Researchers Find Evidence That Mammals Can Use Their Intestines To Respire

A new study published in the journal Med suggests that rodents and pigs possess the ability to use their intestines for respiration.¹

Lessons from gut air breathing fish

In warm climates, such as South America, water environments can be subject to varying oxygen levels. Factors such as decreasing water levels, low depth, increasing microbial respiration and vertical mixing can cause a reduction in the amount of oxygen present in the water, such that it becomes hypoxic.²

To ensure their survival in lower levels of oxygen, aquatic inhabitants of such waters have evolved unique respiratory mechanisms whereby a portion of their intestine is used as an accessory air-breathing organ.^3,4 One example is the Neotropical catfish, Cordoras paleatus, which originates from the Paraná River, the second longest river in the world. This phenomenon has been extensively explored in aquatic organisms.

Research has also studied whether mammals are capable of intestinal breathing, but this has been heavily debated. "[Previously] several attempts were made to explore intestinal breathing using gas infusion via the stomach or the upper GI tract with marginal efficacy, but were discontinued," says Professor Takanori Takebe of the Tokyo Medical and Dental University and Cincinnati Children's.

Takebe is the senior author of a novel study published in the journal Med that exploited enteral ventilation via the anus (EVA) to explore whether mammals had evolved an additional site for gas exchange other than the lungs. "We provide evidence for intestinal breathing in both mice and pigs by devising a liquid ventilation-based system, termed EVA," he says.

Distal gut a site for gas exchange in mammals?

"The mammalian rectum represents a body cavity covered by a relatively thin mucosal layer, particularly around the anal canal, in which abundant vascular drainage is made possible through hemorrhoidal plexuses connected both with the portal and the systemic circulation," the authors write in the study.

They therefore hypothesized that the distal gut could be a site that enables efficient access to submucosal blood vessels for gas exchange in mammals. To explore this, they infused either oxygen gas (a method termed gEVA) or oxygen carrying liquid (known as perfluorocarbon), known as I-EVA, intra-anally in two models of hypoxia and respiratory failure in pigs and mice. The scientists also used a rat model for the purpose of conducting safety analysis. "This is the most standard model for safety in pharmaceutical development," Takebe says.

How do gEVA and I-EVA differ? "gEVA requires mucosal abrasion for providing sufficient support whereas l-EVA can provide efficacy with intact gut," Takebe explains. The team's choice of exploring two methods for oxygen infusion links to their consideration of how this research could potentially translate to humans one day. Intrapulmonary application of perfluorocarbon, either in liquid or aerosol form, is FDA approved and used to reduce lung injury in pediatric cases of severe respiratory issues. If another site of the human body is able to conduct gas exchange, the discovery could have a profound impact on the treatment methods currently adopted for respiratory failure. Takebe discusses this in reference to the current COVID-19 global pandemic: " We favor l-EVA for immediate translational opportunity given the growing tragic loss in some countries, like India, due to limited ventilator/ECMO access."

Collectively, the study results demonstrate that both gEVA and I-EVA were able to provide rescue in the experimental models of respiratory failure, improving survival, behavioral traits such as mobility and systemic oxygen levels. "A rodent and porcine model study confirmed the tolerable and repeatable features of an enema-like l-EVA procedure with no major signs of complications," the researchers write.

Translation to humans

The authors acknowledge that a limitation to their study is the that it involves pre-clinical animal models. In addition, they emphasize that whilst the study evaluated short-term safety of the methods, it will be important to assess mid-long term safety cautiously.

Speaking of the potential utility of such a method for treating respiratory diseases such as COVID-19, Takebe said, "Although gut breathing methods can potentially benefit a condition like COVID-19 with severe respiratory problem[s], we need to cautiously evaluate the safety of this process as COVID-19 has very complicated pathogenesis including inflammation and coagulation problems."

The research group's next steps will involve conducting precise safety analysis and regulatory discussions for conducting a clinical trial, Takebe informs Technology Networks.

Takanori Takebe was speaking to Molly Campbell, Science Writer for Technology Networks.

References:

1.      Okabe R, Chen-Yoshikawa TF, Yoneyama Y et al. Mammalian enteral ventilation ameliorates respiratory failure. Med. 2021.  doi: 10.1016/j.medj.2021.04.004.

2.      Petry AC, Abujanra F, Gomes LC, Julio Jr. HF, Agostinho AA. Effects of the interannual variations in the flood pulse mediated by hypoxia tolerance: the case of the fish assemblages in the upper Paraná River floodplain. Neotrop. ichthyol. 2013;11:413-424. doi.org/10.1590/S1679-62252013005000008.

3.      Plaul SE, Pastor R, Díaz AO, Barbeito CG. Immunohistochemical and ultrastructural evidence of functional organization along the Corydoras paleatus intestine. Microscopy Research and Technique. 2016;79(3):140-148. doi:10.1002/jemt.22614.

4.      Nelson JA. Breaking wind to survive: fishes that breathe air with their gut. Journal of Fish Biology. 2014;84(3):554-576. doi:10.1111/jfb.12323.