gut.  Living an active lifestyle, getting adequate sleep, and managing stress all support a healthy and diverse gut microbial community.

Exposure to probiotic organisms to inoculate the gut is also important. This is discussed in The Benefits of Probiotics and The Health Benefits of Fermented Foods.

Gut Health Quick-Start Guide

Having a healthy gut means more than just fixing a leaky one (see What Is A Leaky Gut? (And How Can It Cause So Many Health Issues?)). It also means restoring gut microbiota to the appropriate diversity, numbers, and locations—different types of bacteria grow in different amounts in different parts of the gut. In general, this means consuming a moderate amount saturated fat, a balanced ratio of omega-3 to omega-6 polyunsaturated fats, and a diversity of fiber types from a wide range of fruits and vegetables. Choosing foods as well as engaging in lifestyle choices that support gut health is a major guiding principle behind the Paleo template.

This is a guide out of my book, Paleo Principles. It represents not just the best choices for gut microbiome health but also gut barrier health, detoxification, hormone regulation and digestion (all aspects of gut health).  You can also learn more in my Leaky Gut Mini-Course.

Citations

Bjarnason, I., Intestinal permeability, Gut. 1994;35(1 Suppl):S18-S22

Blaser MJ. “The microbiome revolution.” J Clin Invest. 2014 Oct;124(10):4162-5.

Purohit, V., et al., Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, Alcohol. 2008;42(5):349-361

Swank GM, Deitch EA. Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J Surg 1996;20:411-417.

Cresci GA, Bawden E. Gut Microbiome: What We Do and Don’t Know. Nutr Clin Pract. 2015 Dec;30(6):734-46. doi: 10.1177/0884533615609899

Wu GD. The Gut Microbiome, Its Metabolome, and Their Relationship to Health and Disease. Nestle Nutr Inst Workshop Ser. 2016;84:103-10. doi: 10.1159/000436993.

Wu GD. Diet, the gut microbiome and the metabolome in IBD. Nestle Nutr Inst Workshop Ser. 2014;79:73-82. doi: 10.1159/000360686

John GK et al. Dietary Alteration of the Gut Microbiome and Its Impact on Weight and Fat Mass: A Systematic Review and Meta-Analysis. Genes (Basel). 2018 Mar 16;9(3). pii: E167. doi: 10.3390/genes9030167.

Tengeler AC et al. Relationship between diet, the gut microbiota, and brain function. Nutr Rev. 2018 Apr 28. doi: 10.1093/nutrit/nuy016.

The post What Is the Gut Microbiome? And Why Should We Care About It? appeared first on The Paleo Mom.

A Brief Summary of the Gut Microbiome

The healthy adult gut is one of the most diverse microbial ecosystems known, home to a vibrant community of microbes that influence nearly all aspects of human biology through their interactions with our bodies. Every person’s gut contains approximately 400 to 1,500 different species of microorganisms—bacteria, archaea and fungi—that are well adapted to survive in the gastrointestinal tract (with about 35,000 species total for all humankind). In fact, it is estimated that there are three to ten times more microorganisms living in our guts than there are total cells in the entire human body! These microorganisms are collectively referred to as our gut microbiota, and the ecosystem as a whole is referred to as our gut microbiome. (See also What Is the Gut Microbiome? And Why Should We Care About It?)

A healthy gut microbiome is working 24/7 to perform many different essential functions that help us to stay healthy. Our gut microbiome acts as a virtual digestive organ, breaking down thousands of food constituents that are incompatible with our own digestive processes, as well as forming important nutrients and impacting their absorption and metabolism. Our gut microbiome regulates and produces many important hormones, including several molecules that double as neurotransmitters. Our gut microbiome contributes to several detoxification pathways. Healthy gut microbiota are critical for the development and maturation of the immune system, helping to maintain the delicate balance required by our immune system by modulating the activities of the various populations of immune cells. And, the gut microbiome directly influences the health and modulates the permeability of the gut barrier—simply restoring a healthy gut microbiome can fix a leaky gut. (See also What Is A Leaky Gut? (And How Can It Cause So Many Health Issues?)).

In fact, every human cell is impacted by the activities of our gut microbes, and we depend on our gut microbiome for health and survival. How does a community of microbes have influence beyond the boundaries of their biological niche, i.e., outside their lovely gut home? Our gut microbes influence our biology through the production of thousands of biologically-active molecules, such as short-chain fatty acids (SCFAs), that are absorbed across the gut barrier and into our bodies. Numerous studies have shown that these microbial metabolites bind with specific receptors embedded within our cell membranes, and in doing so, activate signaling cascades that alter our cellular physiology.

It’s incredible to think that the state of our gut can impact nearly every other aspect of our health, but this is exactly what science continues to show. In fact, at least 90% of all disease can be traced back to the health of the gut and our gut microbiomes. Pathogenic changes in the composition of the gut microbiota is known as gut dysbiosis. This includes too many or too few microorganisms growing in the various segments of the gastrointestinal tract, the wrong kinds of microorganisms, microorganisms in the wrong place, missing important microorganisms, the wrong balance between the different populations of microorganisms, and/or not enough species diversity represented in the community of microorganisms. To date, gut dysbiosis has been linked to: obesity, diabetes, cancer, cardiovascular disease, kidney disease, liver disease, gout, chronic fatigue syndrome/myalgic encephalomyelitis, neurodegenerative disease, schizophrenia, autism spectrum disorder, multiple sclerosis, epilepsy, depression, anxiety, mania, bipolar disease, addiction, lupus, rheumatoid arthritis, multiple sclerosis, thyroid disease, other autoimmune diseases, IBD, IBS, other gastrointestinal diseases, asthma, allergies, food intolerance, skin conditions, osteoporosis, sexual dysfunction, PCOS and…. infection!

The Microbiome and Viral Infection

There’s a large body of scientific evidence linking viral infections to the microbiome. In general, the gut microbiome can suppress or promote viral infection through a variety of mechanisms, including altering the stability of the virion (the virus before it’s infected a host cell), genetic recombination, driving cell proliferation, suppressing viral replication, stimulating attachment to permissive cells, and influencing local and systemic immune responses. Probiotic species may help protect against viral infections by reducing intestinal permeability, reinforcing the innate immune response in the gut mucosa, and affecting the systemic acquired immune response via anti-inflammatory and regulatory effects. And, some probiotic bacteria (such as Lactobacillus species) are able to directly bind to and inactivate viruses before they attach to host cells, in turn inhibiting infection. Through carbohydrate fermentation and the production of lactic acid, Lactobacillus can also alter pH levels and subsequently inactivate some viruses that are sensitive to changes in acidity. Likewise, short-chain fatty acid (SCFA)-producing bacteria (such as Roseburia, Faecalibacterium prausnitzii, Anaerostipes, and Eubacterium rectale) are important for keeping the lumen replete with butyrate to feed epithelial cells, which produce antiviral compounds. SCFAs produced by fiber fermentation by commensal gut bacteria can also be absorbed by, and act upon, immune cells in ways that reduce the inflammatory component of viral infections like influenza. Likewise, segmented filamentous bacteria can increase ACE2 expression—a transmembrane enzyme that many viruses including SARS-CoV-2 utilize to enter and infect a cell— creating more entry points for viruses like SARS-CoV-2 that bind with these receptors.

A recent meta-analysis of 12 randomized controlled trials (totaling 3720 subjects) found that probiotics were able to reduce the average duration of upper respiratory tract infections, lower the number of infections themselves, and reduce the need for antibiotic administration compared to placebo. Probiotic bacteria like Lactobacillus have immunomodulatory properties and can protect against viral infections by enhancing the cytokine antiviral responses in immune cells and respiratory cells, as well as in the intestinal mucosa. (See also Natural Approaches to Cold & Flu Season (and Covid-19!))

Numerous studies have shown that the gut microbiota are critical for controlling replication of the influenza virus. One study in mice found that altering the gut microbiota with antibiotics increased the severity of influenza infection, while stimulating the microbiota with a high-fiber diet reduced the severity (via enhancing Ly6c-patrolling monocytes). Fecal transfer experiments revealed that dysbiotic gut microbiota reduces the lung’s defenses against influenza-associated pneumonia (more specifically, reduced SCFA production by the bacteria leads to a decrease in the bactericidal activity of alveolar macrophages). This means that an unhealthy gut microbiome may increase susceptibility to bacterial infection while the body is fighting viruses like influenza. What’s more, in mice, oral administration of Lactobacillus brevis was shown to protect against influenza infection by enhancing antiviral IFN-α and augmenting IFV-specific IgA production. Lactobacillus plantarum, meanwhile, was shown to significantly reduce titers of human H1N1 and avian influenza H7N9 in the lungs of mice, while also increasing their survival time after infection with a lethal viral challenge. Lactobacillus paracasei was shown to lower the incidence of influenza A H3N2 infection in mice, while also reducing the infiltration of inflammatory cells into the lungs and leading to faster virus elimination.

The microbiota plays complex roles in a variety of other viral infections, too. Lactobacillus brevis has been shown to interact with components of the herpes simplex virus type 2 to inhibit infection. Lactobacillus gasseri has antiviral activity against respiratory syncytial virus (RSV), with some studies showing that taking this probiotic orally reduces the pulmonary RSV titer, reduces the expression of virus-induced pro-inflammatory mediators in the lungs, and upregulates interferon-stimulated genes. Lactobacillus plantarum was able to reduce inflammation induced by pneumonia virus in rodents. In an experimental rhinovirus infection, Bifidobacterium animalis subspecies lactis BI-04 reduced levels of the pro-inflammatory cytokine IL-6. In human adenovirus type 5, exopolysaccharides produced by Lactobacillus species was shown to exert antiviral activity. Gut microbiota also appears to influence susceptibility to cytomegalovirus (CMV), with Staphylococcus aureus associated with earlier CMV infection in children. And, that’s just the beginning of a long list of systemic viruses impacted by the gut microbiota!

Covid-19 and the Gut: What We Know So Far

Although covid-19 hasn’t been around long enough for us to study its connection with the gut microbiota in great depth, there is a growing number of studies and reviews that have examined the link between the gut microbiota and SARS-CoV-2 infection—including the intestine as an important site of infection, and microbiota patterns among patients with covid-19.

For starters, let’s look at how this virus can infect us via the gut. SARS-CoV-2 has extremely high binding affinity for angiotensin-converting enzyme II (ACE2), which is how the virus gains entry into host cells: the virus’s spike-like protein binds to the ACE2 like a key fitting into a lock, initiating infection by releasing the fusion machinery that the virus uses to dump its RNA and viral proteins into the target cell, where it then hijacks the cells organelles to produce viral replicas instead of all of the various proteins that the cell needs to survive. (See also Covid-19 FAQ: Do Face Masks Even Work?) Lungs are targeted so strongly during covid-19 because ACE2 is abundantly expressed in lung tissue. But, ACE2 is also expressed in intestinal cells, especially small intestinal and colon epithelial cells (ACE2 serves as a co-receptor for the uptake of nutrients, especially amino acids, and also plays a key role in intestinal homeostasis). This makes the gut a potentially important entry point for SARS-CoV-2. Indeed, studies have shown that about half of covid-19 patients have SARS-CoV-2 RNA detectable in their stools, and the virus has been shown to replicate in enterocytes (intestinal absorptive cells).

Not surprisingly, a significant number of covid-19 patients (10–20%, according to meta-analyses conducted so far) experience GI symptoms like diarrhea, vomiting, and nausea; this may be due to: reduced intestinal ACE2 expression (SARS-CoV-2 infection decreases ACE2 expression in the lungs and likely does so in the gut, too; see also TWV Podcast Episode 412: Covid-19 FAQ, Part 3); changes in oxygen levels; or, effects on the central nervous system and gut-brain axis (for example, an immune response that induces diarrhea or stimulates the vagus nerve to cause vomiting). Similarly, viral replication within the GI tract could exponentially increase the SARS-CoV-2 load in the gut mucosa, leading to a loss of barrier integrity, imbalance of residence microbes and metabolites (like SCFAs), and subsequent alterations in the immune system—including high cytokine production. A study published this week in Science showed an abundance of gut bacterial DNA and endotoxin in the blood of covid-19 patients, correlating with disease severity.

Along with these effects on the gut, covid-19 infection may alter the gut microbiota itself. Decreases in ACE2 are known to reduce the production of certain antimicrobial peptides that help modulate the microbiota composition, and studies of covid-19 patients specifically have shown that infection is associated with significantly lower bacterial diversity and abundance (including lower relative abundance of butyrate-producing bacteria from the probiotics Ruminococcaceae and Lachnospiraceae, Alistipes onderdonkii, Roseburia, and Faecalibacterium prausnitzii), along with a greater abundance of opportunistic pathogens such as Clostridium hathewayi, Rothia, Veillonella, Actinomyces viscosus, Bacteroides nordii, and Streptococcus. Across multiple studies, an overabundance of Prevotella has been found in infected patients; a study in China found low levels of the essential probiotics Lactobacillus and Bifidobacterium. (Some of these bacteria are also discussed in Paleo, Resistant Starch, and TMAO: New Study Warning Worth Heeding and The Link Between Meat and Cancer.)

A small study of covid-19 patients from Hong Kong found that the abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi positively correlated with disease severity, while the probiotic Faecalibacterium prausnitzii negatively correlated with disease severity—possibly due to the viral infection setting the stage for secondary bacterial infection. A pattern of depletion of symbiotic bacteria and enrichment with opportunistic pathogens persisted even after recovery from SARS-CoV-2 (demonstrated by negative results from throat swab and stool). Likewise, a number of bacteria known to downregulate intestinal ACE2 expression in rodents (including Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus) inversely correlated with the SARS-CoV-2 load in patients’ fecal samples. Fascinatingly, when covid-19 patients were compared with healthy controls, covid-19 infection demonstrated the greatest impact on the gut microbiome compared to other host factors like antibiotics, hyperlipidemia, age, gender, or pneumonia.

Studies of covid-19 also show that infection alters the gut-blood barrier and allows greater entry of systemic endotoxins, bacteria, and microbial metabolites (yes, leaky gut, see also What Is A Leaky Gut? (And How Can It Cause So Many Health Issues?)). In turn, this can affect the body’s initial response to infection and lead to septic shock, cytokine storms, and multisystem dysfunction that can potentially be fatal. (See also Natural Approaches to Cold & Flu Season (and Covid-19!).)

It’s important to note that these gut-related changes appear to be a consequence of SARS-CoV-2 infection, rather than being baseline features that predispose people to getting infected in the first place. It remains unknown how much these gut microbiome changes contribute to the long-term syndrome-like symptoms faced by many covid-19 patients, or if permanent alterations of the gut microbiome due to SARS-CoV-2 could set the stage for future chronic illness.

There are also some clues that the state of the gut microbiota could make someone more or less susceptible to this virus!

A recent Chinese study (currently pre-print) investigated whether certain proteomic biomarkers predicting severe covid-19 progression among infected individuals could also be used to explain disease susceptibility among people who weren’t yet infected—and whether the gut microbiota was involved in regulating those biomarkers. Using a pool of over 300 healthy individuals with data spanning a three years, the researchers identified core gut microbiota features that could predict the proteomic biomarkers and potentially indicate someone’s susceptibility to covid-19: Bacteroides, Streptococcus, Lactobacillus, Ruminococcaceae, Lachnospiraceae, and Clostridiales. In fact, Pearson correlation analysis showed a highly significant 0.59 coefficient between the bacteria-predicted blood proteomic risk score (PRS) and the actual proteomic risk score of the participants—making gut bacteria a better predictor than any other demographic characteristic or laboratory test! The relationship between proteomic risk score and infection was most significant among older individuals. As far as inflammation went, Bacteroides, Streptococcus, and Clostridiales were negatively associated with most of the inflammatory cytokines tested (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α and IFN-γ), while Ruminococcus, Blautia, and Lactobacillus were positively associated with most of these cytokines. The researchers proposed that bacterial metabolites identified in the feces (mostly those associated with amino acid biosynthesis pathways) likely played a key role in mediating the effects of the gut microbiota upon inflammation and metabolism in the host. And most importantly, among these healthy individuals, alterations in the gut microbiota composition preceded changes in the proteomic risk score, pointing to the gut microbiota as the cause of these risk-raising changes (rather than the biomarker changes causing gut dysbiosis). Overall, this fascinating study suggests that certain disruptions in the gut microbiota could predispose individuals to an inflammatory status that increases covid-19 susceptibility and severity.

Although less studied, evidence also suggests that the gut microbiota could play a role in the cytokine storms associated with SARS-CoV-2 infection. Cytokine storms are an over-reactive immune response to infection, in which a disproportionate amount of pro-inflammatory cytokines (small proteins that act as immune messengers, like IL-1β, IL-6, and TNF-α) are released into the bloodstream too quickly and can cause hyper-inflammation, damage cells, and lead to multisystem organ failure and death. Metabolic processes by the gut microbiota strongly influence cytokine production, and the gut microbiota composition may contribute to cytokine reactions seen in severe covid-19 cases.

The Gut-Lung Axis

The gut microbiome interacts with a number of other organs and body systems beyond the GI tract, and the lungs are no exception! (See also How Stress Undermines Health and How Chronic Stress Leads to Hormone Imbalance). The gut-lung axis describes how the composition of the gut microbiota influences susceptibility to lung disease, including viral infections (and as we’ve seen, viral infection can likewise alter the composition of the gut microbiota).

In general, the gut microbiome is a powerful weapon against systemic viral infection, and can remotely boost the body’s response to respiratory infections specifically. The gut microbiota can enhance CD8+ T cell effector function (such as cytotoxic T cells, which promote viral clearance by inducing apoptosis [programmed cell death] of infected cells), and components of the bacterial cell wall, as well as bacterial metabolites like desaminotyrosine (produced by the commensal bacteria Clostridium orbiscendens), support the production of inflammasome-dependent cytokines and type I interferons in lung cells. In mice, segmented filamentous bacteria in the gut have been shown to stimulate pulmonary type 17 helper T cell (Th17) responses, along with protecting against S. pneumonia infection and death; mouse studies have also shown that Bifidobacteria species protect against both viral and bacterial lung infection. So, all the way from our lower GI tract, microbes have a say in what happens in our lungs!

Even beyond viral infections, the gut microbiota have shown important links with maintaining healthy lung function and protecting against airway diseases. For example, SCFAs produced by fiber-fermenting bacteria appear to suppress airway inflammation, leading to improvements in asthma symptoms. One study in mice found that a high-fiber diet increased the production of the SCFA acetate in the gut, in turn enhancing the number and function of regulatory T cells (acetate increases acetylation at the Foxp3 promoter) and suppressing the animals’ allergic airway disease (the equivalent to human asthma). A separate study found that high-fiber feeding conferred protection against food allergies by enhancing the activity of retinal dehydrogenase in CD103(+) DC. Another rodent study found that increasing the fermentable fiber content of the animals’ diet altered their gut and lung microbiomes, leading to higher levels of circulating short-chain fatty acids, and in turn protecting against allergic inflammation in the lungs (in contrast to a low-fiber diet, which increased allergic lung inflammation).

Can we just take yet another moment to say “yay fiber!” Learn more in What Is Fiber and Why Is it Good?, The Many Types of Fiber, Soluble vs. Insoluble Fiber, Fiber, Cholesterol and Bile Salts, Busting the Abrasive Insoluble Fiber Myth, New Science Suggests Fiber Improves Sleep Quality!, Why Fruit is a Good Source of Carbohydrates, Why Root Veggies Are Great for the Gut Microbiome, The Health Benefits of Citrus Fruits, The Health Benefits of Apples, and The Importance of Vegetables.

Age, Microbiota, and COVID-19 Susceptibility

It’s well established that even with high viral loads, children and young adults are much less likely to develop symptomatic covid-19 than older adults. In fact, older age is a major risk factor for severe or fatal covid-19 cases. Could the gut microbiome play a role here, too?

It’s a solid possibility! For example, older individuals tend to display chronic low-grade inflammation and reduced gut barrier integrity (leaky gut), both of which can exacerbate the problems associated with SARS-CoV-2 infection. Likewise, throughout life, the gut microbiota goes through predictable shifts in composition, and by the age of about 60, the average gut microbiome exhibits a drop in diversity and Lactobacillus and Bifidobacterium abundance—potentially translating to greater susceptibility to systemic viral infections like SARS-CoV-2, due to the role of the gut microbiota in immunity (and the specific role of Lactobacillus species in binding to viruses). Indeed, research has shown that age-associated changes in the immune system and inflammation are strongly modulated by changes in the gut microbiota, and can collectively create an over-reactive inflammatory phenotype that predisposes to cytokine storms and other damaging activity for the vital organ systems. As further evidence, a recent study showed that older individuals exhibit a significant association between certain covid-19-related blood proteomic markers and inflammation, and may be particularly susceptible to the cytokine storm associated with more severe cases.

Gut Microbiota and Comorbidities

By now, we have plenty of data showing that certain comorbidities increase the risk of severe or fatal covid-19 infection—particularly diabetes, high blood pressure, and obesity, but also kidney disease, heart disease, COPD, and cancer. (In fact, an exception to the trend of younger people being more protected against severe covid-19 is when one of these comorbidities is involved: regardless of age, someone with diabetes or obesity is at risk of more severe disease than someone without these conditions.) And, it just so happens that these conditions are consistently associated with alterations in the gut microbiota. Whether these comorbidities are such high risk factors for covid-19 due to a role of gut dysbiosis is certainly worth exploring!

One interesting pattern is that these chronic diseases tend to correlate with a lower abundance of Bacteroides species—some of which are reported to suppress ACE2 expression in the colon and calibrate the immune response of the host. That means that some of the microbiota alterations coinciding with these conditions could reduce the body’s ability to fight off SARS-CoV-2 while also providing more entry sites for the virus in the intestine. In addition, infection with SARS-CoV-2 may be particularly dangerous in the presence of comorbidities due to amplifying systemic pathways through gut-related avenues—such as ACE2 disruption, alterations in microbial profiles, intestinal inflammation, and loss of gut barrier integrity.

On a more specific level, each co-morbidity has microbiota signatures that could lower systemic immunity and/or increase ACE2 expression—in both cases, granting entry for SARS-CoV-2 and supporting a higher viral load. For example, microbiota profiles associated with obesity include a lower proportion of Bacteroidetes (while these bacteria tend to be higher among lean individuals), theoretically making the obesity-associated gut microbiota less protective against SARS-CoV-2 infection. Cardiovascular disease is associated with higher levels of endotoxin, a highly inflammatory component of the outer layer of Gram-negative bacteria; along with its role in atherosclerosis (endotoxin is involved in both the initiation and progression of atherosclerosis through pro-coagulant activity, endothelial cell injury, monocyte recruitment, and the transformation of macrophages into foam cells), endotoxin can contribute to systemic inflammation that may increase the risk of a cytokine storm associated with COVID-19. And, many types of cancer are associated with microbiomes low in SCFA-producing bacteria, which could reduce the availability of butyrate for epithelial cells and potentially lessen the body’s defenses against viral infection.

Recent research has suggested an important role of the gut microbiome in chronic kidney disease—another co-morbidity that increases the risk of severe covid-19. Patients with kidney disease tend to have microbiomes characterized by higher production of uremic toxins and low production of short-chain fatty acids (in turn, potentially reducing immune function). Gut dysbiosis can lead to dysfunction of the intestinal barrier and the translocation of bacterial DNA and gut-derived toxins into the bloodstream, eventually triggering a state of systemic inflammation—another predisposing factor for more severe covid-19. Patients with chronic kidney disease also have higher proportions of opportunistic pathogens from gamma-Proteobacteria, and have lower levels of beneficial strains of Roseburia, Coprococcus, Bifidobacteria, Lactobacilli, and Ruminococcaceae, raising the risk of secondary infections from respiratory viruses. Collectively, these features would be expected to make kidney disease patients much more susceptible to SARS-CoV-2 infection due to the impact on intestinal and systemic immunity. In addition, dietary treatments for kidney disease can also contribute to an altered gut microbiome that raises severe covid-19 risk. In order to reduce complications like hyperkalemia, patients with chronic kidney disease are prescribed diets low in fiber, protein, and symbiotic organisms—again causing shifts in the microbiota that reduce production of SCFAs and possibly increase the risk of viral infection and replication. (See also The Paleo Diet for Kidney Disease and The Paleo Diet for Gout).

Fermented Foods and Covid-19

Very recently, a review paper from Europe noted that across countries and regions within countries, cabbage and fermented vegetable consumption is associated with lower covid-19 death rates (as measured by the Comprehensive European Food Consumption Database tracking consumption of fermented vegetables, fermented milk, yogurt, and pickled/marinated vegetables). Out of all the variables examined, fermented vegetables were the only thing that reached statistical significance with national covid-19 death rate. In fact, for each gram per day increase in fermented vegetable intake per capita, covid-19 mortality risk dropped by 35.4%! (Meanwhile, a separate analysis of various vegetables found that only cabbage and cucumber were significantly associated with reduced covid-19 mortality.) See also The Health Benefits of Fermented Foods and Natural Approaches to Cold & Flu Season (and Covid-19!).

Although we should take this correlation with a giant grain of salt (given the numerous potential confounding factors!), there’s actually some mechanistic plausibility for cabbage and fermented foods being protective during SARS-CoV-2 infection. Sulforaphane from cabbage and Lactobacillus (found in lacto-fermented vegetables) are among the most active natural activators of nuclear factor erythroid 2–related factor 2 (Nrf2), which can block the angiotensin II receptor type 1 (AT₁R) axis—an axis associated with oxidative stress, and which becomes enhanced as SARS-CoV-2 binds and downregulates ACE2. Nrf2 has anti-fibrotic effects on the lungs, protects against endothelial damage and lung injury, and protects against acute respiratory distress syndrome—all hallmarks of severe covid-19. It’s not a stretch to speculate that Lactobacillus-containing foods could be protective through this avenue.

Can We Reduce Covid-19 Risk by Improving Our Gut Microbiome?

Don’t rush out to the probiotic aisle in your local grocery store just yet (and if you do, wear a mask, see Covid-19 FAQ: Do Face Masks Even Work?). It’s too early to make any declarative statements about gut-microbiota-modifying strategies, such as taking particular strains of probiotics, impacting susceptibility to or the course of covid-19. We simply don’t have the research yet. But, based on known mechanisms along with studies currently available on covid-19, we can say that improving the state of our gut health certainly won’t hurt, and may improve a number of immune parameters—including ones directly involved with viral infection.

One thing we do know for sure though: Supporting a healthy and diverse gut microbial community is a prerequisite for our good health. In fact, in my six-year-long deep dive into gut microbiome research to write The Gut Health Guidebook, I have yet to find a chronic illness that is not linked to a dysfunctional gut microbiome. Our health really is rooted in our guts.

In my research, I became obsessed with understanding how healthy food choices benefit us, not directly, but instead via improving the gut microbiome. Diet is the single biggest influence on microbiota composition. In fact, diet is directly responsible for more than 60% of the variation in bacterial species in the gut, with probiotic exposure, genetics, gender, age, lifestyle, hormones, drugs, supplements, toxin and environmental exposures collectively responsible for the remaining 40%. As I gathered information, I was very intentional to follow the science wherever it led, rather than cherrypick only those studies that rationalized the standard Paleo or AIP templates. So, in my new e-book The Gut Health Guidebook, I build a new diet for general health from the ground up based on optimizing the gut microbiome.

There’s a really immense amount of information in The Gut Health Guidebook, but it all boils down to 20 keys to gut health. Here’s the cliffsnotes: To best support a healthy gut microbiome, eat a nutrient-dense and varied diet that is moderate-fat and moderate-carb and that includes plenty of veggies, fruit, mushrooms, and seafood, rounded out with nuts, seeds, grass-fed meats, fermented foods, and phytochemical-rich foods like herbs, tea, coffee, cacao and extra virgin olive oil. Lifestyle factors are also essential, like getting enough sleep on a consistent schedule, entrenching a solid circadian rhythm, eating distinct meals instead of grazing, fasting overnight (12-14 hours, not IFing), living an active lifestyle, and managing stress. It’s also super important to optimize vitamin D levels. There are a handful of foods that are traditionally excluded on the Paleo diet that actually are a boon to our gut microbiomes, including A2 dairy (like goat, sheep or camel), most legumes (not soy or peanuts), pseudograins, corn, rice, and gluten-free oats; however, none of these latter foods are fundamental for a healthy gut microbiome in the same way that mushrooms, seafood, and individual families of vegetables and fruit are.

Of course, you can super nerd out on all the details behind all 20 keys to gut health, as well as how the aforementioned non-Paleo foods fit into the picture, in The Gut Health Guidebook (and don’t forget to check out The Gut Health Collection because the companion e-cookbook, which includes 180+ recipes centered on 61 gut health superfoods, is coming is September!).

Citations

Antunes A, et al. “Potential contribution of beneficial microbes to face the COVID-19 pandemic.” Food Res Int. 2020 Oct; 136: 109577.

Biliavska L, et al. “Antiviral Activity of Exopolysaccharides Produced by Lactic Acid Bacteria of the Genera Pediococcus, Leuconostoc and Lactobacillus against Human Adenovirus Type 5.” Medicina (Kaunas). 2019 Sep; 55(9): 519.

Bousquet J, et al. “Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID‐19.” Allergy. Accepted Author Manuscript. 6 Aug 2020. doi:10.1111/all.14549

Budden KF, et al. “Emerging pathogenic links between microbiota and the gut-lung axis.” Nat Rev Microbiol. 2017 Jan;15(1):55-63. doi: 10.1038/nrmicro.2016.142. Epub 2016 Oct 3.

Carvalho-Queiroz C, et al. “Associations between EBV and CMV Seropositivity, Early Exposures, and Gut Microbiota in a Prospective Birth Cohort: A 10-Year Follow-up.” Front Pediatr. 2016; 4: 93.

Gou W, et al. “Gut microbiota may underlie the predisposition of healthy individuals to COVID-19.” MedRxiv. doi: https://doi.org

He LH, et al. “Intestinal Flora as a Potential Strategy to Fight SARS-CoV-2 Infection.” Front Microbiol. 2020; 11: 1388.

Infusino F, et al. “Diet Supplementation, Probiotics, and Nutraceuticals in SARS-CoV-2 Infection: A Scoping Review.” Nutrients. 2020, 12(6), 1718; https://doi.org/10.3390/nu12061718

Kalantar-Zadeh K, et al. “Considering the Effects of Microbiome and Diet on SARS-CoV-2 Infection: Nanotechnology Roles.” ACS Nano. 2020 May 1: acsnano.0c03402.

Li, N et al. “The Commensal Microbiota and Viral Infection: A Comprehensive Review.” Front Immunol. 2019; 10: 1551.

Mendes V, et al. “Mechanisms by Which the Gut Microbiota Influences Cytokine Production and Modulates Host Inflammatory Responses.” J Interferon Cytokine Res. 2019 Jul;39(7):393-409.  doi: 10.1089/jir.2019.0011. Epub 2019 Apr 23.

Tan J, et al. “Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways.” Cell Rep. 2016 Jun 21;15(12):2809-24. doi: 10.1016/j.celrep.2016.05.047.

Trompette A, et al. “Dietary Fiber Confers Protection against Flu by Shaping Ly6c – Patrolling Monocyte Hematopoiesis and CD8 + T Cell Metabolism.” Immunity. 2018 May 15;48(5):992-1005.e8.  doi: 10.1016/j.immuni.2018.04.022.

Trottein F & Sokol H. “Potential Causes and Consequences of Gastrointestinal Disorders during a SARS-CoV-2 Infection.” Cell Rep. 2020 Jul 21; 32(3): 107915.

Viana SD, et al. “ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities – Role of gut microbiota dysbiosis.” Ageing Res Rev. 2020 Sep; 62: 101123.

Zuo T, et al. “Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization.” Gastroenterology. 2020 May 20. doi: 10.1053/j.gastro.2020.05.048

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Glutamine and the Gut Barrier

The gut barrier consists of a single layer of firmly connected cells lining the intestine, serving as a barrier between the external world (our digestive tract, which is technically a tube that runs “outside” our body!) and our internal environment (the inside of our body). When this barrier is functioning properly, it prevents foreign antigens, pathogens, and bacterial toxins from entering our system, while also selectively allowing essential nutrients and water to filter through. When this barrier isn’t functioning properly (as is the case with leaky gut), protein fragments, endotoxin, waste, pathogens, and other harmful substances can leave the gut and enter circulation. In that situation, immune cells in the gut launch an attack on the foreign invaders, leading to a cascade of immune reactions and ongoing inflammation. In short, gut barrier function is essential for keeping us healthy, and when it’s in a compromised state, so are we! (For more on the gut barrier and how leaky gut develops, check out “What Is A Leaky Gut?”,  as well as my Gut Health Fundamentals online course.)

So, where does glutamine come into play?

For one, glutamine is the preferred fuel source for cells lining the gut. In fact, the intestinal mucosa uses about 30% of the body’s total glutamine, demanding more than 15 grams of it per day! Our intestine actually competes with other tissues in our body for use of glutamine from our food and from our body’s amino acid pool! Glutamine is needed in order for those intestinal cells to grow and differentiate (mature), and does so by activating mitogen-activated protein kinases (MAPKs;  which orchestrate cell proliferation and differentiation), and by augmenting the effects of growth factors (like epidermal growth factor, transforming growth factor-α, and insulin-like growth factor-I). In vitro studies have shown that, without enough glutamine, two types of epithelial cells (caco-2, a line of human epithelial colon cancer cells that is widely used to study tight junctions and which I used to use for cell culture studies way back in my cell biology research days, and IEC-6) exhibit slowed growth. Likewise, glutamine supplementation has been shown to decrease mucosal atrophy and reduce oxidant injury in models of ulcerative colitis, due to its role in supporting intestinal epithelial cell growth!

Secondly, glutamine modulates the expression of tight junction proteins, which tightly join together epithelial cells to create the gut barrier. Experiments have shown that glutamine deprivation reduces the expression of several different tight junction proteins (including claudin-1, ZO-1, and occludin, all of which I used to study, so just writing this is bringing back memories of hours and hours in the confocal microscopy suite), significantly increases epithelial cell permeability (AKA leaky gut), and results in villous atrophy (when the intestinal villi erode away, like what happens in celiac disease). And, adding glutamine to glutamine-deprived cells has been shown to improve the barrier function, increase the expression of ZO-1 and occludin proteins (indicating the formation of tighter tight junctions), and prevent chemically induced disruptions of the tight junctions and their permeability. Research using caco-2 cells has shown that glutamine deprivation leads to greater bacterial translocation.

Although the mechanisms aren’t completely understood yet, glutamine appears to influence signaling pathways related to different tight junction components, including the regulation of phosphorylation states of tight junction proteins via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. On top of that, glutamine may help maintain the balance between proliferation (reproduction) and apoptosis (programmed death) of the epithelial cells lining the intestine. These cells have a rapid turnover rate of every four to five days, and if an imbalance occurs between cellular reproduction versus cellular death, a net loss of epithelial cells can result (which we see in conditions like ulcerative colitis, celiac disease, and intestinal bacterial infection!). A variety of cellular stressors like nutrient deprivation, lack of growth factor, endotoxemia, or gut-harming agents that make their way into our bodies can lead to increased apoptosis. But, glutamine may play a key role in preventing this! Studies have shown that glutamine supplementation suppresses the chemically-induced apoptosis of intestinal epithelial cells, and when there’s a shortage of available glutamine, apoptosis of intestinal cells increases.

Glutamine’s anti-apoptotic properties work through a variety of mechanisms. One is through its ability to modulate cellular stress responses, including autophagy (a catabolic process that occurs during metabolic stress conditions, often referred to as a “Spring cleaning” of cellular organelles) and endoplasmic reticulum stress (which has been shown to trigger sustained apoptosis). Another is via glutamine’s role as a precursor for the antioxidant tripeptide glutathione (GSH), which is key for maintaining normal cellular redox status. When glutathione is depleted, excessive oxidative stress can induce apoptosis! Additionally, glutamine can enhance the expression of heat shock proteins, which appear to modulate programmed cell death by helping cells adapt to stressful conditions. In animal experiments, administering glutamine to rats with sepsis was able to significantly increase the expression of two heat shock proteins (HSP-70, which is my personal favorite heat shock protein because I studied it during my PhD research, and HSP-25), while glutamine deprivation reduced the expression of heat shock protein genes and led to increased cell death. And lastly, glutamine regulates the activation of caspases, a family of protease enzymes that act in concert in a cascade to trigger and execute apoptosis. Studies have shown that glutamine-deprived cells demonstrate higher caspase-3 activity, leading to greater levels of cell death. In animal models and human colon cancer cells, administering glutamine has been shown to reduce caspase activity and protect against apoptosis.

So, in a nutshell, glutamine is a huge boon for our gut barrier due to the many ways it keeps our epithelial cells healthy and proliferating!

But, it doesn’t end there! Glutamine also plays a role in intestinal immunity. In particular, glutamine enhances the secretion of immunoglobulin A+ (IgA+) and intestinal secretory immunoglobulin A (SIgA), which helps defend the intestinal mucosal surface against pathogens and enteric toxins. Glutamine is also needed for the growth of immune cells, and not surprisingly, glutamine insufficiency has been shown to increase susceptibility to infection.

Glutamine and the Gut Microbiota

Along with benefiting our human cells, glutamine can influence the composition of the gut microbiota—the massive community of microbes inhabiting our gut, and which plays a major role in human health. (Be sure to check out What is the Gut Microbiome? And Why Should We Care About It?)

Protein is essential for the growth and survival of the bacteria in our digestive tracks. Amino acids are utilized for the synthesis of bacterial cell components or catabolized (broken apart) through different pathways. Certain amino acids have been identified as likely essential for optimal growth of gut bacteria, including arginine, aspartate, asparagine, glutamate, glutamine (yay!), glycine, lycine, serine, threonine, and the branched-chain amino acids (leucine, isoleucine, and valine). Interestingly, our gut bacteria seem to have a preference for glutamine (and arginine, which I’ll talk about in a future article), which is why it can benefit gut microbial composition.

In a trial of overweight and obese adults, consuming 30 grams of supplemental glutamine each day for two weeks resulted in a beneficial reduction in the Firmicutes to Bacteroidetes ratio (from 0.85 to 0.57), lower levels of Actinobacteria, a change associated with leanness and weight loss. The bacteria genera Dialister, Dorea, Pseudobutyrivibrio, and Veillonella (all members of Firmicutes) also significantly decreased.

One investigation looked at the gut microbiota and a variety of metabolites (including fatty acids, lipids, glucose, and amino acids) in 531 Finnish men. The researchers found that glutamine levels were positively associated with microbial richness, as well as with higher levels of Clostridales.

Animal studies have also shed light on the effects of glutamine on the gut microbiota. In one experiment with mice, supplementing with 1% L-glutamine for 14 days resulted in a beneficial decrease in the Firmicutes to Bacteroidetes ratio. In a rat model of colon cancer, glutamine treatment protected against a chemotherapy-induced decline of Clostridium cluster XI and Enterobacteriaceae. Constipated animals supplemented with glutamine saw an increase in beneficial members of Bacteroidetes and Actinobacteria, which played a role in the amelioration of constipation (more specifically, glutamine appears to reduce constipation by affecting nitrogen balance and protein synthesis in the small intestinal microbiota). A study using pregnant constipated pigs found that supplementing the diet with 10 grams of glutamine was enough to reduce their constipation and caused an increase in friendly bacteria, while decreasing levels of the potentially harmful bacteria Oscillospira and Treponema.

Fascinatingly, glutamine also seems to influence how our intestinal bacteria metabolize other amino acids. In one experiment, the addition of glutamine to mixed bacterial cultures as well as individual bacteria strains (including species from Streptococcus, Escherichia coli, and Klebsiella) reduced the bacterial usage of asparagine, lysine, leucine, valine, ornithine and serine, with higher concentrations of glutamine causing greater decreases in the utilization of these amino acids, called an amino acid sparing effect. This is important, because the metabolism of amino acids by our gut microbes affects how much of them are available for the rest of our body!

How to Get the Benefits of Glutamine

So, how can we reap the gut-health rewards of glutamine? Although this amino acid is only considered conditionally essential (meaning that under normal circumstances, we can produce enough of it internally), certain situations can increase our demand beyond what our bodies can supply us with. This includes times of stress, critical illness, infection, wound healing, trauma, severe burns, gastrointestinal disorders, and intense exercise (in fact, reduced glutamine concentrations may play a role in the transient immunosuppression we see following strenuous exercise!). In other words, focusing on getting plenty of glutamine isn’t a bad idea!

In our diet, the best sources of glutamine include broth, seafood (especially crustaceans like shrimp, crab, and lobster, but also saltwater fish), organ meats, poultry, pork, red meat, and protein-rich dairy. Certain plant foods like cabbage, asparagus, and broccoli are also rich in glutamine! In general, aiming for a protein intake of 100 to 150 grams per day, including some glutamine-rich foods, can help ensure we get enough of this amazing amino acid to experience its benefits. (See also Why Broth is Awesome, Broth: Hidden Dangers in a Healing Food?, Bone Broth Risks: Skim the Fat!, Why Fish is Great for the Gut Microbiome, Oysters, Clams, and Mussels, Oh My! Nutrition Powerhouses or Toxic Danger?, The Mercury Content of Seafood: Should we worry?, Should We Be Worried About Radiation from Fukushima?, Grass-Fed Beef: A Superfood worth the Premium Price, Why Everyone Should Be Eating Organ Meat).

In some cases, glutamine supplementation can bring added benefits, such as gastrointestinal disorders, gut dysbiosis, and “leaky gut”, whether primary or secondary to something like autoimmune disease. Most successful trials have used supplementation at levels of 20 – 30 grams of glutamine per day. Because amino acids compete with other high-affinity amino acids for binding with their transporters within the intestine, it’s important to take glutamine on an empty stomach (an hour after food, or 30 minutes before food) so that our bodies can fully utilize it!

Citations

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Yes, we can add yet another reason to eat organ meat and shellfish to the list: A nutrient-dense diet supports a healthy gut microbiome! But, I recognize that some of the most important superfoods that we can eat are, how shall I put this, er, not so tasty?  Lol!  So, instead of yet another article highlighting the value of liver and oysters (see for example Why Everyone Should Be Eating Organ Meat and Oysters, Clams, and Mussels, Oh My! Nutrition Powerhouses or Toxic Danger? ), let’s keep it simple and focus on three food-based supplements to support the microbiome (and us!)!

Beef Liver Capsules from Smidge™ (formally Corganic) for Vitamin A (and more!)

In addition to containing impressive amounts of dozens of important vitamins and minerals, liver is one of the most concentrated sources of vitamin A of any food, and is an outstanding source of vitamin D, vitamin B12 (and other B vitamins), copper, potassium, magnesium, phosphorous, manganese, and iron in the heme form that is readily absorbed and used by the body. And it just so happens that every single one of these nutrients is essential to support a healthy and diverse gut microbiome.

Vitamin A for the Gut Microbiome

Not to be confused with beta-carotene (which is a vitamin A precursor, not vitamin A itself), vitamin A (retinol) is essential for bone growth, tooth remineralization, skin health, vision, reproduction, and immune function. It also is essential for gut barrier health in addition to its specific impact on the composition of the gut microbiome.

In children with persistent diarrhea, those with measured vitamin A deficiency had significantly lower bacterial diversity (diversity is a hallmark feature of a healthy gut microbiome), a higher proportion of problematic Enterococcus species, and a reduction in important butyrate-producing bacteria compared to children with normal vitamin A levels.

In rats, vitamin A deficiency has also been shown to increase the total amount of bacteria in the GI tract (implying vitamin A deficiency can contribute to bacterial overgrowth, for example SIBO), suppress levels of Lactobacillus species, and lead to the appearance of pathogenic Escherichia coli strains. In a mouse model of autoimmune lupus, vitamin A supplementation restored levels of Lactobacillus that were depleted in the lupus-prone mice, correlating with improved symptoms.

In one study of mice inoculated with a murine version of norovirus (the most frequent viral cause of acute gastroenteritis worldwide), administration of retinoic acid (a vitamin A metabolite) inhibited the replication of norovirus, as well as favorably shifted the composition of the gut microbiota. More specifically, retinoic acid treatment significantly increased the abundance of Bifidobacterium, Aggregatibacter, Allobaculum, Dialister, and Enhydrobacter, and increased the abundance of Lactobacillus that was suppressed by norovirus administration. The increase in Lactobacillus appeared to be responsible for the inhibitory effects of retinoic acid against norovirus. In a later study, the same researchers further investigated the mechanisms behind vitamin A’s antiviral activity and found that Lactobacillus species significantly increased the expression the cytokines interferon-β (IFN-β) and IFN-γ, indicating that the activation of interferons by vitamin A via an increase in Lactobacillus plays a critical role in the body’s immune response against norovirus.

Another study of vitamin A deficient versus vitamin A sufficient mice found that the deficient animals had lower levels of butyrate, Clostridium_XVIII, Roseburia, Pseudomonas, Blautia, Parabacteroides, Pseudomonadaceae, Bacteroidia, and Bacteroidetes and higher levels of acetate, Johnsonella, and Staphylococcaceae; the Firmicutes/Bacteroidetes ratio was also higher (linked to obesity and diabetes). In addition, vitamin A significantly affected bacterial pathways involved in macronutrient metabolism: the bacterial pathways in the deficient mice had enhanced amino acid and carbohydrate metabolism associated with lower amino acid biosynthesis, indicating that vitamin A deficiency interferes with the microbiota’s ability to produce and metabolize these nutrients.

Oysterszinc™ for Zinc and Selenium

Oysters are the richest food source of zinc, but are also amazing sources of vitamin D, vitamin B12, selenium, copper, and iron, and contain good amounts of vitamins B1, B2, B3, C, (yes, vitamin C), calcium, magnesium, manganese, phosphorus, and potassium, and oysters even provide some vitamins A, B5, B6, B9 and E plus dozens of trace minerals.  In fact, oysters rival liver in terms of nutrient-density, while complementing the nutrients in liver well.

Let’s zoom in on zinc and selenium in particular, since these two minerals are essential for the gut microbiome and since oysters are particularly impressive sources of them.

Zinc for the Gut Microbiome

Important for nearly every cellular function, from protein and carbohydrate metabolism to cell division and growth. Zinc also plays a role in skin health and the maintenance of sensory organs (that’s why zinc deficiency is associated with a loss of smell and taste) and is a vital nutrient for immune system function. Zinc also plays a vital role in epithelial barrier function by improving tight junction formation. The richest source is oysters, but other good sources include red meat, poultry, nuts and seeds, and legumes.

The gut microbiota has a two-way relationship with the mineral zinc: not only does zinc availability influence the composition of the microbiota, but the microbiota composition also influences the levels of zinc within the body!

Specifically, dietary zinc deficiency has been shown to decrease overall species diversity and richness in the gut microbiota (that’s a bad thing!), leading to reduced production of short-chain fatty acids (also bad!). Furthermore, the zinc-deficiency-induced alterations in microbiota could subsequently limit the absorption and availability of ingested zinc, leading to a negative feedback cycle that could worsen existing zinc deficiency. In fact, as early as the 1970s, research on the gut microbiota showed that conventionally raised mice had dietary zinc requirements that were nearly double that of germ-free mice (microbially sterile mice used for microbiome research), confirming a role of gut microbes in zinc homeostasis. Actually, about 20% of our dietary zinc intake is used just by our intestinal bacteria. More recently, researchers discovered that some bacterial species, including the diarrheal pathogen Campylobacter jejuni, compete for zinc within the intestine, and that zinc deficiency could therefore preferentially spur the growth of bacteria that thrive in low-zinc conditions.

Researchers compared the impact on the microbiome (in mice) of a diet low in total zinc versus a diet containing adequate zinc but also zinc uptake inhibitors (including phytic acid!) to decrease the bioavailability of the zinc versus a control diet with adequate zinc. Both the zinc-deficient and zinc-inhibited diets caused major disruptions to the microbiome, but some species thrived under zinc-inhibited conditions (including Actinobacteria, Lachnospiraceae, and Bacteriodetes species) that did not grow under zinc-deficient conditions, indicating that some bacteria are able to successfully compete for zinc in the presence of zinc uptake inhibitors. And while many important probiotic species were reduced in both the zinc-deficient and zinc-inhibited diets, other bacteria (in particular, the family Lachnospiraceae) were able to thrive in low-zinc conditions. Importantly, these bacterial shifts coincided with changes in markers of gut barrier health as well as significantly higher levels of E. coli endotoxin in the liver, indicating increased intestinal permeability.  What’s more, those changes in gut physiology had consequences for the brain: both the zinc-deficient and zinc-inhibited diets resulted in elevated levels of the inflammatory cytokines interleukin-6 and interleukin-1β in the brain, indicating neuroinflammation.

The takeaway from this important experiment? Not only is ingesting adequate zinc imperative for maintaining a healthy gut (and brain!), but so is ingesting enough bioavailable zinc. Although some bacteria have mechanisms that allow them to compete with zinc uptake inhibitors, many don’t. Therefore, zinc-rich plant foods that are also high in phytate (such as nuts, legumes, and grains) may not be the best place to get our zinc needs met. Oysters to the rescue!

Zinc also decreases the growth of well-known pathogens.  For example, zinc decreases the virulence and adherence to cells of enteropathogenic E. coli—a strain of E. coli that adheres to intestinal cells and is responsible for watery diarrhea. In one study of fecal microbiota transplant recipients, after adjusting for potential confounders, zinc deficiency was associated with an increased risk of recurrence of C. difficile infection, and zinc supplementation among those who were deficient reduced this risk—potentially due to zinc’s role in maintaining a diverse microbiome, improving water and electrolyte absorption, improving immunity, and maintaining mucosal integrity.

There’s also a really good argument for getting zinc from whole food sources.  In a study of mice colonized with C. difficile, excess zinc supplementation (12 times the level found in adequate zinc control diet) changed the microbiota in a way that resembled antibiotic treatment, increased toxin activity, lowered the amount of antibiotics needed to induce susceptibility to infection, and dramatically worsened how severe and lethal the C. difficile-associated disease was. The mechanism involved the zinc-binding protein calprotectin, which exerts antimicrobial effects against C. difficile by limiting the amount of zinc (which is needed by C. difficile) within the intestinal track. Excess dietary zinc, in turn, prevented calprotectin from adequately interfering with the metal uptake of C. difficile and allowed infection to progress. Given zinc’s popularity as an immune-boosting supplement, these findings highlight a potential danger of pushing intake too far beyond what’s provided in a nutrient-dense, whole foods diet. Oysters to the rescue again!

Selenium for the Gut Microbiome

Selenium is required for the activity of twenty-five to thirty different enzymes that protect the human brain and other tissues from oxidative damage. Selenium also helps support normal thyroid function. Good sources include oysters and other shellfish, red meat, poultry, fish, Brazil nuts, and mushrooms.

Because selenium is utilized by some microorganisms and is toxic to others, dietary selenium can influence the composition of the microbiota. About 25% of all bacteria express selenoproteins (and therefore require selenium to grow optimally), and these bacteria increase the selenium requirement of their host due to using it for their own growth.

In a study of mice placed on diets that were deficient, adequate, or enriched in selenium, gut microbial diversity increased as selenium intake increased (high diversity is one of the most important hallmarks of a healthy microbiome). In chickens, selenium increased the abundance of probiotics Lactobacillus and Faecalibacterium, as well as increased gut levels of short-chain fatty acids (particularly butyric acid). On the flip side, selenium deficiency alters the gut microbiota composition in ways that increases susceptibility to Salmonella typhimurium infection and chemically induced colitis.

In a variety of studies, supplementing with selenium-enriched probiotics shows synergistic effects beyond either probiotic bacteria alone or selenium alone.  For example, in mice, selenium-enriched probiotics (Candida utilis, Lactobacillus acidophilus, Lactobacilus rhamosus GG, and Streptococcus thermophilus) were better able to inhibit E. coli infection and mortality than probiotics or selenium alone. In piglets, animals fed selenium-enriched probiotics (in this case, Lactobacillus acidophilus and Saccharaomyces verevisiae) saw greater increases in blood selenium levels than the selenium-only or probiotic-only groups, and also suppressed E. coli levels and reduced incidence of diarrhea, suggesting the combination of probiotics and selenium can benefit the gut ecosystem as well as selenium homeostasis.

Rosita Extra Virgin Cod Liver Oil for Vitamin D and Omega-3 Fats

Rosita Extra Virgin Cod Liver Oil is the only fresh, sustainably- and wild-caught and raw cod liver oil on the market. It contains naturally-occurring vitamins A and D, and a full spectrum of omega fatty acids, including the super important long-chain omega-3 fatty acids EPA and DHA. And these nutrients are very beneficial for the gut microbiome!

Vitamin D for the Gut Microbiome

Assists in calcium absorption, immune system function, bone development, modulation of cell growth, neuromuscular function, and the reduction of inflammation. Although vitamin D can be produced when the sun’s UV rays hit the skin and trigger vitamin D synthesis, it also can be obtained from foods, including oily fish (such as salmon, tuna, and mackerel), mushrooms, fish roe, liver, and eggs.

Vitamin D routinely makes headlines for its importance in both physical and mental health, and it turns out, the gut microbiome is a major mediator for the benefits we credit to vitamin D!

The link between vitamin D and the gut microbiome may actually be a two-way street. While vitamin D can impact the health and composition of the gut, certain bacteria in the gut may also influence vitamin D levels in the blood by influencing vitamin D metabolism. In humans, higher levels of Coprococcus and Bifidobacterium, for instance, appear to promote higher vitamin D levels, though more studies are needed to definitely establish causality.

Vitamin D deficiency is linked with gut dysbiosis and inflammation, including severe colitis. Additional research shows vitamin D deficiency may contribute to metabolic syndrome (that nasty combination of obesity, insulin resistance, and cardiovascular disease risk factors) by aggravating diet-induced imbalances in the microbiota, including by decreasing the production of defensins (anti-microbial molecules needed for maintaining healthy gut flora). In rodents, vitamin D supplementation appears to improve metabolic syndrome via effects on the gut microbiome. And, people with higher levels of vitamin D have been shown to have lower levels of harmful endotoxin in the blood, possibly due to vitamin D’s ability to improve gut barrier integrity as well as normalizing the gut microbiome.

In human studies, vitamin D supplementation alters the composition of the gut microbiome, significantly reducing levels of Gammaproteobacteria (including the most common opportunistic pathogens Pseudomonas and Escherichia/Shigella), and increasing bacterial diversity (again, one of the signature features of a healthy microbiome!).  Vitamin D also promotes the growth of beneficial species of Bacteroiodes and Parabacteroides (like species of Ruminococcaceae and Lachnospira), while inhibiting the growth of problematic species like Blautia.

With vitamin D, as with all nutrients, it’s possible to get much of a good thing. In a mouse model of colitis, animals were supplemented with high-dose vitamin D (10,000 IU/kg), moderate vitamin D (2280 IU/kg), or no vitamin D. The mice receiving the highest dose developed the most severe colitis, and the high-dose control group (receiving vitamin D but not exposed to dextran sodium sulphate to induce colitis) ended up with microbiota compositions that were similar to those of the DSS-treated group, including a rise in Sutterella—suggesting that the high vitamin D dosing caused a shift to a pro-inflammatory microbiome. Additionally, the high-dose vitamin D mice saw a significant drop in serum vitamin D levels in conjunction with developing colitis, likely due to vitamin D metabolites dropping in response to intestinal inflammation that was caused by excessive vitamin D intake. In humans, similar undesirable shifts in the microbiome are seen when serum vitamin D levels are in excess of 75ng/mL. This is yet another reason to test-not-guess when it comes to high-dose vitamin D supplementation, and highlights the importance of repeated testing (ideally every 3 months) when taking vitamin D3 supplements (to dial in your individual dose to achieve the ideal serum vitamin D levels between 50 and 70ng/mL). In the absence of repeated testing, natural (not high-dose) ways to improve vitamin D levels include plenty of sun exposure and food sources of vitamin D, like Rosita Extra Virgin Cod Liver Oil.

Omega 3 Fats for the Gut Microbiome

In case we need another reason to embrace seafood, here it is: omega-3 fats are among the most gut-friendly fats around! In fact, many of the benefits attributed to omega-3 fats on human health are mediated by the gut microbiome. Fish and shellfish are the richest food sources of the two long-chain omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).  DHA is abundant in the brain and retinas and plays a role in maintaining normal brain function, treating mood disorders, and reducing risk of heart disease (or improving outcomes for people who already have it). The richest sources are fatty fish, such as salmon, mackerel, tuna, herring, and sardines.  EPA plays a role in anti-inflammatory processes and the health of cell membranes and may help reduce symptoms of depression. Sources include fatty fish and algae.

Animal studies have helped elucidate the omega-3, gut, and disease connection. In mice, analyses of gut microbes and fecal transfers have shown that higher levels of omega-3 fats in body tissue are associated with greater production and secretion of intestinal alkaline phosphatase (an enzyme that splits cholesterol and long chain fatty acids). This leads to changes in the composition of gut bacteria that ultimately reduce endotoxin production, gut permeability, metabolic endotoxemia, and inflammation, all of which influence disease risk. Additional studies in mice have shown that omega-3-rich diets increase populations of important Lactobacillus and Bifidobacteria bacteria.

In humans, omega-3 supplementation leads to lower levels of Faecalibacterium and greater levels of butyrate-producing bacteria (particularly from the genera Eubacterium, Roseburia, Anaerostipes, and Coprococcus), along with higher levels of the essential probiotics Bifidobacterium and Lactobacillus. Likewise, higher omega-3 levels (reflecting higher consumption) have been linked to more microbial diversity in the gut, as well as a greater abundance of short-chain fatty acid-producing bacteria belonging to the Lachnospiraceae family. Omega-3 fats also appear capable of reversing the dysbiosis associated with irritable bowel disease, and their anti-inflammatory effects can benefit other disorders involving inflammation of the gut.

Omega-3 intake during pregnancy could even influence the offspring’s risk of obesity through gut-mediated mechanisms. One study using fat-1 transgenic mice (which produce high levels of endogenous omega-3 fats) and wild-type mice found that a lower ratio of omega-3 to omega-6 fatty acids in a mother’s body during pregnancy and breastfeeding altered the balance of gut microflora in her offspring, induced indicators of metabolic disruption, and led to significantly more weight gain. Another study using fat-1 mice found that higher levels of tissue omega-3 helped prevent gut dysbiosis induced by early exposure to antibiotics and protected against obesity, insulin resistance, fatty liver, and dyslipidemia later in life.

While eating plenty of vegetables and fruit is essential for a healthy and diverse gut microbiome (see also What Is the Gut Microbiome? And Why Should We Care About It?, Why Root Veggies Are Great for the Gut Microbiome, 5 Reasons to Eat More Fiber, and The Importance of Vegetables), our fiber consumption is just the tip of the iceberg in terms of how our food choices impact the composition and health of our gut microbiome, which in turn are determinants of our health.  Our gut microbes are also sensitive to the amount and quality of the proteins we consume, the fats we consume, phytochemicals and the overall nutrient density of our diets. Yet another check in the “pro” column for a nutrient-focused diet, and obtaining the vital nutrients that both we and our gut microbiomes need from quality food sources!

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