Gut Instincts September 2021

September 2021

• Mucosal membranes act as a network that provides a connection between the gut and vital organs, like the lungs or the brain, but presumably the entire body.
• Short-chain fatty acids are formed in the colon through the fermentation of soluble fiber, and researchers are interested in finding out more about their role as signaling compounds.
• More research is needed to decisively say that one diet is better for the microbiome over another.

Colonies of bacteria flourish deep in the ocean near hydrothermal vents that expel toxic, superheated water from the Earth’s crust. Other bacteria subsist on rivers of sulfuric acid running through subterranean caves. Given the extreme environments where bacteria dwell, it is not surprising that the human digestive system is another popular home for microorganisms.

The gut microbiota is an ecosystem comprised of an estimated 1,000 bacterial species along with archaea, fungi, and viruses that reside in the human intestinal tract. For a century now, researchers have studied this community of microorganisms, but it was not until modern sequencing tools enabled them to genetically distinguish bacterial colonies 20 years ago that the mysteries of the microbiome were revealed. Since then, scientists have come to understand that this ecosystem in our gut, just like any ecosystem, is a complex environment with a delicate balance.

Furthermore, all the latest research has redefined a healthy gut to mean more than just comfortable digestion. Scientists now know that human health overall may rely on what colonies populate the intestines.

Gut bacteria have been shown to influence diseases such as colon cancer, but also neurological disorders like multiple sclerosis and even autism spectrum disorder. The microbes determine the effectiveness of drug treatments like statins, which fail to lower cholesterol sufficiently in certain gut bacteria environments. Fatty acid metabolites from bacteria are emerging as a means of immune system modulation which could be a treatment mechanism in the future. But the biggest question researchers want to answer is, how can dietary habits be adjusted to maintain the healthiest possible gut?

Here is a look at the latest information on what scientists have learned about the gut microbiome.

Immune system

There is growing evidence that the gut microbiome is a significant factor in maintaining human health and avoiding disease. However, it is becoming clear that the gut does not act alone. There are colonies of microorganisms throughout the body, and researchers are identifying communication links that allow “cross-talk” among them that help the immune system maintain health.

During the recent SARS-CoV-2 outbreak, for example, scientists in Brazil determined that the virus attacks certain gut bacteria with a cascading effect on lung immunity, while at the same time lung inflammation alters the microbiota of the respiratory system, consequently killing bacteria in the gut (https://doi.org/10.3389/fimmu.2021.635471). Immunology researchers are in the process of trying to understand what unites these physiological systems that serve such vastly different functions.

One explanation of how the microbiome interacts with the immune system could come from the mucosal membrane, a layer of epithelial cells that line the respiratory and gastrointestinal tracts. In fact, mucus, antimicrobial agents, and immune cells cover all the surfaces of the body that interact with the outside world. (Although, the colon contains the largest, most diverse population of microbes.) Until now, these membranes have been viewed simply as a physical barrier, but scientists have found that pathogens interact directly with mucosal epithelia, triggering cellular changes (https://doi.org/10.3389/fcimb.2020.602312).

In response to a pathogen, immune cells can migrate from mucus to threatened tissue through the lymphatic system (Fig. 1). When this happens, epithelial cells in the mucosal membrane secrete peptides that inhibit specific microbial growth. At the same time, receptors established by genetics orchestrate the colonization of certain bacterial lines. Lymphoid cells also coordinate a response by releasing compounds that regulate bacterial composition in the gut.

The specifics surrounding these observations of the microbiome’s role in the mucosal immune system are still being worked out; however, researchers believe that the relationship between epithelial cells and gut bacteria is established in infancy. The adult immune system is activated at birth when the body is first exposed to microbes outside the womb. According to the hygiene hypothesis, exposure to a variety of new cell types early in life is crucial for training the system. Put another way, a sterile early life disorganizes the immune system, increasing the viability of inflammatory pathologies that can lead to allergies or, possibly, irritable bowel disease later in life.

Mucosal cells on infant skin and in the mouth are the gateway to a healthy microbiome that leads to a robust adult immune system capable of fending off pathogens. Scientists are not sure how long the window to feed the microbiome stays open, but they are realizing it is crucial in way they had not previously imagined (https://www.nature.com/articles/s41385-020-0257-y).

Central nervous system

“There seems to be something about the social brain, in particular, that makes it sensitive to signals from the microbiome,” John Cryan, a biochemist at University College Cork in Ireland, said in a Nature article published last year. In the past five years, researchers have determined that gut bacteria are involved in producing bioactive compounds that travel the central nervous system (CNS) up to the brain, affecting thinking and behavior.

Cryan has been studying the association between microbiome composition and autism spectrum disorder. Studies show that children with autism consistently have less Veillonellaceae, Coprococcus, and Prevotella bacteria in their gut. In a study with just five participants, the microbiomes of autistic individuals were transplanted into mice to see how gut bacteria is involved with brain function (https://doi.org/10.1016/j.cell.2019.05.004). The microbiomes did not produce as much of two specific amino acid metabolites that increase the activity of a neurotransmitter involved in sensory processing and motor control, key deficits in autism spectrum disorder. The results from this small study, along with other animal experiments, have prompted researchers to consider the microbiome as a possible mechanism for autism treatment.

There is also evidence that interactions between the microbiome and the central nervous system regulate synaptic plasticity and cognition. Certain amino acid receptors interact with the microbiome, and elevated cyanobacteria in the intestines correlate with a build-up of neurotoxins in the brain that hinder their function. Diseases like amyotrophic-lateral sclerosis (ALS), Parkinson’s dementia, and Alzheimer’s are all associated with altered CNS neurochemistry that potentially originates in the gut (https://doi.org/10.3389/fncel.2013.00153).

Evidence suggests that the microbiome’s connection with the immune system might be the link that influences CNS behavior, but this nascent area of research is still developing. Some experiments have indicated such a possibility, while other experiments signal a different communication mechanism. Researchers have also found that the presence or absence of short- chain fatty acids (SCFA) produced as metabolites of gut bacteria, may act as signaling molecules that modulate cell activity.

Short-chain fatty acids

Soluble fiber in the human diet is fermented in the colon by resident microbes and turned into short-chain fatty acids, such as butyrate, propionate, and acetate. The SCFA are absorbed by the intestines into the bloodstream where studies show they perform vital roles, like modifying gene expression and regulating cholesterol synthesis.

The common SCFA have been studied for a long time, although researchers still have a lot to learn about them (https://doi.org/10.1038/d41586-020-00195-1). They are used by the colon’s epithelial cells as a source of energy and act as protein receptors that regulate lipid and glucose metabolism. SCFA are known to activate fatty acid oxidation while inhibiting synthesis and lipolysis to reduce the amount of free fatty acids in the blood (https://doi.org/10.1194/jlr.R036012).

While continuing to look for answers to questions about how SCFA fluctuations affect human health, researchers also want to better understand branched short-chain fatty acids. For molecules that are so prevalent in the body, not much is known about how they interact with human tissue or what receptors they trigger.

Branched-chain fatty acids (BCFA) are produced through a different fermentation mechanism than SCFA that involves the fermentation of proteins and amino acids instead of soluble fiber. The breakdown of proteins releases nitrogen, which is essential for bacterial growth. However, degradation of proteins is also accompanied by potentially toxic metabolites, such as amines, phenolic compounds, and volatile sulfur compounds.

The significance of BCFA remains unclear. Published results by a team at Stanford University in Palo Alto, California, led them to believe BCFA might regulate cells that produce a protein in mucous membranes involved in the immune system (https://doi.org/10.1038/d41586-020-00195-1). A recent study by a group of German scientists comparing SCFA and BCFA in vegans versus omnivores found that the amount of protein individuals ate did not influence the BCFA concentration in their guts. The researchers hypothesized that gut bacteria may drive SCFA synthesis and maintain stable levels regardless of nutrient levels, switching to proteins as a source when needed (https://doi.org/10.3390/nu13061808). Not enough data has been gathered on these SCFA to draw any lasting conclusions. In time, we are more likely to understand the role of these ubiquitous compounds.

Eating for a healthy gut

It is clear that multiple factors, such as your genes, birth, environment, and the medicine you take, influence the composition of bacterial colonies in the gut. Add diet to this complex system, and differentiating between important factors for maintaining a healthy microbiome becomes a significant research challenge. Still, different microbes have different optimal conditions for growth, and dietary choices eventually end up in the gut.

Researchers have conducted experiments on specific food items and found that certain options can impart beneficial effects. As mentioned earlier, microbiota living in the colon possess enzymes that break down dietary fiber through fermentation. Results from studies on fruits, vegetables, beans, and whole grains prove that when we eat these high-fiber foods their fermentation releases short-chain fatty acids into the large intestines. The high concentration of SFCA’s lowers the pH, creating an acidic environment where harmful bacteria do not prefer to live.

However, as researchers pointed out in a paper published in May 2021, studies that focus on one food item are incomplete. Dietary components can have counteracting or synergistic effects, and the diet as a whole should be considered when determining what makes a healthy microbiome (https://doi.org/10.1093/ajcn/nqab077). The research team from the Department of Food and Nutrition at the University of Helsinki in Helsinki, Finland, conducted a study examining the gut microbiomes of nearly 5,000 Finnish people who consumed foods recommended for a healthy diet. Participants reported what they ate each day in their omnivorous diets, and the researchers assigned a score to healthy food items. Some participants also provided stool samples for DNA analysis of the microorganisms.

The study did not produce overwhelming results. There was no dramatic difference in the microbiome of individuals with a higher healthy food score. But the researchers do claim that their results show a modest association between healthy food choices and “compositionally distinct microbiota.”

As in previous studies, the Finnish researchers also found that fiber has the greatest influence on gut health. Individuals with higher healthy food scores contain more fiber-degrading species of bacteria in their gut, along with more bacteria that produce SCFA and the resulting metabolic enzymes. They also found that the guts of individuals who reported eating less red and processed meat contained fewer enzymes associated with negative health effects known to contribute to colorectal cancer.

Many studies indicate the gut microbiome does not stray too far from a base bacteria population when it is in a state of homeostasis (Fig. 2). Exceptions include infancy, old-age, and during antibiotic treatments. These are times when bacterial numbers are low, and scientists believe there could be a benefit from adding a probiotic to the diet. Otherwise, the science is still out on whether adding prebiotics and probiotics to the diet provide any advantage during homeostasis.

In general, confusion about connections between the diet and the microbiome stem from a lack of research on the human body. In such a complex system, scientists have no choice but to build pared-down models to begin to understand how the process works. That means most of the experiments performed to explain the microbiome, including those mentioned here, are conducted on genetically engineered mice or in a petri dish. The few human studies that have been conducted involve very small groups of people, often fewer than 50.

This article barely scratches the surface of all the immunological and bioengineering research that has taken place in the past five years—not to mention the nutritional studies scientists have conducted. It is likely that in the next five years, more consumer products and pharmaceuticals will apply this research knowledge to improve gut health which, as we now know, leads to better overall well-being.

In the coming years, more microbiome experiments will head into the clinic. Research is inching toward treatments aimed at manipulating the mucosal layer as a means of fighting off viruses (https://doi.org/10.1038/s41423-021-00650-7). Scientists are also hopeful that they can eventually treat autoimmune disorders, such as lupus, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, with a regiment of pre- and probiotics (https://doi.org/10.1038/d41586-020-00197-z).

About the Author

Rebecca Guenard is the associate editor of Inform at AOCS. She can be contacted at rebecca.guenard@aocs.org

Information

Associations of healthy food choices with gut microbiota profiles, Koponen, K., K., et al., Am. J. Clin. Nutr. 00: 1–12, 2021.

Short- and branched-chain fatty acids as fecal markers for microbiota activity in vegans and omnivores, Trefflich, I., et al., Nutrients 13: 1808, 2021.

Microbiota modulation of the gut-lung axis in COVID-19, de Oliveira, G.L.V., et al., Front. Immunol. 12: 214, 2021.

Mucosal immunity–mediated modulation of the gut microbiome by oral delivery of probiotics into Peyer’s patches, Lin, et al., Sci. Adv. 7: eabf0677, 2021.

Mucosal epithelial cells: the initial sentinels and responders controlling and regulating immune responses to viral infections, Yang, J. and H. Yan, Cell Mol. Immunol. 18: 1628–1630, 2021.

Imprinting of the immune system by the microbiota early in life, Al Nabhani, Z. and G. Eberl, Mucosal Immunol. 13: 183–189, 2020.

The gut microbiome in neurological disorders, Cryan, C.F., et al., Lancet Neurol. 19: 179–194, 2020

The gut microbiome, Brody, H., Nature 577: S5, 2020.