The Role of the Microbiome in Human Physiology

The Role of the Microbiome in Human Physiology

Researchers are learning about and uncovering the microbial ‘Black Box.’
By Lauren Arcuri

Two decades ago, the study of the microbiome—the trillions of bacteria and other tiny organisms that call our bodies home—was in its infancy. As DNA sequencing technologies and germ-free rodent models (among other tools) have developed, so too has research into how the bacteria, viruses, fungi and archaea affect human physiology. From observational studies trying to determine what strains of bacteria are there, to experimental studies with translational applications, and therapeutic approaches that target the microbiome, the field has evolved significantly.

Jun Sun, PhD, professor of medicine at the University of Illinois Cancer Center, studies host-microbiome interactions in inflammation and cancer. “The microbiome is best described as an invisible organ that weighs three pounds, the same as the human heart,” she says. While we used to think the microbes that lived within us were either neutral or pathogenic, Sun says, we now understand that not only are they beneficial, they play an active role in human physiology.

“In early childhood, the microbiome builds up our immune system and teaches us how to respond to pathogens,” Sun says. It also provides a barrier function, protecting the host (the human body) from those pathogens by either crowding them out or secreting chemicals to kill them. And, microbes actually produce energy and micronutrition for the human body.

“The microbiome field has evolved over the last decade or so, from this sort of black box that has a beneficial effect to having a greater grasp of who’s there,” says Melanie Gareau, PhD, professor at the University of California, Davis, and associate editor of the American Journal of Physiology-Gastrointestinal and Liver Physiology (AJP-GI). “And now we’re starting to tackle what they’re doing.”

Initially, 16s rRNA sequencing (a special type of genomic sequencing) helped identify which types of bacteria were there. In recent years, more complex and in-depth metagenomics, bioinformatics, metabolomics and other “omics” studies are analyzing the microbiome to better understand their function and metabolites. “We’ve gone beyond who’s there and have moved to what they are doing and how that impacts the host,” Gareau says.

Mark Frey, PhD, professor of pediatrics and biochemistry and molecular medicine at the University of California and editor-in-chief of AJP-GI, says, “What I think studying the microbiome has done is pushed us all to think of physiology as a homeostatic maintenance state, where if it drifts off in any direction from where it is supposed to be, it’s a problem.”

The Gut-Brain Axis

The human gastrointestinal (GI) tract is the biggest interface of the nervous, immune and endocrine systems. Gut microbes directly interact with immune cells in the gut. They also secrete metabolites that influence the enteric nervous system and enter the bloodstream and eventually travel to other organs. Microbes can also activate endocrine cells that then release hormones that have local and systemic effects.

Recent studies have shown that innate immune pattern recognition receptors, which were previously considered to have only a negative effect on the host, actually play a beneficial role in regulating inflammation and feeding behavior. “Bacterial cell wall components were thought to be pro-inflammatory,” Gareau says, “but it turns out that there are also anti-inflammatory pathways, and the sensing of the bacteria by the host through those immune receptors is not necessarily a bad thing. It might be generating homeostatic or anti-inflammatory responses.”

Some researchers are focusing on the communication between the gut microbiome and other organs and systems, particularly the brain. Through these studies it’s become clear that the gut and brain are in constant communication and that changes in the microbiome are correlated with mood and mental health. Scientists have found that even short-term stress exposure can change the microbiome. Anxiety and depression are also associated with changes in the microbiome. Now they’re trying to figure out exactly how these changes happen.

We’ve discovered important roles for nerves that travel from the periphery to the brain, like the vagus nerve,” Gareau says. “And given that cytokines and other immune factors can travel from the gut to other organs, there are multiple ways signals can leave the gut. Despite this, a lot of the specifics are still being discovered.”

Mechanistic Studies 

To dig deeper into the workings of the microbiome, researchers are devising new, more sophisticated technology. The tools include the ability to track neurons and to label compounds and then measure them systemically or within the brain. With these tools, scientists are conducting mechanistic studies to understand what the microbiome is doing, rather than just what species and strains are there. 

Raz Abdulqadir is a PhD candidate at Penn State College of Medicine who studies beneficial bacterial strains—probiotics. It’s known that Bifidobacterium is a genus of bacteria that helps maintain tight junctions between cells of the intestinal epithelium, the cell layer in the gut that provides a physical barrier between the inside of the intestines and the rest of the body. This barrier is important for overall health and can cause health problems if it becomes compromised. A decrease in Bifidobacterium is associated with inflammatory bowel disease (IBD) and other gut-related inflammatory diseases.

Abdulqadir and her colleagues isolated which specific species of Bifidobacterium had the strongest effect on tight junction function. From there, they began mechanistic studies to see exactly how the bacteria enhance the barrier. The lab identified a host receptor (TLR2) within the intestinal epithelial cells that the Bifidobacterium interacts with, protecting against increased intestinal permeability by suppressing an inflammatory mediator, tumor necrosis factor (TNF).

Abdulqadir’s team is studying specific bacterial strains that are beneficial to human health in hopes of eventually developing custom, targeted probiotic medications that can treat inflammatory gut diseases such as IBD. Understanding the way some strains repair and enhance the gut barrier is an important part of this work. “Our research illuminates the pivotal role of the earliest colonizing bacteria, revealing how these tiny pioneers can be harnessed to combat pathogens and reduce inflammation,” she says.

Role in Disease

Researchers are still trying to pin down exactly what a healthy microbiome is. One thing they know for sure: A diversity of bacterial species is part of it, and a loss of diversity is associated with disease states and less resilience to disease.

Bina Joe, PhD, FAPS, Distinguished University Professor and Chair of physiology and pharmacology at the University of Toledo and immediate past editor of Physiological Genomics, began looking at the impact of the microbiota on blood pressure about 10 years ago. She and her team swapped the microbiota of a rat that had high blood pressure and one that did not. The results surprised them: Swapping a “normal” microbiome into a rat drove the rat’s blood pressure even higher.

The results strongly suggested that the microbiome modulates blood pressure in the host in some way. “Here we are a decade later, and I am hook, line and sinker deep into microbiome research,” Joe says. Next, she took germ-free rats—rats without microbiota—and gave them a microbiome. Germ-free rats have abnormally low blood pressure, but once they acquired a microbiome, their blood pressure became normal.

Since then, researchers have discovered some microbial metabolites, including short-chain fatty acids, that bind to host receptors to influence blood pressure regulation. Joe’s team has also found that conjugated bile acids, made through host-microbiota collaboration, are protective against high blood pressure. Her current work centers around further delineating the connection.

Development of the Microbiome

Gareau and her colleagues are studying the development of the microbiota-gut-brain axis in infancy and childhood. “The microbiome colonizes early in life,” she says. “There is a lot of neurogenesis because neurodevelopment is crucial then and the gut is maturing.” As children transition from formula or breastmilk to food, the GI tract changes. These changes—colonization of the microbiome, neuronal development and the maturation of the GI tract—happen concurrently over a period of weeks in children. 

“If you disrupt one system, if you have a bacterial infection or take antibiotics, you will see changes, but it’s not an instant response in the brain and behavior,” Gareau says. “It takes time to happen. You’re disrupting the pathway from being established properly.”

Some studies suggest that children who have bacterial infections can develop cognitive deficits in adulthood. These are the kinds of long-term effects Gareau hopes to tease out in the lab.

A microbiome that’s disrupted early in life can develop down an alternate pathway that leads to a different microbiome later in life. “It’s potentially more inflammatory or less resistant to challenges,” Gareau says. “So, if something kills off some remaining microbes, you have less ability to recover from it. Your microbiome is too narrow, not diverse enough.”

Gareau also studies the microbiota-gut-brain axis in childhood and its potential effect on mood disorders and stress responses. Studies have shown that children who are under a lot of stress are more susceptible to mood disorders later in life. Various studies are underway looking longitudinally at children with autism and children who develop IBD.

Future Directions 

Although research into the microbiome has been happening for close to two decades, experts say the field is still in its infancy. “We’re just at the beginning of identifying the key components of how the microbiome influences physiology,” Gareau says. “We had a lot of hope that it would answer a lot of questions, and it’s been disappointing in some ways—it’s not the holy grail. But I think we shouldn’t give up on it.” 

Gareau says the field has made a great deal of progress in just 20 years. “We’re moving in the right direction, and I think that research will answer a lot of questions we still have and potentially help with treatment strategies in the future.”

Sun points out that just last year, the U.S. Food and Drug Administration approved the first live bacterial drug for C. difficile patients. “The field is moving forward from a very naive, exciting stage to a stage where we really want to understand the mechanisms behind the microbiome and apply these discoveries to the clinic,” she says. “The field has gotten much better at mechanistic studies. And in the meantime, we have developed many tools.”

Machine learning is one of the tools at the frontier of microbiome research. It will help analyze the large amounts of data from multiple “-omics” studies—the metagenome, the transcriptome, the metabolome—that Sun says will help the field deepen its understanding of how microbes are communicating with the host as well as with each other. “Machine learning algorithms can potentially help us predict the potential disease response to a change in the microbiome,” Sun says.

The microbiome is largely made up of bacteria, but there are other organisms present, too. Research is just beginning to tease apart the roles of viruses, especially bacteriophages—viruses that “eat” bacteria, fungi and archaea in our physiology. The interactions between these organisms and gut bacteria are proving to be fertile ground. A recent study, for example, showed that stress changes the gut virome, which then affected behavior in mice.

Frey says during his training in the 1990s as a signal transduction biologist, many people would have said: You find the one step in a pathway that’s wrong, you fix it, and everything is better. “But it turns out it’s not that simple. It’s a bunch of interlocking, interdependent pieces that are all required.” He says that as the mechanism-focused research proceeds, scientists will have to consider the complexity of these interactions and how dysregulation of one can potentially produce unwanted but durable changes in others. “One of the next big questions is: How do you view all those pieces as part of a dynamic balancing act? And when it goes wrong in disease, how do you get the system back to homeostasis?”

Joe emphasizes that there is a need for greater funding for microbiome studies that help move the field toward the large-scale mechanistic studies to which researchers aspire.

“This science is still in its infancy. You can’t go to college until you learn the alphabet,” she says. “There is still a disconnect between the enormity of the effects the microbiome has on the human body and the appreciation at the scientific level for that enormity.”

This article was originally published in the September 2024 issue of The Physiologist Magazine. Copyright © 2024 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.