Endocannabinoid Anandamide Attenuates Acute Respiratory Distress Syndrome through Modulation of Microbiome in the Gut-Lung Axis.

Muthanna Sultan,Osama A Abdulla,Alina Hall,Taylor Carter,Narendra Singh,Saurabh Chatterjee,Mitzi Nagarkatti,Kiesha Wilson,Prakash Nagarkatti,Philip Brandon Busbee

doi:10.3390/cells10123305

Abstract

Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.

Highlights

Acute respiratory distress syndrome (ARDS) is defined as a form of respiratory failure that is caused by a variety of insults, including pneumonia, sepsis, trauma, and certain viral infections [1,2]
Recent studies have shown that the diversity of the gut microbiota may be regulated by endocannabinoids [19,26]. This raises an important question of whether endocannabinoids can alter the microbiota in the gut and the lungs during ARDS, thereby providing increased protection from pathogenic bacteria as well as suppressing hyperinflammation. We tested this hypothesis and our results demonstrated that AEA-mediated attenuation of Staphylococcus enterotoxin B (SEB)-induced ARDS may result from causing an increased abundance of beneficial bacteria that produce short-chain fatty acids (SCFAs) that are anti-inflammatory and by inducing antimicrobial peptides (AMPs) and tight junction proteins that prevent the emergence of pathogenic bacteria
We analyzed for the expression of IL-6, a key cytokine induced during ARDS by SEB [36], and found that it was highly induced following SEB treatment and was significantly attenuated following treatment with AEA both in the serum (Figure 1D) and Broncho Alveolar Lavage Fluid (BALF) (Figure 1E)

Summary

Introduction

ARDS is defined as a form of respiratory failure that is caused by a variety of insults, including pneumonia, sepsis, trauma, and certain viral infections [1,2]. One of the common features of ARDS is the hyperactivation of the immune response, systemically and in the lungs, leading to the development of pulmonary edema, alveolar damage, and respiratory failure [3]. ARDS is considered to be a major worldwide health problem in the field of clinical respiratory medicine [4]. ARDS affects approximately 200,000 patients every year in the United States and causes over 75,000 deaths annually [5,6]. ARDS, and nearly 37% of ARDS patients die annually. 10% of intensive care unit admissions represent ARDS cases, which accounts for over 3 million patients annually [7]

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