Virus World

Research into bacteriophages adds to evidence that gut and brain interactions influence our behaviour. Viruses are widely regarded as harmful to our health, but a subset of viruses living in the gut could play a crucial role in regulating stress, research suggests. The discovery adds to mounting evidence that interactions between the gut and brain influence people’s behaviours, and could eventually lead to new treatments for stress-related conditions that target the vast community of viruses living inside us. While previous studies have suggested that the composition of microbes living in the gut changes in response to stress, these have largely focused on bacteria, rather than on this “virome”. “The way the virome interacts with bacteria, and how they affect stress-related health and disease status is largely unexplored,” said Dr Nathaniel Ritz, of the APC Microbiome Ireland research centre at University College Cork. “Our research opens up the potential to target the virome to treat and reduce the effects of stress.”

Ritz and his colleagues focused on a subset of viruses called bacteriophages, which infect bacteria and replicate alongside them. They studied what happened to these viruses when the mice they inhabited were exposed to chronic social stresses, such as being housed alone or in overcrowded conditions, and found that stress exposure led to changes in the composition of the viruses and the bacteria in the animals’ guts. Next, they harvested viruses from the droppings of unstressed healthy animals, and transplanted some of them back in, once the mice had been exposed to chronic social stress. The research, published in Nature Microbiology, suggested these transplants reduced levels of stress hormones and curbed depression- and anxiety-like behaviour in the mice. While further studies are needed to assess whether virus transplants are beneficial to humans suffering from stress-related conditions, the research provides some of the first evidence that gut viruses are involved in the response to stress, and that manipulating them could have therapeutic benefits. “Given that the virome composition varies greatly among individuals, it may open the door for personalised medicine approaches for stress-related disorders in the future,” said Prof John Cryan at APC Microbiome Ireland, who led the research. “One thing for certain, we must acknowledge that not all viruses are bad and they can play a key role in keeping the bad bacteria in our gut at bay especially in times of stress.”

Cited research published in Nature Microbiology (Feb.5, 2024):

https://doi.org/10.1038/s41564-023-01564-y 

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

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn’s disease, and certain viral infections.

In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.

Published in Signal Transduction and Targeted Therapy (April 29, 2022):

https://doi.org/10.1038/s41392-022-00986-0 

The presence of specific microbiota, or microorganisms that live in the digestive tract, can prevent and cure rotavirus infection, which is the leading cause of severe, life-threatening diarrhea in children worldwide, according to a new study by the Institute for Biomedical Sciences at Georgia State University.

The findings, published in the journal Cell, may explain why rotavirus causes severe, life-threatening disease in some people and only mild disease in others. It could lead to possible treatments and preventive measures for rotavirus infection. There are no existing treatments for rotavirus besides administering fluids to avoid dehydration. Rotavirus is a highly contagious virus that can cause severe diarrhea, vomiting, fever, abdominal pain and death. Rotavirus infection occurs as a result of direct contact with an infected person or exposure to their fecal matter. Infants and young children are the most susceptible to this disease, and the illness can lead to severe dehydration, hospitalization or even death. Rotavirus leads to an estimated 215,000 deaths worldwide in children younger than 5 years old, according to the Centers for Disease Control and Prevention. Susceptibility to rotavirus is not well understood and can vary vastly among individuals and regions. Rotavirus causes relatively mild disease in both developed countries and poor regions of central America, but it kills many thousands of children each year in poor regions of Sub-Saharan Africa and India. Even within particular societies, rotavirus causes mild disease in some individuals and severe life-threatening disease in others.

"This study shows that one big determinant of proneness to rotavirus infection is microbiota composition," said Dr. Andrew Gewirtz, senior author of the study and a professor in the Institute for Biomedical Sciences at Georgia State. Gut microbiota is the collective term for microorganisms living in the intestinal tract. Microbiota composition was known to influence bacterial infection, but a role for microbiota in influencing viral infection was totally unknown. "This discovery was serendipitous," Gewirtz said. "We were breeding mice and realized that some of them were completely resistant to rotavirus whereas others were highly susceptible. We investigated why and found that the resistant mice carried distinct microbiota. Fecal microbiota transplant transferred rotavirus resistance to new hosts."

Further investigation revealed that a predominant determinant of resistance to rotavirus was the presence of a single bacterial species called Segmented Filamentous Bacteria, or SFB. The Georgia State researchers found SFB reduces rotavirus infectivity and protects against rotavirus by causing epithelial cells to be shed and replaced with new, uninfected cells. "It's a new basic discovery that should help understand proneness to rotavirus infection," Gewirtz said. "It does not yield an immediate treatment for humans, but provides a potential mechanism to explain the differential susceptibility of different populations and different people to enteric viral infection. Furthermore, it may lead to new strategies to prevent and treat viral infections."...

Published in Cell on October 10, 2019:

https://doi.org/10.1016/j.cell.2019.09.028

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 recent publication by a Stanford scientist, Bali Pukendran, reviews how the microbiome may play a key role in vaccines efficacy.

Multiples examples have highlighted the role of the microbiota. Earlier studies have evaluated the role of the microbiota small animal models in which  depletion of their microbiota by antibiotics or the testing with germ-free animals resulted in reduced vaccine efficacies. Other studies in human have helped understand how the microbiome influences vaccine's responses by monitoring the vaccine's  signature. The use of  artificial intelligence has been used to predict immune responses.

Immunization with influenza vaccines led to the discovery of potential  links with the microbiota.  The inactivated influenza vaccine induces expression of Toll-like-receptor 5 (TLR5), a key protein recognizing  bacterial components and triggering an innate immune response. Mice deficient in tlr5 induce poor anti-influenza antibody  responses upon vaccination. Similar results have been observed with an adjuvant-free polio vaccine, but not with vaccines containing adjuvants, suggesting that the microbiota may act as an endogenous adjuvant, and may play an even more important role when the individuals have no pre-existing immunity against the pathogen the are immunized against.

Several studies have revealed that in addition to specific gene signatures, antibiotics also lead to significant changes in the blood metabolome, including changes in bile acids that have been shown to modulate inflammatory responses in humans. Furthermore, age may increase gut permeability, exacerbating the effects of the bacterial metabolome and perhaps playing a role in the limited  vaccine efficacy observed in elderly patients.

These findings highlights the importance of avoiding antibiotic use during vaccination, especially in children, where pre-existing responses may be limited. They also highlight the importance to stratify patients in vaccine trials by their microbiomes and bacterial metabolomes, to better elucidate which patients better response to future experimental vaccines.

Published in Science (29 November , 2019):

https://doi.org/10.1126/science.aau6975

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