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The Microbiome Conundrum

Why is it so hard to show causality between the microbiome and immune system?

Key points

  • Microbes and inflammatory diseases are highly correlated.
  • Specific causality is difficult to ascertain due to feedback effects.
  • Nevertheless, dietary interventions can work to break a vicious cycle.

“Big data cannot yield complicated descriptions of causality. Especially in healthcare. Almost all of our diseases occur in the intersections of systems in the body.” —Clayton M. Christensen

Who's in charge here?

The collection of microbes that colonize our colon—our microbiome—is a marvelous buffer against the ravages of nature. If we could guide those microbes, we might be able to prevent or cure dozens of intractable inflammatory diseases, including arthritis, heart disease, diabetes, and dementia.

But there is feedback between gut microbes and inflammation that complicates an already challenging issue. We know that an unhealthy gut microbiome can cause systemic inflammation. But inflammation can also wipe out gut microbes, potentially making things worse.

The microbiomes of some unhealthy people seem to be unbalanced or “dysbiotic,” but no one really knows exactly what that means. Given our ignorance, how can we take advantage of the power of the microbiome?

Embracing Our Ignorance

What we do know is that the greater the microbial diversity, the less inflammation. It’s not much to go on, but it’s a start. It implies that we could encourage a healthy microbiome with a highly varied diet of fiber-filled veggies and fruit.

There may be some identifiable villains. Some bacterial families, such as Enterobacteriaceae, are found lurking in greater numbers in inflammatory conditions. This family includes such notables as Salmonella, E. coli, Shigella, Enterobacter, Citrobacter, and Klebsiella. Most of these have flagella, so they can swim to attractive targets, like the mucus that coats our gut from stem to stern. They also have fimbria, which are like tiny grappling hooks these microbes use to attach themselves to human cells. One other feature: They love sweets.

The outer membrane of these microbes is composed of fat and sugar. The fatty part is a lipid that helps to create the membrane, and the sugar part forms threads resembling cotton candy hair on the bacteria. This bacterial building block is called lipopolysaccharide (LPS) in honor of its two main components.

When one of these microbes dies, the membrane breaks up into LPS molecules that are well-known to the immune system. We have battled these microbes long enough to have LPS detection baked into our genes, as part of our innate immune system.

If you inject someone with LPS, within minutes, they will become highly anxious and run a fever. In sufficient doses, they will become septic. In lower doses, chronic exposure to LPS is associated with a host of diseases, including depression and anxiety.

It’s Complicated

But correlation is not causation, and therein lies the conundrum.

When the immune system discovers LPS, it can heavy-handedly attack bacteria in the intestines. When a bacterium enters a gut cell, the immune system doesn’t politely go in after it. Instead, it destroys the cell outright, killing both the intruder and the hostage. In this way, the immune system can inadvertently create a leaky gut.

Bacteria that produce LPS can then breach the gut lining and enter the bloodstream. From there, they can take their pick of tissues to colonize. These displaced gut microbes spur the immune system into further action, escalating the war and leading to systemic inflammation. This becomes a feedback loop where bacteria and immune cells take turns making us sick.

So does the microbiome shape the immune response, or does the immune system shape the microbiome? The answer is yes.

It would all end well if the immune system could wipe out the pathogens and declare victory. But as long as we diligently feed those pathogens, an endless battle is guaranteed.

The Gut-Brain Axis is Also a Cycle

There’s more: The gut and the brain are connected by the vagus nerve. Communications from the gut microbiome travel up the vagus to alert the brain to irregularities. You are not always directly aware of problems in your gut, but they often manifest as anxiety or depression.

The vagus, however, is a two-way channel, and the brain can talk back to the gut, affecting hormones and the immune system. So once again, the back and forth makes it tricky to show causality.

These problems are not due to experimental flaws; they are intrinsic to the way the microbiome has taken up residence in our bodies. There is an essential circularity to our cohabitation with microbes. That cycle can be virtuous or vicious. And for better or worse, it is pretty stable.

However, it is still possible to disrupt the cycle. While it is difficult to block the immune system, it is easy to derail the microbiota: Simply stop feeding the bad bacteria and start feeding the good. That means easing sugar out of the diet and substituting prebiotic fiber. Within a few days, the ecology of the gut should diversify and become healthier.

Fiber-consuming bacteria produce butyrate, a small molecule that nourishes and heals your gut lining, plugging the leaks. With bacteria where they belong, the immune system will stand down, and your precious tissues will no longer be under attack.

In Sum

In biology, nothing is simple. Evolution works by continuously layering new features over the existing chassis. The concept of recruiting your own set of microbes to protect you from other microbes is a perfect example of this tendency.

Biology is complex because the world is full of novelty, and much of it would like to eat you. The only way to keep up is to acknowledge it and go with the flow, not against it. There are no guarantees in life, but a diet rich in diverse veggies and berries is a healthy start.


Walker, A.W., Hoyles, L. Human microbiome myths and misconceptions. Nat Microbiol 8, 1392–1396 (2023).

Patil, Abhinandan, and Neha Singh. “Microbiota Modulation: Examining the Effects on Pathogen Colonization and Infection.” Preprints, July 17, 2023.

Schneider, Tamar. “The Microbiome Function in a Host Organism: A Medical Puzzle or an Essential Ecological Environment?” Biological Theory, March 27, 2023.

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