Crohn’s Disease: Cause Finally Revealed!

If you have Crohn’s, or perhaps someone close to you has it, then you’ll be familiar with the common medical refrain of “we don’t know”.

While this honesty is laudable, it’s not reassuring. So, it’s good that researchers in recent years have been making progress in understanding such things as why many people with Crohn’s may respond differently not only to lifestyle interventions, but also to various relevant drugs—allowing doctors to gradually get better at prescribing the right treatment for the right person.

For example, last year, researchers (Dr. Pradipta Ghosh et al.) created gut organoids from adult stem cells taken directly from Crohn’s patients during colonoscopies. Unlike organoids made from reprogrammed pluripotent stem cells, these retained the “epigenetic memory” of each patient’s gut—its microbial history, inflammation patterns, and oxygen/pH conditions—allowing a faithful replication of the disease environment.

Learn more: A living organoid biobank of patients with Crohn’s disease reveals molecular subtypes for personalized therapeutics

That didn’t tell us the cause, though. But now…

When macrophages go wrong

Dr. Ghosh didn’t stop there; she assembled another team, and—by analysing thousands of macrophage gene expression profiles—identified a 53-gene signature that distinguishes inflammatory macrophages from healing ones—pinpointing girdin (a particular kind of protein) as a critical player in this process.

Let’s back up slightly and explain:

Macrophages are part of the immune system, specialist white blood cells that “eat” things that need to be removed. There are two kinds, inflammatory and non-inflammatory. The former aggressively “eat” invaders. The latter are more like cellular janitors.

In Crohn’s disease, the balance of these two kinds of macrophage becomes imbalanced, and guess which kind goes on the rampage. If you guessed “not the janitors”, you guessed correctly.

But why exactly they become imbalanced has been a mystery until now, and where science doesn’t understand the cause, it’s difficult to treat anything deeper than the symptoms.

Now we know: in a healthy gut, NOD2 gene binds to girdin in non-inflammatory macrophages, helping them suppress inflammation and promote tissue repair. The most common Crohn’s-linked mutation deletes the part of NOD2 that connects to girdin, disrupting this balance and allowing chronic inflammation to take over.

This discovery was made by very complex statistical modelling, but then it was tested empirically:

How, you ask? Mice bred without the girdin protein developed intense gut inflammation, gut microbiome disruption, and (often fatal) sepsis, confirming the NOD2-girdin connection in maintaining intestinal immune balance.

You can read about this here: Distinct colitis-associated macrophages drive NOD2-dependent bacterial sensing and gut homeostasis

You may be wondering: great, but what am I supposed to do if I have this mutation?

And well, it’s still a case of doing what we can to dial down the inflammation (see for example: How to Prevent (or Reduce) Inflammation)

However, armed with more knowledge, knowing that this has to do with gut dysbiosis, then we can now also focus on addressing that directly, for example: How Much Difference Do Probiotic Supplements Make, Really?

And in order for those probiotics to actually work, see: Stop Sabotaging Your Gut

“But I can’t eat fibrous foods, it all flares up!”, we here you (validly) cry.

…and unfortunately, that changes everything, in terms of what’s usually considered healthiest for most people, i.e. a whole-foods majority plant-based diet.

What stays the same:

• You still ideally want to eat a lot of plants
• You definitely want to avoid meat and dairy in general
• Eating fish is still usually fine, same with eggs
• Get plenty of water

What needs to change:

• Consider swapping grains for potatoes or pasta (at least: avoid grains)
• Peel vegetables that are peelable; discard the peel or use it to make stock
• Consider steaming fruit and veg for easier digestion
• Skip spicy foods (moderate spices, like ginger, turmeric, and black pepper, are usually fine in moderation)

Much of this latter list is opposite to the advice for people without Crohn’s Disease.

To that end, if you take probiotics supplements that come with their own tiny-but-right-there supply of prebiotic fiber (such as inulin), that will probably be enough to help your probiotics “take”, without simultaneously setting your macrophages off because you just fed your entire gut microbiome at once with a big meal full of fiber.

Here’s an example product on Amazon, but by all means feel free to shop around, and if you’re working with a dietician, do discuss it with them, of course.

Take care!