Covid-19 causes gastrointestinal symptoms, such as nausea and diarrhoea, about 10% of the time. Anything that affects the gut inadvertently involves the gut microbiota therein. Not by analogy, but because the state of gut microbiota partly depends on the host’s gut physiology, and vice-versa.
Gut inflammation leads to leaky gut, for example, which alters the microbial composition in the gut. Lack of butyrate-producing gut bacteria will not provide sufficient butyrate that heals the gut lining and lowers inflammation.
The long-awaited question is: Does Covid-19 lead to significant alterations in the gut microbiota? Or does gut dysbiosis contribute to Covid-19 severity? Understanding this is paramount, considering that the gut microbiota influences 12 other organs in the human body.
In a published paper in Gastroenterology, 21 researchers at the Chinese University of Hong Kong sequenced the gut microbiome of 15 moderate-to-severe Covid-19 patients, six pneumonia controls, and 15 healthy controls. They tracked changes in their gut microbiota throughout the hospital stay (median = 21 days) and correlated it with measures of disease states.
What the Gut Microbiota of Covid-19 Patients Look Like
Covid-19 patients had increased abundance of opportunistic gut pathogens known to cause bacteremia — such as Clostridium hathewayi, Actinomyces viscous, and Bacteroides nordii — in comparison to all controls. This finding is independent of age, sex, disease comorbidities, or antibiotic usage.
On top of that, beneficial gut microbes — such as Fecalibacterium prausnitzii, Lachnospiraceae bacterium, Eubacterium rectale, Ruminococcus obeum, and Dorea formicigenerans — were depleted in Covid-19 patients vs controls.
These undesirable gut microbial alterations were worse in Covid-19 patients undertaking antibiotics (n = 7).
On the 10th day follow-up after recovery and being tested negative from the throat swab and stool, the gut dysbiosis remained in 10 out of 15 ex-Covid-19 patients. Their gut microbiota were still markedly different, in a bad way, from those who never had Covid-19.
“Among all host factors, Covid-19 infection showed the largest effect size in affecting the gut microbiome, followed by hyperlipidemia, pneumonia, and antibiotics, while age and gender showed no significant effects on gut microbiome alterations,” the researchers found.
Baseline Gut Microbiota and Covid-19 Outcomes
The Hong Kong researchers then determine if baseline gut microbes upon hospital admission could predict who is more likely to suffer more severe Covid-19.
The three bacteria that had the strongest correlation with increasing Covid-19 severity were Coprobacillus species, Clostridium ramosum, and Clostridium hathewayi. The latter two are causative agents of human bacteremia infection based on existing literature. And Corpobacillus species is known to magnify ACE2 expression in the mice gut.
In contrast, Alistipes onderdonkii and Faecalibacterium prausnitzii were the two top bacteria that correlated with good Covid-19 prognosis. Alistipes species participate in the tryptophan-serotonin metabolism essential for gut homeostasis. Faecalibacterium prausnitzii is one of the largest butyrate producers in the gut, providing a substantial anti-inflammatory resource.
Gut Microbiota and Fecal Virus Clearance
This study also pinpointed 14 gut bacteria that correlated with efficient viral clearance. Four of these are Bacteroidetes species known to lower ACE2 expression in the mice gut. “These data suggest that Bacteroides species may have a potential protective role in combating SARS-CoV-2 infection by hampering host entry through ACE2,” the authors wrote.
Only Erysipelotrichaceae bacterium species correlated with increasing faecal viral load, indicating a poor viral clearance. And this bacterium is known to contribute to gastrointestinal inflammatory disorders like Crohn’s disease. Baseline levels of Erysipelotrichaceae were also associated with severe Covid-19. The authors, hence, wrote that “gut Erysipelotrichaceae may play a role in augmenting SARS-CoV-2 infection in the host gut.”
To Sum Up the Study
Notably, the present study included a sample of only 15 moderate-to-severe Covid-19 patients. So, findings may not apply to mild or asymptomatic cases. Notwithstanding this caveat, they provided multiple pioneering discoveries:
- Compared to pneumonia and healthy controls, Covid-19 patients had a distinct gut bacterial profile characterized by the loss of beneficial species important for maintaining gut homeostasis and the growth of opportunistic and inflammatory species.
- The gut dysbiosis persisted at the 10th day following recovery and virus clearance in the majority of ex-Covid-19 patients.
- Some degree of gut dysbiosis at baseline predicted who were more likely to have more severe Covid-19.
- Several gut Bacteroidetes species correlated with efficient virus clearance.
- Covid-19 patients with antibiotics usage had the worse gut dysbiosis among all — advocating for the prudent use of antibiotics.
[5th June update]: This study also corroborates that of China where they examined gut microbiota profiles of 30 Covid-19 patients, 24 influenza patients, and 30 healthy controls. It was found that Covid-19 patients had lowered gut microbiota diversity and levels of butyrate-producers, and higher levels of opportunistic pathogens including Streptococcus, Rothia, Veillonella and Actinomyces species. And this gut dysbiosis further correlated with pro-inflammatory and pro-coagulant biomarkers of Covid-19 severity.
Although influenza patients also suffered reduced gut microbial diversity, the composition is still different from Covid-19 patients. As the study concluded: “The gut microbial signature of patients with COVID-19 was different from that of H1N1 [influenza] patients and healthy controls.”
The Gut-Lung Axis
Before this study appeared, several research groups have already pondered on the implications of the gut-lung axis in Covid-19. And whether probiotic or diet interventions would confer therapeutic potential.
“The gut-lung axis is supposed to be bidirectional…and when inflammation occurs in the lung, it can affect the gut microbiota as well,” said a 2020 review appearing in Virus Research. Likewise, gut dysbiosis could weaken the lung immunity too. To this end, they proposed that a diet providing nutrients that nourishes gut microbes could help the lung immunity to stay in top shape.
In another research review published in the Frontiers of Cellular and Infection Microbiology, researchers wrote that the “gut-lung axis can shape immune responses and interfere with the course of respiratory diseases.” Their premise is based on mice studies showing that antibiotics-induced gut dysbiosis increased their vulnerability to the influenza virus. Isolating lung immune cells from these mice revealed lower phagocytic activities. Germ-free mice bred in a sterile environment and, thus, lack a gut microbiota were also more likely to die from lung infections.
Would Probiotics Help?
In humans, two meta-analyses of randomized controlled trials (RCTs) have calculated that probiotics could decrease the incidence and duration of respiratory virus infections. In two RCTs, one with 146 and the other with 235 patients on mechanical ventilation, probiotics improved pneumonia outcomes compared to placebo.
Still, “the rationale for using probiotics in COVID-19 is derived from indirect evidence,” Professor Joyce WY Mak and colleagues wrote in the Lancet Gastroenterology and Hepatology after reviewing these meta-analyses and RCTs. Until there’s more direct human data, “blind use of conventional probiotics for COVID-19 is not recommended.”
Other researchers are bolder. “Probiotics are generally safe, even in the most vulnerable populations and in intensive care settings,” David Baud, a professor of obstetrics and gynaecology, and colleagues stated in a review paper in the Frontiers of Public Health. “Rather than consider intensive care patients too ill to receive probiotic and prebiotic therapy, RCTs of probiotics for the prevention of ventilator-associated pneumonia provide a reason to consider them.” They further listed relevant probiotics for consideration during the Covid-19 pandemic.