Can Mammals "Breathe" Through Their Intestines?

演化之聲
Aug 10
4 min read

For patients with respiratory failure, maintaining adequate oxygen levels in the blood is one of the most urgent priorities in life-saving care. Mechanical ventilation can be used to support pulmonary gas exchange, while patients with extremely severe respiratory failure may require extracorporeal membrane oxygenation (ECMO). Yet some animals have evolved an unusual survival strategy: when oxygen becomes scarce, they can absorb oxygen through their intestines. This led a Japanese research team to ask a bold question: if the lungs of a mammal temporarily fail to provide enough oxygen, could the intestine serve as an additional route for oxygen delivery?

The idea was inspired by animals capable of intestinal respiration, including the dojo loach (Misgurnus anguillicaudatus). Under well-oxygenated conditions, loaches rely primarily on their gills for respiration, but during severe hypoxia, the posterior intestine can participate in gas exchange. This region has a relatively thin epithelial layer and an abundant capillary network, allowing oxygen in the intestinal lumen to reach the circulation more readily. The researchers also noted that the mammalian rectum is covered by a relatively thin mucosal layer and is surrounded by an extensive vascular network. Anatomically, this provides a potential route through which substances in the intestinal lumen could rapidly access the bloodstream.

Loaches can obtain oxygen through their intestines（Image source：Timur Kalininsky， CC BY 4.0 ）

The researchers called this concept enteral ventilation via anus (EVA). They first tested a gas-based approach by delivering pure oxygen directly into the intestines of mice. However, the intact intestinal mucosa of mammals forms an effective barrier that limits oxygen diffusion. To improve gas exchange, the researchers mechanically abraded the mucosa of the distal intestine to a moderate degree, bringing luminal oxygen into closer contact with the blood vessels beneath the mucosal layer.

This treatment markedly improved oxygenation. Under conditions of extreme hypoxia, all mice that received no intestinal ventilation died, with a median survival time of less than 11 minutes. Mice that received intestinal oxygen while retaining an intact mucosa survived for a median of approximately 18 minutes. Among mice that underwent moderate mucosal abrasion before receiving gas-based EVA, 75% were still alive after 50 minutes.

These findings demonstrated that oxygen can indeed pass from the distal intestine of a mammal into the systemic circulation, and that under severe hypoxic conditions, this route can provide enough oxygen to influence survival. From a clinical perspective, however, deliberately abrading the rectal mucosa to facilitate oxygen uptake would clearly be impractical. The researchers therefore turned to another strategy that could enhance gas exchange while leaving the intestinal mucosa intact.

Their solution was perfluorodecalin (PFD), a type of perfluorocarbon with a remarkable capacity to carry dissolved gases. PFD can dissolve substantial amounts of oxygen and can also carry carbon dioxide. The researchers bubbled pure oxygen through the liquid until it became highly oxygenated and then administered the oxygen-loaded PFD into the rectum. This approach was termed liquid-based EVA (l-EVA).

Molecular structure of perfluorodecalin（Image source：Snubcube，CC0 1.0 ）

When hypoxic mice received oxygen-loaded PFD, their condition improved rapidly. Hypoxia normally caused a pronounced reduction in activity, but mice treated with oxygenated PFD showed a significant increase in walking distance. Continuous monitoring of oxygen saturation also showed that the improvement in oxygenation could be maintained for at least 60 minutes. Even 120 minutes after treatment, the partial pressure of oxygen in the inferior vena cava remained approximately 9.4 mmHg higher than in control animals, while the difference in oxygen partial pressure in blood from the left ventricle reached approximately 23.8 mmHg.

The researchers then extended the experiment to pigs, a much larger mammalian model. The animals were placed under hypoventilation to induce hypoxia, after which 400 mL of oxygen-loaded PFD was administered into the rectum. Following treatment, oxygen saturation increased from an average of approximately 66.6% to 81.8%, while arterial oxygen partial pressure rose from about 57.2 mmHg to 70.8 mmHg. Once the oxygen carried by the PFD had been depleted, the liquid could be removed and replaced with a fresh dose of oxygen-loaded PFD, allowing the oxygenation cycle to be repeated.

The animals treated with oxygen-loaded PFD also showed a tendency toward lower blood carbon dioxide partial pressure. The researchers suggested that this may reflect the strong capacity of perfluorocarbons to carry both oxygen and carbon dioxide. If this mechanism is confirmed in future studies, PFD within the intestine may potentially contribute not only to oxygen delivery but also to the removal of excess carbon dioxide.

Turning such an unusual physiological phenomenon into a medical technology also requires careful evaluation of safety. The researchers therefore repeatedly administered PFD to rats. Even when the animals received six administrations per day, no obvious diarrhea or dehydration was observed during the short-term study period. Measurements of blood cells, albumin, electrolytes, and several markers of liver and tissue injury likewise showed no abnormal changes suggesting major systemic toxicity.

The concentration of PFD detected in the blood remained below the study's lower limit of quantification. Pathological examination of the intestine, liver, bile ducts, and spleen in pigs and rats also found no evidence of the characteristic tissue changes associated with systemic PFD absorption and accumulation. In addition, bacterial endotoxin levels in the blood of mice and pigs remained below the detection limit, providing no evidence that the procedure caused substantial bacterial translocation from the intestine during the period examined.

Based on the results obtained in pigs, the researchers further estimated how the approach might scale to humans. If a 60-kg person were to achieve a similar efficiency of intestinal gas exchange, approximately 600–1,200 mL of oxygen-loaded PFD might provide a clinically meaningful improvement in oxygenation. This remains an extrapolation from animal experiments and has not yet been demonstrated in humans.

If the technique can eventually be developed into a safe and effective clinical procedure, potential applications could include conditions requiring rapid supplemental oxygenation, such as acute asthma attacks, airway stenosis, neonatal asphyxia, and acute respiratory failure. Its most plausible role would be as a short-term adjunctive means of oxygenation—a temporary additional route for supporting patients when conventional pulmonary gas exchange is severely compromised.