It was the late 1800s when Elie Metchnikoff made one of the most important observations in the history of immunology. While investigating the behavior of various cells under a microscope, he noted that some of them spend much of their time devouring things from their surroundings. Whatever he presented to them, from foreign particles to other cells, these gourmands gobbled down indiscriminately. This striking finding shaped the rest of Metchikoff’s scientific journey; he spent the following decades extensively investigating the cells we now know as macrophages (from Greek macro – “large” and phage – “eater”) and hypothesizing about their fundamental importance for our health.

A century later, macrophages remain a major focus of biomedical research. Since their initial discovery, these “big eaters” have been shown to be extremely versatile; from modulation of the heartbeat to regulation of bowel movements, they have turned out to take on distinct roles at the different sites of the body.

This year, scientists discovered yet another novel function of macrophages: a study published in the journal Cell reports that macrophages living in the gut stretch their cellular limbs to get a taste of the fluid in the intestine, monitoring it for harmful fungi-produced toxins. The study is not only a significant advancement in our understanding of these cells’ functions, but it is also a welcomed contribution to a topic that scientists know relatively little about – how our bodies interact with the fungal microbiome found in our guts.

Fluid absorption: from the gut to the blood (and beyond)

You might have heard that you should drink four to six glasses of water a day; after all, staying hydrated is really important for your health. What you might not be aware of is that, in itself, drinking a lot of fluids is not enough. To be used by the body, the water that enters your mouth must travel down the esophagus and into the intestine. There, the water is absorbed through the gut wall and makes its way to the bloodstream, allowing it to travel to various tissues of the body.

This process of water absorption is a highly regulated one. The primary cells in charge of this task are the cells that compose the intestinal epithelium, or the wall of your gut. In response to changing conditions in the intestine, these so-called absorptive cells fine-tune the amount of fluids that traverse the gut wall and the rate at which this absorption happens.

Microbial products: the danger from within

If you’ve ever had to rush to the bathroom after eating food that went bad, you’ve experienced first-hand how important this fine-tuning by intestinal epithelial cells is. The absorption regulators must constantly monitor the conditions in the gut and adjust the movement of fluid through the gut wall accordingly. One condition that requires alteration of water absorption, for instance, is the detection of harmful substances in the fluids in the gut. Disregarding the presence of such toxins could have dire consequences; their absorption could result in disturbances of the intestinal epithelium as well as more serious effects on the whole body.

And the word toxins here doesn’t necessarily refer to deadly substances such as cyanide or ricin. Potentially noxious compounds can be found not only around us, in the food we eat for instance, but also within us – they can be produced by our microbiome. If absorbed into the bloodstream, these harmful substances produced by bacteria, viruses, and especially fungi that inhabit our guts could make us quite sick. The mechanisms in place to make sure that doesn’t happen have been largely unknown, until now.

Macrophages taste the waters to protect the gut against fungal toxins

That’s where we return to the heroes of our story – macrophages. These cells, present in the gut in high numbers, have been found in close proximity to the intestinal epithelium, suggesting the two cell types could potentially interact.

Given these facts, scientists from Institut Curie in France wondered if the gut macrophages could be involved in the regulation of fluid absorption by the intestinal epithelium.

To test the hypothesis, the authors turned to laboratory animal models, specifically mice that lack macrophages. If these cells are important for monitoring the fluids in the gut for the presence of toxins, they reasoned, then their absence should affect the absorptive gut cells and lead to altered water absorption.

When the researchers investigated the intestines of the mice lacking macrophages, they found lots of dying intestinal epithelial cells – a concerning observation that pointed to their importance in maintaining the health of the gut epithelium (Figure 1). Moreover, when they measured water absorption in these animals, they discovered it, too, was abnormal. The mice deficient in macrophages absorbed more water than the regular animals, suggesting that these cells are involved in determining the fate of the ingested fluids.

To better understand the role of the “big eaters” in the protection of the intestinal epithelium and regulation of water absorption, the authors turned to microscopy. What they saw when they zeroed in on the macrophages in the vicinity of the intestinal epithelial cells was quite a surprise. Rather than assume their typical shape, characterized by fine projections stretching out of the cell bodies, these cells formed bulging protrusions resembling balloons. These cellular balloons extended towards the intestinal epithelium, wrapping tightly around the cells of the gut wall. Inside these ballooning projections, the macrophages accumulated water which, the researchers showed, was likely acquired from the intestinal epithelial cells.

Taken together, the findings paint the following picture: in the intestine, macrophages extend their balloon-shaped cellular limbs to sample fluids from the absorptive intestinal epithelium. In their absence, the fluids run unchecked, leading to rampant absorption and the death of the cells of the gut wall. 

But what is it about the unmonitored fluids that kills the epithelial cells? What are the macrophages monitoring the fluids for, exactly?

The answer to these questions came from the analysis of germ-free mice, or mice lacking all bacteria, viruses, and fungi. When the authors zoomed in on the intestines of these animals, they observed no balloon-like protrusions. This somewhat serendipitous finding pointed to a potential role of these macrophages’ cellular extensions in checking the fluids for harmful compounds derived from microorganisms found within. When the scientists probed further to find out what specifically the “big eaters” were on the lookout for, they discovered it was the toxins of fungal origin that the cells sensed. By stretching their balloon-like cellular limbs and tasting the water in the gut, macrophages make sure no harmful substances produced by fungi make it through, thereby protecting the mice from their toxic effects (Figure 2).

Whether disruption of this process underlies certain gastrointestinal disorders such as Ulcerative Colitis or Crohn’s disease is currently unknown, a question the scientists are actively investigating. What is clear is that Elie Metchnikoff was right; whether they feast on foreign particles or simply taste the intestinal waters, macrophages are indeed indispensable for our health.