Modifying the gut microbiota: the past, the present, and the future

In a Perspective published in Science, surgeon-scientist Jennifer Wargo explores recent advances in modulating the microbial community within the human gut.
Share on facebook
Share on twitter
Share on linkedin
Share on telegram
Share on whatsapp
Share on email

• Altering gut microbes
• Poo transplant
• The role of diet

What is already known on this topic
For centuries, scientists and physicians have tried to modulate the thousands of billions of microbes within the human body to treat a plethora of conditions—from gut diseases to cancer. Strategies to alter the composition of the gut microbiota include dietary interventions, prebiotics, and the transfer of fecal material from one individual to another.

What this research adds
Surgeon-scientist Jennifer Wargo reviews recent advances in modulating the microbial community within the human gut. Wargo explores the advantages and limitations of fecal microbiota transplantation (FMT), which involves the transfer of fecal material from a healthy donor to a sick individual. The approach is used to treat people with C. difficile infections, and has shown promise for inflammatory bowel disease, after hematopoietic stem cell transplant, and in autism spectrum disorders. Wargo also looks at recently developed approaches, including dietary interventions and microbial consortia, which are being tested in cancer immunotherapy to boost people’s response to some anti-cancer drugs.

Conclusion
To treat conditions associated with a disrupted microbiota, personalized approaches that include FMT, dietary interventions, and prebiotics will likely be needed. More research aimed at understanding the relationship between gut dysbiosis and disease as well as what constitutes an optimal gut microbiota could also have a broad impact on public health.

For centuries, scientists and physicians have tried to modulate the thousands of billions of microbes within the human body to treat a plethora of conditions—from gut diseases to cancer. Now, in a Perspective published in Science, surgeon-scientist Jennifer Wargo at MD Anderson Cancer Center explores recent advances in modulating the microbial community within the human gut.

“The idea that disruptions in the gastrointestinal tract could contribute to systemic disease was championed centuries ago by Hippocrates, a physician in ancient Greece,” Wargo writes. And the first use of fecal microbiota transplantation (FMT), which involves the transfer of fecal material from one individual to another, was documented to treat gastrointestinal disorders as far back as the fourth century BCE in China.

Scientists have also known that animals often eat fecal material, which could help to increase gut microbial diversity, improving digestion and other physiologic processes within the host. But it was not until 1958 that a US surgeon published the first use of FMT in the clinics to treat Clostridioides difficile infection. Since then, FMT and other strategies to alter the gut microbiota have gained increased popularity, and their applications are being explored in clinical trials for several conditions, including gut disorders, neurodegenerative diseases, multiple sclerosis, and cancer.

Altering gut microbes

Strategies to modulate the gut microbiota fall into three categories: FMT, microbial consortia, and dietary interventions, which include the use of prebiotics. “Nonetheless, much still needs to be learned to implement true ‘precision’ modulation of the gut microbiota,” Wargo says.

She notes that some diseases, such as C. difficile infection, are characterized by a profoundly disrupted microbiota, or dysbiosis, whereas others show a subtler alteration of gut microbes. This difference, she says, should be taken into account when considering the appropriate strategy for modulating the gut microbiota.

“The approach aims to restore a more ‘healthy’ gut microbial community—although the definition of a ‘healthy’ gut microbiota is not clearly established,” Wargo writes. However, she notes, “data suggest that a diverse microbial community with a high degree of functional redundancy is associated with better overall health and better outcomes in several disease states.”

Poo transplant

Today, FMT is often used to treat people with C. difficile infections who had failed to respond to other treatments. In these cases, FMT has been shown to be “generally safe and highly effective,” Wargo says. However, she adds that it’s key to have guidelines for screening donor stool for infectious diseases and disorders that alter the gut microbiota. For example, after reports that several people with C. difficile infections developed antibiotic-resistant bacterial infections following FMT, scientists now recommend screening donor stool for antibiotic-resistant microbes and even SARS-CoV-2, the virus that causes COVID.

In clinical trials, FMT has been successfully used for inflammatory bowel disease, after hematopoietic stem cell transplant, and in autism spectrum disorders. One advantage of FMT is that it allows the transfer of diverse microbes, including bacteria, viruses, and fungi. “This diversity represents a potential advantage over strategies that administer minimal-complexity microbial consortia, which may not engraft and may not be sufficient in reestablishing a ‘favorable’ gut microbiota,” Wargo says.

However, this diversity could also create issues with reproducibility and scalability of FMT. Other limitations of this approach include variability in trial design and outcome measures, as well as factors related to stool donors that could affect FMT efficacy, Wargo says. What’s more, it’s still unclear what the optimal dosage is and which route of delivery is the best one. “Additional studies are critically needed to interrogate the success (or failure) of this approach for these indications and to develop optimal strategies for use of FMT,” Wargo writes.

The role of diet

In recent years, researchers have developed other strategies to modulate the gut microbiota, such as consortia of specific bacteria that include microbes with presumed health benefits, known as probiotics. For example, microbial consortia are being tested in cancer immunotherapy to boost people’s response to some anti-cancer drugs. However, results from clinical trials are mixed, and microbial consortia have not yet been approved for use by drug regulators such as the US Food and Drug Administration.

Another approach to alter the gut microbiota is through dietary intervention. Several studies have shown that changes in diet can influence gut microbes. But if the diet is not sustained, the changes in microbiota composition last only for a short period of time. Researchers are also assessing the use of prebiotics such as resistant starches and polyunsaturated fatty acids, as these compounds could help beneficial microbes to thrive.

It is probable that a personalized approach will be needed, incorporating strategies such as FMT, administration of live biotherapeutics, dietary strategies, and prebiotics,” Wargo writes. “Through additional research and collaborative efforts, the true definition of dysbiosis in the gut microbiota as it relates to disease states can be better understood, as well as what constitutes an optimal gut microbiota to promote overall health, which could have broad impact for public health.”