Virus World

Large and giant double-stranded DNA viruses within the phylum Nucleocytoviricota are diverse and prevalent in the environment where they substantially affect the ecology and evolution of eukaryotes. Until now, these viruses were only sporadically found in the digestive system of vertebrates. Here, we present the identification and genomic characterization of a proposed third order of viruses within the class Pokkesviricetes that currently consists of poxviruses and asfuviruses. Members of this newly identified order we provisionally named Egovirales are abundant in the digestive system of vertebrates worldwide and occur in high abundances in >10% of livestock animals, >2% of humans, and wild animals. Egoviruses have linear genomes up to 360 kbp in length that likely produce multilayered icosahedral capsids, similar to those of asfuviruses.

The diversity of egoviruses already far exceeds that of all known poxviruses and animal-associated asfuviruses. Phylogenetic analyses and patterns of virus distribution across vertebrates suggest that egoviruses can be either specialists or generalists associated with a single or multiple vertebrate species, respectively. Notably, one egovirus clade is human-specific, evolutionarily constrained, and spread across continents, demonstrating a long-lasting association between Egovirales and the human population on the global scale. Egoviruses not only expand the ecological and evolutionary scope of Pokkesviricetes, but also appear to be the most diverse, widespread, and abundant group of double-stranded DNA viruses infecting eukaryotic cells in the digestive system of vertebrates.

Preprint in bioRxiv  (March 23, 2024):

https://doi.org/10.1101/2024.03.23.586382 

Significance

Abstract

Alzheimer’s disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer’s disease by showing specific alterations in the gut microbiome composition of Alzheimer’s patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer’s symptoms. To understand the involvement of Alzheimer’s patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer’s patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer’s patient transplants.

Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer’s systemic environment on proxy neurogenesis readouts. Serum from Alzheimer’s patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer’s.

Piublished in Brain (Oct. 18, 2023):

https://doi.org/10.1093/brain/awad303

A team of biologists from the Wellcome Sanger Institute, the European Bioinformatics Institute and the Universidad de los Andes has identified 142,809 species of bacteriophages -- viruses that infect and replicate in bacteria -- living in the human gut. 

Using a DNA-sequencing method called metagenomics, Wellcome Sanger Institute’s Dr. Luis Camarillo-Guerrero and colleagues explored and catalogued the biodiversity of the viral species found in 28,060 public human gut metagenomes and 2,898 bacterial isolate genomes cultured from the human gut. “It’s important to remember that not all viruses are harmful, but represent an integral component of the gut ecosystem,” said co-author Dr. Alexandre Almeida, a postdoctoral researcher at the European Bioinformatics Institute and the Wellcome Sanger Institute. “For one thing, most of the viruses we found have DNA as their genetic material, which is different from the pathogens most people know, such as SARS-CoV-2 or Zika, which are RNA viruses.”

“Secondly, these samples came mainly from healthy individuals who didn’t share any specific diseases.” “It’s fascinating to see how many unknown species live in our gut, and to try and unravel the link between them and human health.” The researchers also identified a previously unknown clade of bacteriophages, named Gubaphage. This was found to be the second most prevalent virus clade in the human gut, after crAssphage, which was discovered in 2014. “An important aspect of our work was to ensure that the reconstructed viral genomes were of the highest quality,” Dr. Camarillo-Guerrero said. “A stringent quality control pipeline coupled with a machine learning approach enabled us to mitigate contamination and obtain highly complete viral genomes.” “High-quality viral genomes pave the way to better understand what role viruses play in our gut microbiome, including the discovery of new treatments such as antimicrobials from bacteriophage origin.” The team’s results form the basis of the Gut Phage Database, a highly curated database of phage genomes that will be an invaluable resource for those studying bacteriophages and the role they play on regulating the health of both our gut bacteria and ourselves. “Bacteriophage research is currently experiencing a renaissance,” said Dr. Trevor Lawley, a researcher at the Wellcome Sanger Institute. “This high-quality, large-scale catalogue of human gut viruses comes at the right time to serve as a blueprint to guide ecological and evolutionary analysis in future virome studies.”

Findings published in Cell (Feb. 18, 2021):

https://doi.org/10.1016/j.cell.2021.01.029

Researchers at the top-ranked hospital in Boston compared search interest in loss of taste and appetite, and diarrhea with the reported incidence of Covid-19 in 15 U.S. states from January 20 to April 20. Using Alphabet Inc.s Google Trends online tool, they found the volume of searches correlated most strongly with cases in New York, New Jersey, California, Massachusetts and Illinois - states with high disease burden - three to four weeks later. Internet searches on gastrointestinal symptoms predicted a rise in Covid-19 cases weeks later, researchers at Massachusetts General Hospital found, demonstrating a novel early warning system for hot spots of the pandemic disease. 

The research, published in the journal Clinical Gastroenterology and Hepatology, showed that the same approach used to monitor pandemic influenza trends more than a decade ago could be deployed for the coronavirus, the hospital said in a report this month. Patients with Covid-19 often report gastrointestinal symptoms, such as abdominal pain and diarrhea, sparking interest in conducting the study. “Our data underscore the importance of GI symptoms as a potential harbinger of Covid-19 infection and suggests that Google Trends may be a valuable tool for prediction of pandemics with GI manifestations,” Kyle Staller, a gastroenterologist and the director of Mass General’s gastrointestinal motility laboratory, and colleagues wrote in the study. Scientists are also testing for traces of the coronavirus in wastewater to identify places where Covid-19 is spreading.

The highly contagious norovirus causes diarrhea and vomiting and is notorious for spreading rapidly through densely populated spaces, such as cruise ships, nursing homes, schools and day care centers. Each year, it is responsible for some 200,000 deaths, mostly in the developing world. There are no treatments for this intestinal virus, often incorrectly referred to as stomach flu. Now, a new study led by scientists at Washington University School of Medicine in St. Louis has shown that gut microbes can tamp down or boost the severity of norovirus infection based on where along the intestine the virus takes hold.  The study, published Nov. 25 in the journal Nature Microbiology, suggests new routes to possible therapies for norovirus infection. Collaborators included researchers at the University of Florida, the University of Michigan and Yale University Medical School.

"There are currently no treatments for norovirus, which is very easily spread through fecal-oral transmission," said co-senior author Megan T. Baldridge, MD, Ph.D., an assistant professor of medicine at Washington University. "Norovirus is especially dangerous in young children, older adults and people with compromised immune systems. We are trying to understand how the gut microbes interact with norovirus in an effort to pursue new therapeutic strategies." In these mouse studies, the researchers found that normal gut bacteria boosted the severity of viral infection in the lower small intestine, which is in line with past work in the field. But simultaneously, normal gut bacteria blocked or inhibited viral infection in the upper small intestine. In other words, gut microbes can have totally opposite effects on norovirus infection depending on the infection's location along the length of the gut. "These results were a huge surprise to us," Baldridge said. "We showed that different parts of the intestine can show dramatically different responses to this type of infection. Our research reveals that we can't view the gut as a homogeneous tube that responds to infection in a uniform way."

Baldridge and her colleagues found that the difference in response was driven by bile acids, which are mainly known for their roles in digestion. "Bile acids are powerfully regulated by bacteria all along the gut," Baldridge said. "But there had not been a realization that these bile acids could prime the gut to mount an immune response against intestinal viruses." In the new study, the researchers showed that bile acids in the upper small intestine—but not the lower—stimulated the immune system to respond to the infection. The researchers determined that bile acids in that region of the gut triggered a molecule called interferon III—one of the body's key antiviral defenses in the intestine—to become activated. Baldridge noted that this complexity of interactions between gut microbes and bile acids could explain some of the variability seen in norovirus infections. Some people become extremely ill with this virus; others develop no symptoms at all. "The different ways people respond to viral infections could be related to their individual gut microbial community," Baldridge said. "The severity of an infection could be tied to where exactly along the gut you get an infection, and that might be controlled by your individual microbiome. Subtle differences along the intestine could end up having dramatic effects on how the gut perceives the virus and responds to it."...

Published in Nature Microbiology (25 November 2019):

https://nature.com/articles/s41564-019-0602-7

Antibiotics can leave the lung vulnerable to flu viruses, leading to significantly worse infections and symptoms, finds a new study in mice.

The research discovered that signals from gut bacteria help to maintain a first line of defence in the lining of the lung. When mice with healthy gut bacteria were infected with the flu, around 80% of them survived. However, only a third survived if they were given antibiotics before being infected.

"We found that antibiotics can wipe out early flu resistance, adding further evidence that they should not be taken or prescribed lightly," explains Dr Andreas Wack, who led the research at the Francis Crick Institute. "Inappropriate use not only promotes antibiotic resistance and kills helpful gut bacteria, but may also leave us more vulnerable to viruses. This could be relevant not only in humans but also livestock animals, as many farms around the world use antibiotics prophylactically. Further research in these environments is urgently needed to see whether this makes them more susceptible to viral infections."

To test whether the protective effect was related to gut bacteria rather than local processes in the lung, the researchers treated mice with antibiotics and then repopulated their gut bacteria through faecal transplant. This restored interferon signalling and associated flu resistance, suggesting that gut bacteria play a crucial role in maintaining defences.

These studies were published in Cell Reports:

 https://doi.org/10.1016/j.celrep.2019.05.105

Highlights

Summary

Researchers from Karolinska Institutet in Sweden have discovered that the gut microbiome can influence how well people respond to mRNA COVID vaccines. The study, published in the journal npj Biofilms and Microbiomes, suggests that certain bacteria in the gut can enhance the immune response to the vaccine, whereas other bacteria may weaken it. The gut microbiome is the collection of microorganisms that live in our digestive tract. It plays an important role in many aspects of our health, such as digestion, metabolism, and immunity. The researchers wanted to find out if the gut microbiome also affects the response to mRNA COVID vaccines. To do this, the researchers collected stool samples from 68 people living with HIV and 75 healthy individuals before their first mRNA COVID vaccine dose. The researchers analysed the microbiome composition using a technique called 16S rRNA sequencing, which identifies the types and relative abundance of bacteria in the samples. They also measured the levels of antibodies and immune cells that were produced after the vaccination.

The results showed that the initial makeup of the gut microbiome could predict the immune response to the vaccine in both groups. They found that a less diverse gut microbiome was associated with a stronger vaccine response, marked by higher levels of spike protein antibodies and spike specific CD4 T-cells. These are key components of the immune system that help to neutralize the virus and prevent severe infection. The researchers also identified specific bacteria that were linked with better or worse vaccine responses. For example, they found that Lactobacillus, Bacteroides, and Lachnospira were associated with higher antibody and immune cell levels, while Cloacibacillus was associated with lower antibody levels. They also found that Bifidobacterium and Faecalibacterium were microbial markers of individuals with higher antibody levels.

According to the researchers, the study highlights the significant role of the gut microbiome in the effectiveness of mRNA COVID vaccines. The findings could lead to developing microbiota-focused treatments to enhance vaccine responses, especially in groups that may have weaker responses, such as the elderly or immunocompromised individuals. The potential strategies could include changing the diet or taking probiotics to improve the gut microbiome and immunity, the researchers suggest. The study was conducted in collaboration with the Karolinska University Hospital, and SciLifeLab National Genomics Infrastructure in Stockholm, Sweden. The research was funded by Region Stockholm, the Swedish Research Council, and Physicians Against AIDS.

Cited study published in NPJ Biofilms and Microbiomes (Dec. 20, 2023):

https://doi.org/10.1038/s41522-023-00461-w 

Scientists have uncovered a possible explanation for one of COVID-19's most vexing legacies: the stubborn neurological symptoms of long COVID, such as brain fog, memory loss and fatigue. The first clue emerged when researchers scoured the blood of long COVID patients: It was serotonin – specifically, a lack of the neurotransmitter circulating in the body — that grabbed their attention. Their analysis revealed that having low levels of that chemical predicted whether or not someone was suffering from persistent symptoms following an infection. Next, the team of researchers at the University of Pennsylvania carefully recreated the chain of events that might be depleting serotonin and causing downstream consequences that could line up with some of the symptoms characteristic of long COVID.

Their findings, published in the journal Cell, point to an intriguing hypothesis that winds its way from the gut up through the vagus nerve and ultimately into the brain. "Basically, we can explain some of the neurocognitive manifestations of long COVID through this pathway that leads to serotonin reduction," says Christoph Thaiss, a senior author on the study and an assistant professor of microbiology at the University of Pennsylvania. The work has made an impression on those studying long COVID, a condition that still has no validated treatment or widely accepted biomarker that doctors can use to diagnose the condition. The study weaves together several prominent lines of evidence on the potential drivers of the condition — the ongoing presence of viral material, blood clotting and chronic inflammation — and offers up possible targets for clinical trials that can test treatments in humans. "I'm impressed by the study," says Dr. Michelle Monje, a professor of neurology at Stanford University. "I think they did a beautiful job showing the causality of these changes." Given that much of the work was done on mice, the implications for long COVID patients still need to be fully explored in future studies, but the results tell a "very nice linear story," says Akiko Iwasaki, an immunologist at Yale University. "Everyone who's engaged in this research should now be thinking about this serotonin pathway," says Iwasaki.

So what exactly did they find?

Tracing the cause of brain fog

With serotonin on their minds, the researchers tried to start from the very beginning of the disease process, primarily using experiments on mice to trace its course. Their hunch was that "viral persistence" — a major suspect in long COVID — could underlie the depletion of serotonin. Multiple studies show that well after the initial illness passes, some long COVID patients may have a lingering infection in certain parts of the body, sometimes called a "viral reservoir," which could be driving some of their symptoms. Maayan Levy, a senior author, says they looked for evidence of viral persistence by checking the stool of their long COVID subjects for genetic material from the virus. "In about 30% of patients, we could find viral RNA in their gastrointestinal tract, so we took this and tried to model it in mice," says Levy, an assistant professor of microbiology at the University of Pennsylvania. Those experiments revealed that a chronic viral infection (they used lymphocytic choriomeningitis virus as a stand-in for SARS-CoV-2) also led to reductions in serotonin and that the body's own immune response seemed to be the culprit. This led to further experiments focused on a cytokine, called type 1 interferon, revealing that this signaling protein was driving inflammation and interfering with serotonin levels in the bloodstream in several ways. The gut produces 90% of serotonin in the body. The amino acid tryptophan is critical to this task — it's a precursor to serotonin and gets absorbed in the gastrointestinal tract from the food we eat. Except, this inflammatory response in the gut actually impaired the absorption of tryptophan. "If there's less tryptophan, there's less serotonin production," says Thaiss. On top of that, these cytokines also lead to clotting of blood platelets — which store serotonin — further reducing the amount of serotonin in circulation.

The brain connection

Here, the detective work moved away from the gut to the vagus nerve, which essentially acts like the brain's monitoring system of the body and connects to the gastrointestinal tract and many other organs. Levy says they found this reduction in serotonin impairs communication between the vagus nerve and the brain, which then reduces some activity in a region of the brain known as the hippocampus. What's promising, though, is that the cognitive symptoms the Penn researchers documented in mice could be reversed. "We can make the animals remember perfectly again by just reactivating their vagus nerve or by restoring their serotonin signaling," says Thaiss, referring to a cognitive behavioral test they performed on their mouse models of long COVID. "Whether the exact same thing is true in individuals with long COVID is something we don't know." Because much of this work was done on mice, there are limitations to what conclusions can be drawn about humans. Levy points out that their data can't prove a viral reservoir is causing these events in humans and that a lack of good mouse models of long COVID still hampers research. "To make any recommendations for patients, we need to perform a large clinical trial that is well-controlled," she says, "The obvious next step would be for us to to try an intervention that will increase serotonin levels or stimulate the vagus nerve in other ways or [to] supplement tryptophan." In their experiment, they gave the mice a generic form of Prozac — a class of medication known as an SSRI that's typically prescribed for depression and increases circulating serotonin in the brain.

Untangling the complex causes of long COVID

The research offers new insights into how immune problems outside of the nervous system can have far-reaching consequences on the brain and other functions in the aftermath of COVID-19, says Stanford's Monje. "It's not the whole puzzle — and it's not meant to be the whole puzzle — but it's a really important aspect of it," she says. Indeed, scientists don't expect to find a single mechanism that, once unearthed, will resolve all these problems. "There are many ways that COVID can influence the nervous system that are not mutually exclusive," says Monje. "Any individual might be suffering from some combination of those." For example, her lab has found that, in mice, a mild COVID-19 infection in the lungs sets off an inflammatory cascade that impairs neuron production in the hippocampus. The long COVID "brain fog" syndrome encompasses a constellation of symptoms, everything from problems with memory and attention to speed of information processing to executive function and fatigue. Monje says research on the effects of COVID-19 have revealed neurobiological changes elsewhere in the brain, too. "It's broader than just the hippocampus, but certainly the hippocampus has been implicated." As with all long COVID research, the challenge is figuring out how these findings fit into our ever-changing understanding of the disease. "Long COVID is a heterogeneous disorder. There are many different manifestations," says Dr. Saurabh Mehandru, a professor of medicine at Mount Sinai in New York. "It's novel, exciting data. I would consider this as important but initial findings which have to be further studied." Mehandru says "it makes sense the tryptophan-serotonin pathway is being affected" given that SARS-CoV-2 utilizes the ACE-2 receptor, which is widely expressed on the surface of the small intestines. "It's expressed there because it plays a role in absorption of amino acids" like tryptophan, he says. But he says there are still many open questions about this business of viral persistence in the gut of long COVID patients.

Because these cells renew every three to five days, "for anything to be persistently active in this layer, it would by definition imply there's some level of replication," he says. It's not clear, however, exactly what's replicating. Multiple studies have found evidence of genetic material and viral proteins in different tissues. Yet, no one has actually cultured the virus from intestinal tissue, which is admittedly difficult to do, he says. "These are active and important scientific areas of interest." While it's possible a chronic viral infection in the gut could be driving these symptoms in some patients, as the Penn study suggests, Yale's Iwasaki says the neurocognitive dysfunction in long COVID can be "downstream of many different things, including circulating inflammatory factors and autoantibodies." "Even though the dots are very well connected with animal models and patient samples, whether this is happening in patients and what proportion might be suffering from this particular pathology, that still requires future studies," says Iwasaki, whose research has found that low levels of the stress hormone cortisol are also associated with long COVID symptoms. Ultimately, this research may not explain all the neurological symptoms that surround long COVID — and that's okay, says Monje. "It's not that we have to put all the pieces of the puzzle together to begin to make meaningful therapeutic changes," she says. "I think it's worth further pursuing."

Research published in Cell (October 16, 2023):

https://doi.org/10.1016/j.cell.2023.09.013

Scientists are studying whether long COVID could be linked to viral fragments found in the body months after initial infection.  In the chaos of the first months of the coronavirus pandemic, oncologist and geneticist Ami Bhatt was intrigued by widespread reports of vomiting and diarrhoea in people infected with SARS-CoV-2. “At that time, this was thought to be a respiratory virus,” she says. Bhatt and her colleagues, curious about a possible link between the virus and the gastrointestinal symptoms, began to collect stool samples from people with COVID-19. Thousands of miles away from Bhatt’s lab at Stanford Medicine in California, gastroenterology internist Timon Adolph was puzzled by accounts of gut symptoms in infected people. Adolph and his colleagues at the Medical University of Innsbruck in Austria started to assemble specimens, too — gastrointestinal-tissue biopsies. Two years into the pandemic, the scientists’ foresight has paid off: both teams have recently published results1,2 suggesting that pieces of SARS-CoV-2 can linger in the gut for months after an initial infection. The findings add to a growing pool of evidence supporting the hypothesis that persistent bits of virus — coronavirus “ghosts”, Bhatt has called them — could contribute to the mysterious condition called long COVID. Even so, Bhatt both urges scientists to keep an open mind and cautions that researchers have not yet nailed down a link between persistent viral fragments and long COVID. “Additional studies still need to be done — and they’re not easy,” she says.

Long COVID is often defined as symptoms that linger beyond 12 weeks after an acute infection. More than 200 symptoms have been associated with the disorder, which ranges in severity from mild to debilitating. Theories about its origins vary, and include harmful immune responses, tiny blood clots and lingering viral reservoirs in the body. Many researchers think that a mix of these factors contributes to the global burden of disease. An early hint that the coronavirus might persist in the body came in work3 published in 2021 by gastroenterologist Saurabh Mehandru at the Icahn School of Medicine at Mount Sinai in New York City and his colleagues. By then, it was clear that cells lining the gut display the protein that the virus uses to enter cells. This allows SARS-CoV-2 to infect the gut. Mehandru and his team found viral nucleic acids and proteins in gastrointestinal tissue collected from people who’d been diagnosed with COVID-19 an average of four months earlier. The researchers also studied participants’ memory B cells, which are pivotal players in the immune system. The team found that antibodies produced by these B cells were continuing to evolve, suggesting that, at six months after the initial infection, the cells were still responding to molecules made by SARS-CoV-2. Inspired by this work, Bhatt and her colleagues found that a few people continued to shed viral RNA into their stool seven months after an initial mild or moderate SARS-CoV-2 infection, well after their respiratory symptoms had ended.

Virus goes for the gut

Adolph says the 2021 paper inspired his team to look at their biopsy samples for signs of coronavirus. They found that 32 of 46 study participants who had had mild COVID-19 showed evidence of viral molecules in their gut seven months after acute infection. About two-thirds of those 32 people had long-COVID symptoms.

But all of the participants in this study had inflammatory bowel disease, an autoimmune disorder, and Adolph cautions that his data do not establish that there is active virus in these people, or that the viral material is causing long COVID. In the meantime, more studies have suggested lingering viral reservoirs beyond the gut. Another team of researchers has studied tissue collected from autopsies of 44 people who had been diagnosed with COVID-19 and found evidence of viral RNA in many sites, including the heart, eyes and brain4. Viral RNA and proteins were detected up to 230 days after infection. The study has not yet been peer reviewed.

Viral hideouts

Nearly all of the people in that sample had had severe COVID-19, but a separate study of two people who had had mild COVID-19 followed by long COVID symptoms found viral RNA in the appendix and the breast5. Pathologist Joe Yeong at the Institute of Molecular and Cell Biology at the Agency for Science, Technology, and Research in Singapore, who is a co-author of the report, which has not been peer reviewed, speculates that the virus might infiltrate and hide out in immune cells called macrophages, which can be found in a variety of the body’s tissues. All of these studies support the possibility that long-term viral reservoirs contribute to long COVID, but researchers will need to do more work to conclusively show a link, says Mehandru. They will need to document that the coronavirus is evolving in people who are not immunocompromised, and they will need to link such evolution to long COVID symptoms. “Right now there is anecdotal evidence, but there are a lot of unknowns,” Mehandru says Bhatt is hopeful that samples will become available to test the viral-reservoir hypothesis. The US National Institute of Health, for example, is running a large study called RECOVER, which aims to tackle the causes of long COVID and will collect biopsies from the lower intestines of some participants. But Sheng says he does not need to wait for a billion-dollar study to get more samples: an organization of people with long COVID has contacted him and offered to send samples from members who have had biopsies for various reasons, such as a cancer diagnosis, after their infections. “It’s really random, the tissue can come from everywhere,” he says. “But they don’t want to wait.”

Published in Nature (May 11, 2022):

https://doi.org/10.1038/d41586-022-01280-3 

An enzyme that helps COVID-19 (coronavirus) infect the body also plays a role in inflammation and patient outcomes in inflammatory bowel disease (IBD), according to a new study led by Cedars-Sinai. The findings raise the possibility that anti-inflammatory drug therapies for IBD may aid recovery from coronavirus. The multisite study, led by Cedars-Sinai and published today in the journal Gastroenterology, focused on angiotensin-converting enzyme 2 (ACE2), which normally plays a crucial health role by activating a hormone that helps regulate blood pressure. But in COVID-19 infections, the SARS-CoV-2 virus binds to ACE2 and uses it to invade and infect cells, "hijacking" them to spread the virus.  To learn more about how ACE2 affects the body, investigators examined its role in Crohn's disease and ulcerative colitis—two types of IBD that can cause inflammation and scarring (fibrosis) in the digestive tract along with diarrhea, cramping and loss of appetite. "We chose these disorders because COVID-19, while known for attacking the lungs, frequently causes gastrointestinal symptoms," said Dermot P. McGovern, MD, Ph.D., the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and senior author of the new study. "It was important for us to understand how COVID-19 might affect IBD patients who are treated with anti-inflammatory medications. Also, there is increasing evidence that the GI tract may serve as an alternate route for uptake of SARS-COV-2 in general."

By examining records of nearly 1,000 patients at Cedars-Sinai, Washington University in St. Louis, Missouri, and multiple other centers across North America, the team found that levels of ACE2 in the small bowel were lower in Crohn's patients and higher in the colons of ulcerative colitis patients than they were in patients without IBD. The differing ACE2 levels were associated with poorer outcomes and more severe disease in the IBD patients.  "We saw that the effect of ACE2 depended on both its specific location in the gastrointestinal tract and the specific disease involved," said McGovern, professor of Medicine and Biomedical Sciences. "So, this enzyme was a double-edged sword." In both types of IBD, treatment with infliximab, an anti-inflammatory drug, normalized the levels of ACE2 and was associated with improved disease outcomes in patients. This finding suggests these drugs, commonly used in autoimmune diseases, also might improve outcomes in COVID-19, the investigators said.

"Overall, our study supports the potential paradoxical function of ACE2 in inflammation and COVID-19," McGovern explained. "Individuals with higher ACE2 expression may be at increased risk of infection with SARS-CoV-2. But judging from our discoveries of how ACE2 works in IBD, this enzyme likely has anti-inflammatory and anti-fibrotic functions that also could help certain COVID-19 patients recover from the virus." Further research is needed to delineate the processes involving ACE2 and what they might mean for treating COVID-19 patients, he said. In support of that effort, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health recently awarded a two-year grant of $677,036 to McGovern to examine overlaps in the mechanisms that drive inflammation in IBD and COVID-19.

Original study published in Gastroenterology (Nov. 5, 2020):

https://doi.org/10.1053/j.gastro.2020.10.041

Gut organoids, three-dimensional cell culture models of the intestine, have been used to demonstrate that the coronavirus SARS-CoV-2 can infect cells of the intestine and multiply there. The models indicate that SARS-CoV-2 might also infect and replicate in the cells lining the human intestine. It is even possible that the human intestine is—as researchers have suspected—a significant route for SARS-CoV-2 transmission. That is, SARS-CoV-2 transmission via gastrointestinal organs, as well as that via the respiratory organs, may account for the devastating spread of COVID-19. Patients with COVID-19 show a variety of symptoms associated with respiratory organs—such as coughing, sneezing, shortness of breath, and fever—and the disease is transmitted via tiny droplets that are spread mainly through coughing and sneezing. One-third of the patients, however, also have gastrointestinal symptoms, such as nausea and diarrhea. In addition, the virus can be detected in human stool long after the respiratory symptoms have been resolved. This suggests that the virus can also spread via so-called fecal-oral transmission.

Though the respiratory and gastrointestinal organs may seem very different, there are some key similarities. A particularly interesting similarity is the presence of the ACE2 receptor, the receptor through which the COVID-19 causing SARS-CoV-2 virus can enter the cells. The inside of the intestine is loaded with ACE2 receptors. However, it has been unclear whether intestinal cells could get infected and produce virus particles. To explore the possibility of an intestinal route, scientists in the Netherlands generated human small intestinal organoids (hSIOs) derived from primary gut epithelial stem cells. The scientists—who represented—Hubrecht Institute, Erasmus University Medical Center, and Maastricht University—asserted that such hSIOs contain all the proliferative and differentiated cell types of the in vivo epithelium. When grown in four different culture conditions, the hSIOs contained cells that expressed varying amounts of ACE2 and were thus capable, in theory, of being infected with SARS-CoV-2. To see if the cells actually experienced infection, the scientists observed them closely, as described in an article (“SARS-CoV-2 productively infects human gut enterocytes”) that appeared May 1 in the journal Science. “In hSIOs, enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal and electron microscopy,” the article’s authors wrote. “Consequently, significant titers of infectious viral particles were detected. mRNA expression analysis revealed strong induction of a generic viral response program.”

Published in Science (May 1, 2020): 

https://doi.org/10.1126/science.abc1669

Most of the viruses present in people’s guts are bacteriophages, but how they interact with resident bacteria is still an open question. There’s a lot that scientists don’t know about the gut microbiota, and when it comes to the viruses present there they know even less. To learn more, researchers have monitored the gut viromes of nine people for a full year and that of one person for more than two years. They find that many types of bacteriophages are present and that each individual’s virome is stable over time and different from that of the other subjects.

This study “generates an important database for phages in the gut,” says Corrine Maurice, a microbiologist at McGill University who did not participate in the work. “That’s a database that we just didn’t have, and so that data is going to allow us to formulate some really cool hypotheses going forward. It’s really providing us with tools to . . . look further into what these phages may be doing for our health. “It confirms recent reports that there is no such thing as a core gut virome shared between adult individuals, which is in contrast with the bacterial component of our microbiota where there are more members shared between humans,” Evelien Adriaenssens, who studies gut viruses at the Quadram Institute in the UK and was not involved in the work, writes in an email to The Scientist. “We need more studies on the gut virome like these to establish a baseline about what a healthy human gut virome looks like, taking into account differences in for example geography, ethnicity and lifestyle. After we know what is healthy, we can start looking at complex disease syndromes . . . and identify what changes in the virome can be used as a marker for disease.”

There’s a lot that scientists don’t know about the gut microbiota, and when it comes to the viruses present there they know even less. To learn more, researchers have monitored the gut viromes of nine people for a full year and that of one person for more than two years. They find that many types of bacteriophages are present and that each individual’s virome is stable over time and different from that of the other subjects.

This study “generates an important database for phages in the gut,” says Corrine Maurice, a microbiologist at McGill University who did not participate in the work. “That’s a database that we just didn’t have, and so that data is going to allow us to formulate some really cool hypotheses going forward. It’s really providing us with tools to . . . look further into what these phages may be doing for our health.”

“It confirms recent reports that there is no such thing as a core gut virome shared between adult individuals, which is in contrast with the bacterial component of our microbiota where there are more members shared between humans,” Evelien Adriaenssens, who studies gut viruses at the Quadram Institute in the UK and was not involved in the work, writes in an email to The Scientist. “We need more studies on the gut virome like these to establish a baseline about what a healthy human gut virome looks like, taking into account differences in for example geography, ethnicity and lifestyle. After we know what is healthy, we can start looking at complex disease syndromes . . . and identify what changes in the virome can be used as a marker for disease.”

Andrey Shkoporov, a microbiologist at University College Cork, and colleagues set out to establish that baseline. “We thought, ‘Okay, before we embark on comparative studies of the virome in different health conditions, why don’t we look at the longitudinal stability and inter-individual variability of the gut virome between healthy human subjects,’” he tells The Scientist. 

The research team collected fecal samples from 10 adults—four men and six women—every month for a year. From one female subject, they collected three additional samples at months 19, 20, and 26. Then they separated viral particles from fecal matter and cells and isolated and sequenced viral nucleic acids. Because 99 percent of gut viruses are unknown to science, Shkoporov says, it was not possible to rely on existing viral sequence databases to figure out what was there. Instead, the authors assembled the reads into overlapping DNA sequences, predicted protein coding genes, and then tried to detect any similarities between proteins in databases with those likely encoded by the long stretches of DNA. “This can help to get a rough idea what kind of viruses we are dealing with,” Shkoporov adds. The researchers reported yesterday (October 9) in Cell Host & Microbe  that the individual viromes were stable over the 12 or 26 months of the study and diverse, meaning there were many types of bacteriophages present. While the subjects’ viral communities stayed consistent over time, each person’s complement of gut viruses looked different from that of the others.....

Published in Cell Host & Microbe on October 9, 2019:

https://doi.org/10.1016/j.chom.2019.09.009