Summary: Staphylococcal enterotoxin, a bacterial toxin implicated in some ARDS cases, can be prevented by treatment with the cannabis compound THC. Findings also suggest a potential role for using cannabinoids to treat ARDS caused by COVID-19.
Source: University of South Carolina
Acute Respiratory Distress Syndrome (ARDS), when caused by a bacterial toxin known as Staphylococcal enterotoxin, can be completely prevented by treatment with Δ9-tetrahydrocannabinol (THC), a cannabinoid found in the cannabis plant. This exciting finding, recently published in the highly cited British Journal of Pharmacology, also suggests a possible treatment for ARDS caused by COVID-19.
This new paper is based on research studies from the laboratories of Dr. Mitzi Nagarkatti and Dr. Prakash Nagarkatti at the University of South Carolina (UofSC) School of Medicine, Department of Pathology, Microbiology and Immunology. The Nagarkattis published “Protective Effects of Δ9-Tetrahydrocannabinol Against Enterotoxin-induced Acute Respiratory Distress Syndrome is Mediated by Modulation of Microbiota,” with co-authors Amira Mohammed, Hasan Alghetaa and Juhua Zhou, who also work in their UofSC School of Medicine laboratories, and Saurabh Chatterjee from the UofSC Arnold School of Public Health. Drs. Mitzi and Prakash Nagarkatti have for years studied how plant-derived compounds can be used to prevent and reduce inflammation throughout the body.
The incidence of ARDS in the United States is 78.9 per 100,000 persons/year and the mortality rate is 38.5 percent. When inhaled, Staphylococcal enterotoxin can cause ARDS by activating immune cells to produce massive amounts of cytokines leading to “cytokine storm,” which can cause the lungs and other organs to fail, often resulting in death. This immune process is similar to that seen in patients with severe COVID-19 who are admitted to the hospital and develop ARDS accompanied by cytokine storm, which leads to respiratory and multi-organ failure. These studies therefore raise the exciting possibility of using cannabinoids to treat ARDS seen in COVID-19 patients.
These studies also showed that Staphylococcal enterotoxin alters the microbiome in the lungs leading to the emergence of pathogenic microbiota. But THC helps this symptom too, by promoting beneficial bacteria that suppress inflammation thereby preventing the damage to the lungs.
“Acute respiratory distress syndrome is triggered by a variety of etiologic agents. Currently, there are no FDA-approved drugs to treat ARDS because of which the mortality rate is close to 40 percent. Our studies suggest that THC is highly effective to treat ARDS and thus, clinical trials are critical to investigate if this works,” said Mitzi Nagarkatti.
“Cytokine storm is a huge clinical issue which leads to multiorgan failure and often death. It is also seen in COVID-19 patients, and there are no effective treatment modalities against this syndrome. We have been working on cannabinoids for over 20 years and found that cannabinoids such as THC are highly anti-inflammatory. Thus, our studies raise the exciting suggestion to test THC against ARDS seen in COVID-19 patients,” said Prakash Nagarkatti.
The Nagarkatti laboratory has performed decades of pioneering studies on cannabinoids. In fact, their studies on the use of another cannabinoid derived from the cannabis plant, cannabidiol (CBD), to treat autoimmune hepatitis have been well-recognized in the field and have led to FDA approval of CBD as an orphan drug to treat this disorder.
The Nagarkatti Laboratory has published extensively to demonstrate that cannabinoids are potent anti-inflammatory agents that can be used safely to treat a variety of inflammatory and autoimmune diseases such as multiple sclerosis, colitis, hepatitis and the like.
Protective Effects of Δ9‐Tetrahydrocannabinol Against Enterotoxin‐induced Acute Respiratory Distress Syndrome is Mediated by Modulation of Microbiota
Background Staphylococcal enterotoxin‐B (SEB) is one of the most potent bacterial superantigens that exerts profound toxic effects by inducing cytokine storm. When SEB is inhaled, it can cause Acute Respiratory Distress Syndrome (ARDS), which is often fatal and currently there are no effective treatment modalities.
Experimental Approach We used mouse model of SEB‐mediated ARDS to test the efficacy of Δ9‐tetrahydrocannabinol (THC). These mice were monitored for lung inflammation, alterations in gut and lung microbiota and production of short‐chain fatty acids (SCFA). Gene dysregulation of lung epithelial cells was studied by transcriptome arrays. Fecal microbiota transplantation (FMT) was performed to confirm the role of microbiota in suppressing ARDS.
Key results While SEB triggered ARDS and 100% mortality in mice, THC protected the mice from fatality effects. Pyrosequencing analysis revealed that THC caused significant and similar alterations in microbiota in the lungs and gut of mice exposed to SEB. THC significantly increased the abundance of beneficial bacterial species, Ruminococcus gnavus, but decreased pathogenic microbiota, Akkermansia muciniphila. FMT confirmed that THC‐mediated reversal of microbial dysbiosis played crucial role in attenuation of SEB‐mediated ARDS. THC treatment also led to increase in SCFA, of which propionic acid was found to inhibit the inflammatory response. Transcriptome array showed that THC up‐regulated several genes like lysozyme‐1&2, β‐defensin‐2, claudin, zonula‐1, occludin‐1, Mucin2 and Muc5b while downregulating β‐defensin‐1.
Conclusions Current study demonstrates for the first time that THC attenuates SEB‐mediated ARDS and toxicity by altering the microbiota in the lungs and the gut as well as promoting anti‐microbial and anti‐inflammatory pathways.