Issue: December 2021
Source: Healio Interview
Disclosures: Hazan reports founding ProgenaBiome; cofounding Topelia Therapeutics; serving as CEO of Venture Clinical Trials; and spearheading the nonprofit Microbiome Research Foundation. Khoruts reports treating patents pertaining to preparation and preservation of gut microbiota. Kelly and Petersen report no relevant financial disclosures. Stollman reports consulting for OpenBiome.
December 20, 2021
10 min read
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Much still to discover on role of gut microbiome in immune system

Issue: December 2021
Source: Healio Interview
Disclosures: Hazan reports founding ProgenaBiome; cofounding Topelia Therapeutics; serving as CEO of Venture Clinical Trials; and spearheading the nonprofit Microbiome Research Foundation. Khoruts reports treating patents pertaining to preparation and preservation of gut microbiota. Kelly and Petersen report no relevant financial disclosures. Stollman reports consulting for OpenBiome.
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There is a complex interplay between the immune system and the gut microbiota, according to a review published in Nutrients.

With 70% to 80% of the body’s immune cells located in the gut, physicians recognize the importance of nutrition on gut microbiota composition and the immune system, as well as the impact a healthy gut has on overall health.

Source: Neil H. Stollman, MD, FACP, FACG, AGAF.
Neil H. Stollman, MD, FACP, FACG, AGAF, of the East Bay Center for Digestive Health in Oakland, California, said the bugs in our gut microbiome are still not clear. He said as of now, they are just a list of bacteria that act as a field guide.
Source: Neil H. Stollman, MD, FACP, FACG, AGAF.

Although many details concerning the gut microbiome and how it affects the immune system are understood, there are still many unknowns. Further research is needed to discover the intricacies of the gut microbiome. For example, many are now looking at what role the gut plays — if any — in COVID-19 severity.

To learn more, Healio Gastroenterology spoke with experts regarding the gut’s involvement with the immune system, its relationship with nutrition and its possible role in COVID-19.

Gut Health

“We’re all individuals, we’re all different,” Sabine Hazan, MD, creator of ProgenaBiome and founder of Ventura Clinical Trials in Ventura, California, told Healio Gastroenterology. “The idea of one pill fits all — or one yogurt, or one vitamin — it’s probably not the right idea. I think we have to look at people in their environment, people in their culture, their races and kind of fine tune a method of [gut health] improvement in those people. It’s more of personalized precision medicine.”

When someone’s gut is not healthy, Hazan said, it means there is something in the microbiome that is not being touched by the foods we eat. She added that physicians need to figure out a patient’s “balance” of the bacteria — or bugs — living in their gut.

Sabine Hazan, MD
Sabine Hazan

“Some people have high, good bacteria and some have low, bad bacteria, but you know they sustain a certain balance that keeps them healthy,” Hazan said. “That’s really the essence of the microbiome — going through trillions of bugs and figuring out what the culprit is that caused that person to have a disease. That’s the holy grail, but we are not there yet.”

Chemical exposure can also impact an individual’s gut microbiome, Vikki Petersen, DC, CCN, CFMP, founder of Root Cause Medical Clinic in Saratoga, California, and Clearwater, Florida, said in an interview with Healio Gastroenterology.

“When someone’s gut health is not the way it should be, it can be that the burden coming in the immune system is too much for it to maintain strong immunity and strong gut health,” Petersen said.

Antibiotics can have a negative impact on that strong gut health, too. In an interview with Healio Gastroenterology, Colleen R. Kelly, MD, FACG, of the Warren Alpert School of Medicine at Brown University in Providence, Rhode Island, said unnecessary courses of antibiotics should be avoided since they are known to be detrimental to the gut bacteria.

In considering how gut health affects overall health, Neil H. Stollman, MD, FACP, FACG, AGAF, of the East Bay Center for Digestive Health in Oakland, California,told Healio Gastroenterology that many physicians believe gut health impacts conditions such as depression, autism, Alzheimer’s disease and Parkinson’s disease, although he added there is not enough evidence to prove it just yet. Because of cause-effect, Stollman said, causality from association cannot be assumed.

According to Stollman, the bugs in our gut microbiome are still not clear. Physicians know the organisms work in consortium, that they work together and help each other. But they can also repel each other.

“So, all we have today is this list, this field guide,” Stollman said. “That’s incredibly uninformative, unfortunately.”

The Gut-brain Connection

Everything begins in the gut, Hazan said, and any gut alteration or a leaky gut creates toxins that can travel to the nervous system and the brain. Therefore, it makes sense that if the gut can be fixed, so can the brain, according to Hazan.

Hazan noted this is where her research at ProgenaBiome began. She had a case of a patient with Alzheimer’s disease who could not remember important dates in their life. She performed fecal microbiota transplantation for Clostridioides difficile infection by using a family member’s microbiome. After 6 months, the patient began to remember things again.

“This means that if I change the gut, the brain changes, and that was the beginning,” Hazan said.

She noted in recent years there have been more cases of Alzheimer’s disease, Parkinson’s disease and autism and she feels this is connected to the gut.

“Something is happening to the microbiome of civilization that is causing us to get into that world, [but] what is that something?” Hazan said. “That’s the mystery and that’s the big question.”

Hazan said research is still not there with fully understanding the gut.

“To attain a cure, understand the microbiome,” Hazan said.

According to Hazan, learning how to fix the patient is dependent on looking at what is in the microbiome, the “trillions of bacteria,” and understanding these microbes and their balance.

“The gut is amazing because the lining is a single layer of cells, and when they talk about the gut being the second brain, it comes from a hierarchy system in the human body where nothing is unimportant,” Petersen said.

Vikki Petersen, DC, CCN, CFMP
Vikki Petersen

Petersen said the brain-gut connection can affect the immune system, demonstrating why a lot of stress can weaken the immune system.

“The two don’t seem to have an obvious connection, but they absolutely are [connected],” Petersen said.

The brain and gut health can be affected by lack of sleep and also, most importantly, by diet. She said people with a lot of stress tend to go for sweets, which can fuel the source of viruses and bacteria.

“You’re taking your army and cutting it in half and saying ‘good luck’ with your diet,” Petersen said. “If you compound that with no exercise, not enough water, not enough sleep, then what are you down to?”

Kelly said gut bacteria create metabolites which can activate immune pathways down the road.

Colleen R. Kelly, MD, FACG
Colleen R. Kelly

“As gastroenterologists, we’re focused on GI conditions like irritable bowel syndrome, Crohn’s disease and ulcerative colitis, and we’ve known for a long time that dysbiosis and alterations in gut bacteria are a signature of those diseases,” she said.

“We are seeing now that the gut plays a role in many different diseases such as autoimmune and neurologic conditions and the metabolic syndrome,” Kelly said. “It’s pretty fascinating.”

While many believe there is a brain-gut connection, Stollman believes there is not enough research to truly connect the two. He said the questions on the gut outnumber the answers.

“If there’s a ration of things we know and don’t know, there’s more stuff that we don’t know,” Stollman said. “There’s good, logical, plausible, theoretical reasons to connect the two, but I don’t think we have any good data to put the two together.”

Importance of Diet for Gut

Alexander Khoruts, MD, of the University of Minnesota in Minneapolis, told Healio Gastroenterology that a general rule for a healthy gut is a good diet — mostly plants and fewer meats and processed foods.

“That’s a general rule that is probably true, but how much an individual will benefit from that is highly variable,” Khoruts said.

He said physicians are still learning about the variability between the composition and functionalities of the gut microbiota that individuals have.

Kelly also noted individuals should eat more “fresh” foods and avoid foods with additives such as emulsifiers which can be found, for example, in pre-packaged breads.

Petersen and Kelly noted physicians are still getting to know whether probiotics really help maintain a healthy gut. Petersen said there are certain probiotics that work for certain conditions. This is going to blossom over the next few years, according to Petersen. She noted there are 10 trillion cells in the body and 30 trillion organisms in the large intestines, and physicians are still trying to understand them and what their roles are.

Sugar, including artificial sweeteners, is not good for maintaining a healthy gut, according to Petersen. Prepackaged or preserved foods should also be avoided. Petersen said people need to be eating at least seven to nine servings of fruits and vegetables a day, especially those that are organic.

Fiber, Petersen noted, is also important.

“Research has shown that fiber is not like cardboard,” Petersen said. “It has a lot of these nutrients in it. It’s all about keeping the digestion. It gets down into the lower large intestine to feed good bacteria and your immune system.”

Stollman also said fiber is vital for a healthy gut. He noted the Western diet is low on fiber, and that although physicians recommend about 25 g of fiber a day, the average intake in the United States is 15 g.

Stollman said fermented foods have also shown to help maintain a healthy gut.

“An important part of this is not just fermented foods, but a breadth of fermented foods,” he said. “The one thing that we do know is that a more diverse biome is healthier than a less diverse biome. Diversity matters. It is a slogan in the world but it’s also a slogan for our biome.”

Stollman also noted things such as antibiotics, steroids or chemotherapy are not good for the gut and constrict the diversity of the microbiome.

The Gut and Immune Response

Kelly said the gut does play a role in the immune system and overall health.

“It is the first line of defense against pathogenic organisms,” Kelly said.

She said someone with a robust healthy gut microbiota is able to fight against C. difficile infection and other infections including Salmonella, for example.

Khoruts said the main interaction the immune system has on a daily basis with the microbial world is inside the microbes in our guts.

“So, it’s not surprising that when the gut microbiome is altered, we can see some changes in immune responses,” Khoruts said.

In 2019, Thomas Hagan, PhD, and colleagues published a study in Cell which found that antibiotics given to healthy individuals may decrease the effectiveness of the flu vaccine. The researchers had 22 participants in the study. Half of them were administered antibiotics for 5 days and on day 4 were given the flu vaccine. The other half did not take antibiotics and were also given the vaccine on day 4. The antibiotic treatment decreased the gut-bacterial population by 10,000-fold, and individuals treated with antibiotics had higher inflammatory responses and markedly lower antibody responses to the vaccine.

Gut’s Impact on COVID-19

“The first thing to appreciate is that 80% of our immune system is in our gut,” Petersen said. “In order to have a robust immune response, one needs a healthy gut because they really go hand in hand.”

She said if an individual has a strong immune system, its ability to fight viruses is very good.

In a preprint study awaiting publication, Hazan and colleagues performed a cross-sectional study where they used next-generation sequencing to assess microbiome composition and diversity in 50 patients with SARS-CoV-2 PCR-confirmed infections and 20 SARS-CoV-2 PCR-negative exposed controls. Patients presented to Ventura Clinical Trials from March 2020 to January 2021. They compared microbiome diversity and composition between the patients and exposed controls and among all patient subgroups at all taxonomic levels.

Hazan and colleagues found patients compared with controls had significantly less bacterial diversity, a lower abundance ofBifidobacterium and Faecalibacterium and other bacteria, and a higher abundance of Bacteroides at the genus level. There was an inverse correlation observed between disease severity, bacterial diversityand Bifidobacterium and Faecalibacterium abundance.

Investigators noted the reduction in pro-immune function may have been due to the low bacterial diversity and depletion of Bifidobacterium and Faecalibacterium genera either before or after infection. This led to SARS-CoV-2 infection becoming more symptomatic.

“This particular dysbiosis pattern may be a susceptibility marker for severe symptoms from SARS-CoV-2infection and may be amenable to pre-, intra- or post-infection intervention,” Hazan and colleagues wrote.

Hazan and colleagues believe that boosting Bifidobacterium or Faecalibacterium may be a path to recovery in these patients. More importantly, they feel that we need to look at the microbiomes of these patients and understand that immunity may not be equal for all. This could impact placebo control trials.

“If low relative abundance of Bifidobacterium preceded infection, boosting levels might reduce susceptibility or minimize symptom severity,” Hazan and colleagues wrote. “Alternatively, if the reduction follows infection, then refloralization of the gut microbiome may reduce long-term effects of SARS-CoV-2.”

Another study published in Gut earlier this year by Yun Kit Yeoh, PhD, of the department of microbiology at The Chinese University of Hong Kong in Shatin, Hong Kong, and colleagues found a correlation between gut microbiota composition, cytokine levels and inflammatory markers among COVID-19 patients demonstrated the gut microbiome is linked with the severity of COVID-19.

“[This] survey of gut microbiota alterations in association with immune dysregulation revealed that gut microorganisms are likely involved in the modulation of host inflammatory responses in COVID-19,” Yeoh and colleagues wrote. “With mounting evidence that gut microorganisms are linked with inflammatory diseases within and beyond the gut, these findings underscore an urgent need to understand the specific roles of gut microorganisms in human immune function and systemic inflammation.”

Researchers obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Up to 30 days after clearance of SARS-CoV-2, investigators collected serial stool samples from 27 out of the 100 patients. Shotgun sequencing total DNA extracted from stools was used to characterize gut microbiome compositions. Plasma was used to measure concentrations of inflammatory cytokines and blood markers. The study found the gut microbiota composition in patients with COVID-19 was concordant with disease severity.

On the other hand, Stollman said it is unclear by how much the gut is related to the severity of COVID-19. He said while it is clear traces of COVID-19 are found in the stool of those infected, finding these traces does not necessarily have anything to do with the disease. The same goes for the fact that patients with COVID-19 do have GI symptoms and they can have post-COVID GI manifestations, Stollman said.

Khoruts also believes the connection between poor gut health and severity of COVID-19 has not been studied enough. He said poor gut health may lead to a delayed protective immune response against COVID-19 and greater degree of inflammation, which usually happen in older patients. This can lead to greater morbidity and mortality.

Kelly said it really is not known if the gut plays a role in the severity of COVID-19, but that they are correlated. Patients with metabolic syndrome, such as overweight, obesity or diabetes, have severe COVID-19 and those with these conditions have abnormalities in the gut bacteria. Therefore, according to Kelly, there is a possible connection.

“The gut misbehaves after any insult, whether that insult is salmonella, diverticulitis or COVID-19,” Stollman said. “You insult the gut and once the insult goes away, the gut stays messed up for a while. ... I’m not sure there is any data that has suggested that you can mitigate your COVID-19 course by having a biome profile.”