Rodents and pigs share with certain aquatic organisms the ability to use their intestines for respiration, finds a study publishing May 14th in the journal Med. The researchers led by Dr. Takanori Takebe from Tokyo Medical and Dental University and Cincinnati Children’s Hospital Medical Center demonstrated that the delivery of oxygen gas or oxygenated liquid through the rectum provided vital rescue to two mammalian models of respiratory failure.

“Artificial respiratory support is critical in the clinical management of respiratory failure due to severe illnesses such as pneumonia or acute respiratory distress syndrome,” says Dr. Takebe. “While the side effects and safety in humans must be thoroughly evaluated, our approach may offer a new paradigm for supporting critically ill patients with respiratory failure.”

Several aquatic organisms have evolved unique intestinal breathing mechanisms that use organs other than the lungs or gills to survive in low-oxygen environments. Sea cucumbers, freshwater loaches, and particular freshwater catfish, for example, use their intestines for breathing. However, whether mammals have similar abilities has been hotly debated.

Dr. Takebe and his colleagues present evidence for intestinal breathing in rats, mice, and pigs in their new study. First, they devised an intestinal gas ventilation system to deliver pure oxygen to mice via the rectum. They demonstrated that no mice survived 11 minutes of highly low-oxygen conditions without the system. More oxygen reached the heart with intestinal gas ventilation, and 75% of mice survived 50 minutes of usually lethal low-oxygen conditions.

Because the intestinal gas ventilation system necessitates abrasion of the intestinal mucosa, it is unlikely to be clinically feasible, particularly in critically ill patients, so the researchers also developed a liquid-based alternative based on oxygenated perfluorochemicals. These chemicals have already been clinically proven to be biocompatible and safe for humans.

Rodents and pigs exposed to non-lethal low-oxygen conditions benefited from the intestinal liquid ventilation system. Mice that received intestinal ventilation could walk farther in a 10% oxygen chamber, and more oxygen reached their hearts than mice that did not receive intestinal ventilation. Pigs produced similar results. Intestinal liquid ventilation reversed skin pallor and coldness while increasing oxygen levels without causing apparent side effects. In two mammalian model systems, the results show that this strategy effectively provides oxygen that reaches circulation and alleviates respiratory failure symptoms.

The researchers plan to expand their preclinical studies and pursue regulatory steps to accelerate the path to clinical translation with support from the Japan Agency for Medical Research and Development to combat the coronavirus disease 2019 (COVID-19) pandemic.

“The recent SARS-CoV-2 pandemic has overwhelmed the clinical need for ventilators and artificial lungs, resulting in a critical shortage of available devices and endangering patients’ lives around the world,” Dr. Takebe says. “If scaled for human application, the level of arterial oxygenation provided by our ventilation system is likely sufficient to treat patients with severe respiratory failure, potentially providing life-saving oxygenation.”

Journal Reference:

Ryo Okabe, Toyofumi F. Chen-Yoshikawa, Yosuke Yoneyama, Yuhei Yokoyama, Satona Tanaka, Akihiko Yoshizawa, Wendy L. Thompson, Gokul Kannan, Eiji Kobayashi, Hiroshi Date, Takanori Takebe. Mammalian enteral ventilation ameliorates respiratory failure. Med, 2021; DOI: 10.1016/j.medj.2021.04.004

About the Author

Takanori Takebe, MD, Ph.D.

Dr. Takebe is an Assistant Professor at the Cincinnati Children’s Hospital Medical Center and Associate Professor at Yokohama City University, Japan. His lab is developing and applying mini-organ technologies from human stem cells – namely organ bud transplants – in patients with a rare congenital metabolic disorder, ultimately expanding the clinical applications to diseases like liver cirrhosis. He completed his postdoctoral studies at Yokohama City University, Japan.