Host-Microbiome Crosstalk in Health and Disease

Metabolism is the set of all chemical reactions that occur within cells to sustain function and viability. The primary inputs into cellular metabolism are nutrients, such as glucose, amino acids, and fatty acids, with nutrient preferences varying widely based on the cell type, the organism, and the status of the organism.

For example, in a fasted healthy human at rest, skeletal muscle cells primarily burn fatty acids taken up from the circulation to create energy. Conversely, muscle cells that are contracting vigorously primarily burn glucose, broken down from stored glycogen, to power energy production.

The primary outputs of metabolism are macromolecules like protein, glycogen, and triglycerides, as well as heat and chemical energy in the form of ATP. Metabolism also generates “waste” products that cells excrete. However, decades of research has revealed that these waste products are actually taken up by other cells and used productively.

For example, contracting muscle generates lactate from glucose to quickly produce energy via glycolysis (i.e., the pathway responsible for breaking down glucose). Then, the lactate is excreted into the circulation and taken up by the liver which uses it to synthesize glucose.

Finally, this glucose can return to the muscle via the bloodstream to further power contraction. This is but one example of the widespread, dynamic interplay between the organs of the body.

However, in addition to our organs sharing metabolites to support their complementary functions, there is also extensive crosstalk and exchange between the gut microbiome and the organs of the body.

The Importance of Gut Health

The gut microbiome constitutes a vast and unfathomably diverse ecosystem of viruses, bacteria, and fungi.  With respect to bacteria, there are upwards of 100 trillion present in the gut ranging more than 5,000 species. Not only do these microbes feed on the foods that we eat, but they also consume metabolites and macromolecules made by our human cells. However, this exchange is far from one-sided.

Using the nutrients provided by our diets and bodies, bacteria make thousands of unique bioactive metabolites, with the repertoire of the metabolic outputs varying dramatically based on the species and strain of bacteria performing the chemistry. These range from molecules that can feed other bacteria in the gut and support microbial diversity to molecules that can feed our gut cells, modulate our immune systems, and influence our psychological states.

Short Chain Fatty Acids

One such class of molecules is the short chain fatty acids (SCFAs). SCFAs are the product of the fermentation of fiber and other indigestible carbohydrates by specific species of anaerobic bacteria in the colon. The most abundantly produced SCFAs are acetate, propionate, and butyrate which are present in a roughly 3:1:1 ratio in a healthy colon.

While bacteria within the phylum Firmicutes are the primary butyrate producers (e.g., Faecalibacterium prausnitzii and Clostridium leptum), Actinobacteria like Bifidobacteria produce acetate and lactate, and Akkermansia mucinaphila from the phylum Verrucomicrobia produce propionate and acetate.

Acetate, propionate, and butyrate confer benefits to not only the cells of the intestines, but also to immune cell populations surrounding the gut and even the brain. Butyrate is involved in the maintenance of the gut barrier by supporting the integrity of tight junctions (i.e., the connections between cells in the intestines).

The breakdown of these tight junctions leads to a phenomenon known as leaky gut where bacterial endotoxin enters into the circulation and drives systemic inflammation in the body. Not only does butyrate exert anti-inflammatory actions by preventing and ameliorating leaky gut, but it also directly inhibits inflammatory signaling pathways and stimulates the release of anti-inflammatory cytokines by immune cells.

Butyrate also modulates gene expression and regulates cellular proliferation which results in anti-cancer effects in the colon. Thus, the implementation of dietary and supplementation strategies to optimize for butyrate production may reduce or prevent leaky gut, inflammatory bowel disease (IBD), ulcerative colitis, and bowel cancers. 

Such strategies would include indigestible carbohydrates such as resistant starches, fructo-oligosaccharides (FOS) like inulin, galacto-oligosaccharides (GOS), and human milk oligosaccharides like 2-fucosyllactose.

Propionate promotes the release of hormones involved in satiety and is therefore associated with lower caloric intake and protection against weight gain. In addition, propionate is associated with reductions in both liver fat and visceral fat levels both of which are risk factors for the development of insulin resistance. In this way, propionate is protective against metabolic syndrome.

Acetate is the most abundant SCFA in the gut and in the body. Unlike butyrate which is largely cleared by colon cells, and propionate which is cleared by the liver, acetate can reach beyond the liver and enter the general circulation.

Moreover, acetate is also produced by organs like the liver making it the only SCFA that is not exclusively synthesized by the microbiota. Acetate can fuel energy production in most tissues and is a precursor to fat and cholesterol synthesis.

In the gut lumen, acetate produced by specific species of bacteria is taken up by other species and converted into butyrate. This exchange, known as a cross-feeding interaction, is critical for the maintenance of optimal acetate:propionate:butyrate ratios in the colon.

If acetate levels dominate beyond the optimal 3:1:1 ratio in the long term, pathological consequences may result which include fatty liver, increased fat mass, and insulin resistance.

Gut and Brain

In addition to its effects on metabolism and gut health, the microbiome also has a powerful connection to host psychological well-being and cognitive function. In fact, there are strong associations between gut dysbiosis (i.e., abnormal microbiome composition) and Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, autism, seizure disorders, bipolar disorder, schizophrenia, and depression.

One mechanism by which the gut microbiome is believed to influence the brain is via SCFAs. Like the lining of the gut, the blood brain barrier (BBB) is composed of cells that are connected to one another via tight junctions. When these tight junctions begin breaking down (i.e. “leaky brain”), inflammatory mediators can enter into the brain.

The result is chronic neural inflammation which is closely associated with depression, cognitive impairment, and other neurological abnormalities. Analogous to their actions in the gut, SCFAs can modulate gene expression and immune cell behavior to reduce markers of inflammation.

Furthermore, they appear to directly enhance tight junction integrity in the BBB. However, further research is needed to determine the mechanism underlying this benefit.

 The Vagus Nerve 

Another mechanism by which gut bacteria can directly influence central nervous system function is via the vagus nerve which directly connects the gut to the brain. The vagus nerve is a key component of the parasympathetic (i.e.,“rest and digest”) branch of the autonomic nervous system and plays critical roles in managing appetite, mood, stress response, and even regulating inflammation in the body.

Specific strains of bacteria have been shown to influence the vagus nerve and, in doing so, alter human behavior. For example, administration of a probiotic containing Lactobacillus rhamnosushas been shown to improve anxiety and depression over the course of several weeks.

Several strains of bacteria in the gut have also been shown to synthesize the neurotransmitters GABA, dopamine, serotonin, and norepinephrine. However, it is unclear at this time whether changes in the levels of these neurotransmitters in the gut can directly influence their levels in the brain, or whether the changes can indirectly affect brain chemistry via interaction with the vagus nerve.

Cells and the Gut  

In addition to bacterially-produced metabolites affecting human physiology and metabolism, factors produced by our cells also shape and influence gut microbial populations. For example, mucin, the primary mucus protein secreted by the cells lining the gut, is a food source for the species Akkermansia muciniphila. In turn, these bacteria produce factors that strengthen the tight junctions between intestinal cells, decreasing gut permeability and inflammation in the body.

In inflammatory bowel disorders, the mucus layer is degraded and Akkermansia populations plummet. Thus, the treatment of such disorders should prioritize decreasing inflammation to re-establish the mucus layer and restoring levels of Akkermansia.

To this end, dietary polyphenols (such as those found in dark fruits) are key as they not only exert anti-inflammatory effects but can also directly support Akkermansia which feast on these colorful molecules. The red polyphenols found in apple peels are particularly effective at bolstering levels of this species.

Specific antigen molecules secreted by intestinal cells also directly influence microbial colonization in the gut. Antigens are proteins or complex sugars that are recognizable by the immune system. However, 20% of individuals are unable to secrete these antigens due to mutations in the gene FUT2. This “non-secretor” phenotype is associated with significantly lower levels of Bifidobacteria in the gut and higher incidence of IBD, ulcerative colitis, and Crohn’s disease. To learn more about FUT2 and how to determine your FUT2 status, read our previous blog post on the topic.

{Read FUT2 Status Blog Post Now}

The Bottom Line 

In summary, the myriad of exchanges that take place between the host and microbiota play critical roles in both the maintenance of health and the etiology of disease. Targeted modulation of the microbiome to produce beneficial molecules like SCFAs can improve gut functioning, metabolic health, and cognition. On the flipside, understanding an individual’s unique health challenges and genetics can help practitioners decide on the most prudent interventions to improve quality of life and prevent disease progression.

Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions. Follow Dr. Cowan on Instagram: @dralexisjazmyn

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