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Snapshots of Life: Tales from the (Intestinal) Crypt!

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Caption: This “spooky” video ends with a scientific image of intestinal crypts (blue and green) plus organoids made from cultured crypt stem cells (pink). 

As Halloween approaches, some of you might be thinking about cueing up the old TV series “Tales from the Crypt” and diving into its Vault of Horror for a few hours. But today I’d like to share the story of a quite different and not nearly so scary kind of crypt: the crypts of Lieberkühn, more commonly called intestinal crypts.

This confocal micrograph depicts a row of such crypts (marked in blue and green) lining a mouse colon. In mice, as well as in humans, the intestines contain millions of crypts, each of which has about a half-dozen stem cells at its base that are capable of regenerating the various types of tissues that make up these tiny glands. What makes my tale of the crypt particularly interesting are the oval structures (pink), which are organoids that have been engineered from cultured crypt stem cells and then transplanted into a mouse model. If you look at the organoids closely, you’ll see Paneth cells (aqua blue), which are immune cells that support the stem cells and protect the intestines from bacterial invasion.

A winner in the 2016 “Image Awards” at the Koch Institute Public Galleries, Massachusetts Institute of Technology (MIT), Cambridge, this image was snapped by Jatin Roper, a physician-scientist in the lab of Omer Yilmaz, with the help of his MIT collaborator Tuomas Tammela. Roper and his colleagues have been making crypt organoids for a few years by placing the stem cells in a special 3D chamber, where they are bathed with the right protein growth factors at the right time to spur them to differentiate into the various types of cells found in a crypt.

Once the organoids are developmentally complete, Roper can inject them into mice and watch them take up residence. Then he can begin planning experiments.

For example, Roper’s group is now considering using the organoids to examine how high-fat and low-calorie diets affect intestinal function in mice. Another possibility is to use similar organoids to monitor the effect of aging on the colon or to test which of a wide array of targeted therapies might work best for a particular individual with colon cancer.

Links:

Video: Gut Reaction (Jatin Roper)

Jatin Roper (Tufts Medical Center, Boston)

Omer Yilmaz (Massachusetts Institute of Technology, Cambridge)

The Koch Institute Galleries (MIT)

NIH Support: National Cancer Institute; National Institute on Aging


Mouse Study Finds Microbe Might Protect against Food Poisoning

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T mu in a mouse colon

Caption: Scanning electron microscopy image of T. mu in the mouse colon.
Credit: Aleksey Chudnovskiy and Miriam Merad, Icahn School of Medicine at Mount Sinai

Recently, we humans have started to pay a lot more attention to the legions of bacteria that live on and in our bodies because of research that’s shown us the many important roles they play in everything from how we efficiently metabolize food to how well we fend off disease. And, as it turns out, bacteria may not be the only interior bugs with the power to influence our biology positively—a new study suggests that an entirely different kingdom of primarily single-celled microbes, called protists, may be in on the act.

In a study published in the journal Cell, an NIH-funded research team reports that it has identified a new protozoan, called Tritrichomonas musculis (T. mu), living inside the gut of laboratory mice. That sounds bad—but actually this little wriggler was potentially providing a positive benefit to the mice. Not only did T. mu appear to boost the animals’ immune systems, it spared them from the severe intestinal infection that typically occurs after eating food contaminated with toxic Salmonella bacteria. While it’s not yet clear if protists exist that can produce similar beneficial effects in humans, there is evidence that a close relative of T. mu frequently resides in the intestines of people around the world.


Creative Minds: Making a Miniature Colon in the Lab

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Gut on a Chip

Caption: Top down view of gut tissue monolayer grown on an engineered scaffold, which guides the cells into organized crypts structures similar to the conformation of crypts in the human colon. Areas between the circles represent the flat lumenal surface.
Credit: Nancy Allbritton, University of North Carolina, Chapel Hill

When Nancy Allbritton was a child in Marksville, LA, she designed and built her own rabbit hutches. She also once took apart an old TV set to investigate the cathode ray tube inside before turning the wooden frame that housed the TV into a bookcase, which, by the way, she still has. Allbritton’s natural curiosity for how things work later inspired her to earn advanced degrees in medicine, medical engineering, and medical physics, while also honing her skills in cell biology and analytical chemistry.

Now, Allbritton applies her wide-ranging research background to design cutting-edge technologies in her lab at the University of North Carolina, Chapel Hill. In one of her boldest challenges yet, supported by a 2015 NIH Director’s Transformative Research Award, Allbritton and a multidisciplinary team of collaborators have set out to engineer a functional model of a large intestine, or colon, on a microfabricated chip about the size of a dime.


Creative Minds: New Piece in the Crohn’s Disease Puzzle?

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Gwendalyn Randolph

Gwendalyn Randolph

Back in the early 1930s, Burrill Crohn, a gastroenterologist in New York, decided to examine intestinal tissue biopsies from some of his patients who were suffering from severe bowel problems. It turns out that 14 showed signs of severe inflammation and structural damage in the lower part of the small intestine. As Crohn later wrote a medical colleague, “I have discovered, I believe, a new intestinal disease …” [1]

More than eight decades later, the precise cause of this disorder, which is now called Crohn’s disease, remains a mystery. Researchers have uncovered numerous genes, microbes, immunologic abnormalities, and other factors that likely contribute to the condition, estimated to affect hundreds of thousands of Americans and many more worldwide [2]. But none of these discoveries alone appears sufficient to trigger the uncontrolled inflammation and pathology of Crohn’s disease.

Other critical pieces of the Crohn’s puzzle remain to be found, and Gwendalyn Randolph thinks she might have her eyes on one of them. Randolph, an immunologist at Washington University, St. Louis, suspects that Crohn’s disease and other related conditions, collectively called inflammatory bowel disease (IBD), stems from changes in vessels that carry nutrients, immune cells, and possibly microbial components away from the intestinal wall. To pursue this promising lead, Rudolph has received a 2015 NIH Director’s Pioneer Award.


Who Knew? Gut Bacteria Contribute to Malnutrition

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Photo of an African girl with thin limbs and a distended abdomen.

A child suffering from kwashiorkor.
Source: CDC/Phil

Here’s a surprising result from a new NIH-funded study: a poor diet isn’t the only cause of severe malnutrition. It seems that a ‘bad’ assortment of microbes in the intestine can conspire with a nutrient poor diet to promote and perpetuate malnutrition [1].

Most of us don’t spend time thinking about it, but healthy humans harbor about 100 trillion bacteria in our intestines and trillions more in our nose, mouth, skin, and urogenital tracts. And though your initial reaction might be “yuck,” the presence of these microbes is generally a good thing. We’ve evolved with this bacterial community because they provide services—from food digestion to bolstering the immune response—and we give them food and shelter. We call these bacterial sidekicks our ‘microbiome,’ and the latest research, much of it NIH-funded, reveals that these life passengers are critical for good health. You read that right—we need bacteria. The trouble starts when the wrong ones take up residence in our body, or the bacterial demographics shift. Then diseases from eczema and obesity to asthma and heart disease may result. Indeed, we’ve learned that microbes even modulate our sex hormones and influence the risk of autoimmune diseases like type 1 diabetes. [2]


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