Answer to COVID-19 severity in people with HIV may lie in the gut

People with HIV who develop severe COVID-19 experience major changes in gut bacteria that persist for months after infection and may explain both the severity of COVID-19 and the extent of post-COVID symptoms, Japanese researchers report in the journal BMC Microbiology.

Although the researchers emphasise that their findings are tentative and need to be confirmed by larger studies, they think that the investigation of the microbiome – the bacteria population in the gut – is a promising avenue not only for understanding COVID-19 but for managing severe COVID-19 and long COVID.

Bacteria in the gut influence immune responses and defences against infections. Gut bacteria can also promote or switch off inflammation. Too many of the bacteria types that promote inflammation, or too few of the types that damp down inflammation and promote healthy immune responses, may contribute to numerous illnesses and chronic conditions.

There is growing interest in the links between gut bacteria and COVID-19 severity, as well as the persistence of post-COVID symptoms.

One study, carried out in Hong Kong, collected stool samples from 27 people without HIV hospitalised with severe COVID-19 for 30 days after admission to hospital. People with more severe COVID-19 had fewer bacteria promoting helpful immune responses and more bacteria associated with inflammation at baseline and throughout the follow-up period.

Another study which followed people without HIV in China showed that the types of bacteria found in stool samples at admission to hospital with COVID-19, one month after admission and six months after admission were strongly correlated with the presence of post-COVID symptoms such as fatigue, poor memory and breathlessness. People who went on to develop long COVID had a restricted range of bacteria and a greater number of opportunistic bacterial species. The researchers even found a correlation between different post-COVID symptoms and specific types of bacteria.

To investigate the relationship between gut bacteria populations and COVID-19 severity in people with HIV, Japanese researchers at the University of Tokyo recruited 12 men with HIV admitted to hospital with COVID-19, 25 men with HIV without COVID-19 and 19 men without HIV or COVID-19.

Study participants with COVID-19 had a median age of 46 years and 10 out of 12 were gay or bisexual men. All participants with HIV had suppressed viral load and had been taking antiretroviral treatment for approximately nine years. Those diagnosed with COVID-19 were slightly heavier than people with HIV without COVID-19 (body mass index of 27.5 vs 24.7) but did not have a higher burden of comorbidities. They had higher median CD4 counts (671 vs 539) than people with HIV without COVID-19.

COVID-19 was moderate or severe in five out of 12 people with HIV. Those with COVID-19 were discharged from hospital after an average of 10 days. Six out of 12 received antiviral medications (remdesivir, molnupiravir) to treat COVID-19 and three received steroid treatment. Only one received antibiotic treatment in hospital.

People with HIV with COVID-19 provided stool samples after admission to hospital, within two to six days of the onset of symptoms. All but one provided a second sample nine to ten days after the onset of symptoms and seven provided a third sample between 31 and 85 days after the onset of symptoms. Participants in the two control groups provided up to three samples at comparable intervals.

Samples were sequenced to analyse the diversity of gut bacteria. There was no difference between people with HIV with COVID-19 and the control groups of people with HIV and people without HIV in the diversity of bacteria in stool samples.

However, when stool samples were compared over time, people with HIV with COVID-19 showed reductions in the types of bacteria that have anti-inflammatory effects (Clostridia), both at the time of admission to hospital and for up to a month afterwards. Clostridia, like other short-chain fatty acid-producing bacteria, support the maintenance of the intestinal epithelium as a barrier against bacterial leakage into the bloodstream. A loss of these types of bacteria may be a consequence of acute infection or it may exacerbate the inflammatory effects of acute viral infection.

People with moderate or severe COVID-19 in this study tended to show slower recovery of short-chain fatty acid-producing bacteria after admission to hospital.

Levels of harmful bacteria were higher in people with COVID-19, remained elevated one month after admission to hospital and were higher in people with higher body weight.

Two people with HIV experienced post-COVID symptoms (long COVID) and provided stool samples for up to a year after the onset of symptoms. In both cases, a sustained decrease in the diversity of gut bacteria was observed, unlike in four out of five people with COVID who provided post-hospitalisation samples and who did not have post-COVID symptoms.

The researchers say that larger studies are needed to further explore the implications of their findings. A control group of people without HIV who were diagnosed with COVID-19 would provide valuable information on the extent to which changes in the microbiome are HIV-specific. Information on the gut microbiome before SARS-CoV-2 infection would be useful for the assessment of changes during infection. This study was not able to address the question of whether characteristics of the microbiome in gay and bisexual men or people with HIV might predispose to more severe COVID-19.

The study authors note that gay and bisexual men tend to have lower populations of ‘friendly’ Bacteroides species that modulate immune responses to viral infections, but higher populations of Prevotella species that have been linked to chronic immune activation. And in people with HIV, the microbiome resembles the profile seen in chronic inflammatory diseases, with an additional deficiency in the bacterial types that contribute to the integrity of the barrier between the gut and the rest of the body.