Tag: gut

Rockefeller University researchers were already interested in the small molecules that human-associated bacteria produce and their effect on the body’s host cells and coinhabiting organisms of the microbiome. So, when the pandemic hit New York City, they pivoted their diverse laboratories to study the SARS-CoV-2 virus’s interactions with the human microbiome.

The scientists posed this question: Can the human microbiome produce metabolites, or small molecules, that inhibit the growth of the SARS-CoV-2 virus?

In a mSphere journal article, first author Dr. Frank J. Piscotta collaborated with principal author Dr. Sean F. Brady and a team of diverse Rockefeller University chemists, molecular biophysicists, and virologists to tackle this complex question.

Dr. Sean F. Brady, the head of the Rockefeller University’s Laboratory of Genetically Encoded Small Molecules, said that the team “expected somewhere between zero and a few [results].”

Although thousands of different bacteria form the human microbiome, the researchers chose to study a diverse, representative group of 50 bacteria. They did this by isolating bacterial compounds and testing their antiviral proprieties in laboratory cultures of cells.

The researchers streamlined these cultures to find 10 bacteria that reduced viral infection by SARS-CoV-2 by 10{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809}. They then refined this group to include only bacteria whose metabolites inhibited viral growth by more than 90{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809}.

The researchers identified three major metabolites with anti-SARS-CoV-2 activity:

• a pyrazine called 2,5-bis(3-indolylmethyl)pyrazine (BIP)
• a 5-hydroxytryptamine (5-HTR) receptor agonist tryptamine
• a compound named N₆-(Δ²-isopentenyl) adenosine (IPA)

The researchers tested all three microbiome-derived anti-SARS-CoV-2 active metabolites for activity against a panel of RNA viruses, in addition to SARS-CoV-2. This panel included the seasonal coronavirus, the yellow fever virus, and the human parainfluenza virus 3.

Of these, IPA demonstrated the broadest antiviral activity. Tryptamine preferably inhibited coronaviruses, and BIP had a similar, slightly more limited spectrum compared with IPA.

Among other important findings, the Rockefeller researchers recognize that, to their knowledge, this is the first study finding specific molecules with antiviral activity that the human microbiome has produced.

Dr. Picotta, Prof. Brady, and their colleagues discovered startling aspects of the antiviral metabolites that their cohort of study bacteria produced. The three active metabolites possessed similarities with three synthetic compounds that scientists have observed to have antiviral properties.

These compounds are FDA-approved agents that have undergone testing in either COVID-19 clinical trials or observational studies.

The researchers identified the following mimicry between nature and pharmaceuticals:

• IPA is structurally similar to remdesivir, a medication that doctors use to treat some severe COVID-19 infections.
• Tryptamine is similar to serotonin. The selective serotonin reuptake inhibitor fluvoxamine is a medication that doctors typically use to treat OCD.
• BIP parallels central aspects of the structure of favipiravir, an oral antiviral medication that clinical trials are testing as a treatment for mild COVID-19 disease and comparing with remdesivir for treating moderate disease.

Additionally, the Rockefeller researchers observed that tryptamine’s ability to inhibit SARS-CoV-2 strongly paralleled observations in clinical studies showing that people who were taking fluvoxamine had improved COVID-19 outcomes.

When MNT asked how natural metabolites and synthetic drugs could be so similar in structure, Dr. Brady explained:

“One hypothesis is that scientists/chemists had been inspired by nature to develop drugs for a very long time. And so, you could argue that it is baked into the drug development system: natural inspirations.”

“The other possibility is that there are a limited number of simple chemistries that inhibit viruses, and whether those are identified by synthetic chemists, or by nature, the molecules may just end up being the same general structural classes — sort of intellectual convergent,” he added.

Regarding how the microbiome interacts with human physiology, Dr. David Gozal, professor and pulmonologist at the University of Missouri in Columbia, told MNT that the results were not unexpected.

“It should not come as a surprise that within an ecosystem such as the microbiome, there will be microbial products that restrict the dominance of other microbes such as to enable an equilibrium and ‘peaceful’ co-existence,” he said.

“When new invaders show up, such evolutionarily developed systems will rally to either eliminate the invader or allow for its incorporation into the ecosystem under control such as to not jeopardize the rest of the communities living there,” he further explained.

The research could have future implications for the treatment of viral infections, particularly SARS-CoV-2.

“By exploring the specific microbially-derived compounds that exhibit effective SARS-CoV-2 antiviral activity, we can potentially create chemical mimics that will have applicability in the treatment of this pandemic,” said Dr. Gozal.

He said that this could also afford scientists a better understanding of whether microbiomes that can produce these specific compounds “enable specific resistance to infection and modify the individual susceptibility to disease caused by the novel coronavirus.”

“In other words, some of the phenotypic variance to COVID-19 disease may reside in the microbiome of the individuals being infected, in addition to other factors that have been explored to date — genetics, T-cells, etc.”

– Dr. David Gozal

MNT asked Dr. Sean Brady about the take-home message of Dr. Piscotta’s and Rockefeller University’s multidisciplinary teamwork. Dr. Brady replied:

“The idea was to explore whether the human microbiome produces molecules that might inhibit the viral infection. Our studies indicate that it definitely does produce a number of such molecules. However, at this point, we don’t know if there is an ecological role for the microbiome in controlling or mitigating infection through small molecules.”

He pointed out that they may be “random discoveries” that have not much to do with what is going on ecologically.

“The human microbiome may produce such a large repertoire of structurally diverse small molecules that some happen to inhibit viral infection,” he said.

“The interesting question to ask now is whether our study represents serendipitous discoveries of molecules that inhibit viral infection, or is it telling us something about what is happening ecologically?”

– Dr. Sean Brady

Dr. Brady cautioned that it was important not to oversimplify the results of the study and that the team’s work presents an initial set of experiments.

However, he acknowledged that the research could open up a new line of inquiry for developing pharmaceuticals.

“The jury is still out on whether the chemistry of the human microbiome is going to be dramatically different from that which we have already explored in bacteria from other microbiomes. There’s reason to believe that there might be new chemistry. It’s a new environment where bacteria are interacting with the human host, which is quite different from bacteria in other environments like the soil environment, from which many drugs used today come,” said Dr. Brady.

Dr. Brady concluded that the findings warrant additional investigation into the role of such metabolites in host-microbiome interactions. He added that it was likely that further research would reveal additional small molecules within the human microbiome that had antiviral activity.