Pandas are lazy!

Pandas are closely related to carnivorous mammals (like all the other bears), but they consume mostly bamboo.  Their digestive tracts are short and adapted for digesting meat, not cellulose that is found in plants.  In fact, they only digest about 20% of all the bamboo they eat, and they eat a lot of bamboo (30-60 pounds a day)!  How are these large, adorable bears able to get enough energy to function from their inefficient digestion of bamboo?  Researchers in China and Scotland addressed this question by studying captive and wild pandas, described in a recent Science article.

Low energy expenditure

Nie et al. measured the daily energy expenditure of the pandas and found that they used an unusually low amount of energy, only 37.7% of the predicted value based on their body mass.  In fact, pandas are expending energy at levels similar to the three-toed sloth, the epitome of a low-energy mammal.  The measly amount of nutrients they get from all that bamboo would be able to sustain such a low energy expenditure, so that’s how the panda is able to get by with such a maladapted digestive system.

How do the pandas manage to spend so little energy?  There must be some adaptations that are allowing the panda to survive without expending so much energy.  The authors found a number of these adaptations:

1) Pandas have a thick layer of fur, so they can maintain their internal body temperature with less heat loss through the skin.  The researchers measured temperature at the surface of various animals and the pandas consistently were cooler than other mammals (like a cow or dog).  Their internal body temperature would be considerably warmer because the fur helps insulate them, so they don’t have to spend as much energy on maintaining their body temperature.

2) Pandas are lazy.  No surprise: pandas spend more time inactive and when they do move, it is slowly.  So that is less energy needed for muscle contractions.

3) Pandas have small brains, livers and kidneys, so their organs need less energy.

4) Pandas have a low resting metabolic rate, which is driven by the thyroid hormones, T3 and T4.  In fact, levels of these two hormones were considerably lower than for other mammals of the same body mass, even lower than a hibernating bear.  The thyroid hormones regulate protein, carbohydrate and fat metabolism, as well as growth and development.  If the pandas don’t need to produce as much heat or energy, then there is no reason to have a high metabolic rate.

Interestingly, pandas have a single mutation in a gene called DUOX2, which is not found in any other mammals.  DUOX2 encodes for a protein that is necessary for the production of T3 and T4.  The mutation causes a premature “stop” in the protein, so it likely affects the function of DUOX2. 

In other words, pandas cannot synthesize T3 and T4 as well because of this mutation, so they have a reduced metabolic rate.  But that’s okay, because they are good at maintaining their body temperature and they have developed an enjoyable lifestyle of relaxing and eating.  The fact that their digestive tracts have not evolved for plant digestion is alright given the fact that they don’t really need that much energy from their food.  So it all works out: pandas are able to survive on their diet of bamboo and we can watch them sit around.

Probiotics for autism

The human microbiome is a hot topic in biology these days.  It is becoming clear that the microbes living in and on our body can have major consequences for our health and happiness.  In fact, abnormalities in the gut microbiome may underlie one of the great medical mysteries of our time: autism.   That some bacteria in our intestines could affect our behaviors and brain development is mind blowing.

Hsiao et al. recently published a study in the journal Cell that investigated the connection between the gut microbiome and autism using a mouse model of autism.  They were drawn to this subject based on the fact that individuals with autism spectrum disorder (ASD) often have gastrointestinal abnormalities, like irritable bowel syndrome and increased intestine permeability.

Autistic mice?

Apparently you can produce mice that exhibit the “core communicative, social and stereotyped impairments” associated with ASD, by injecting their pregnant mothers with a molecule that stimulates an immune response.  In humans, maternal infection is linked to increased risk of autism in their children.  The production of these mice was the most questionable part of the paper in my opinion.  They never call these mice autistic, and the mice do show impairments associated with neurological diseases.  So perhaps we should think of it as a model of a generic neurological disorder.  For the sake of simplicity, though, I will refer to them as “autistic mice”, but remember that it is not a perfect model system.

They find that the autistic mice have various defects in their gastrointestinal (GI) tract.  For instance, their intestinal walls are leaky, so molecules that are not supposed to be absorbed can cross from the gut into the blood stream.  This problem seems to be caused by the fact that these mice express less of the proteins that make the tight junctions between cells.  Think of these as fences between cells, so molecules can’t sneak through there into the body.  In an ideal situation, all molecules that are absorbed from the gut must go through the cells, a process which is highly regulated. 

Tight junctions prevent molecules from passing from the gut into the blood.  Image adapted from dbriers.com

They find a number of metabolites that are produced in the intestine from bacteria, which end up in the blood of autistic mice, but not in the normal mice.  In other words, these are potentially toxic molecules that they need to get rid of, but the toxins are leaking into the blood of the autistic mice.  That’s not good.  In fact, if you inject one of these molecules into a normal mouse, it will become more anxious, similar to the autistic mice.  They couldn’t reproduce all of the behaviors of the autistic mice just with this one molecule, but it’s a good proof of principle.  Presumably it’s the build up of all of these metabolites in the blood that cause impairments of the nervous system.

Dysbiosis of the intestinal flora

I love that word “dysbiosis”.  It means that the intestinal microbiome is out of whack.  The wrong types of bacteria are in there messing stuff up.  Hsiao et al. found a number of species present in the autistic mice that were not in normal mice and vice versa.  Presumably this imbalance in the microbiome is what is making the gut leaky. 

To prove this, the authors fed the autistic mice a probiotic (a “good” type of bacteria) called Bacteroides fragilis (B. frag).  Interestingly, B. frag never actually colonized the guts of the mice, but just having it pass through helped to restore the normal microbiome.  Some of the species that were only present in autistic mice disappeared after they consumed B. frag.  The leakiness of the gut was almost completely reversed, including expression of tight junction proteins.  It wasn’t a perfect reversal, but a number of those metabolites in the blood decreased back to normal.

Behavior affected by microbiome

To review: when a pregnant mouse has an infection, her offspring show signs of autism (a mouse-version).  Somehow this infection causes the wrong bacteria to colonize the guts of the offspring.  The dysbiosis leads to changes in gene expression and a leaky gut that allows toxic molecules into the blood stream, thus affecting the development of the nervous system.  Consumption of a probiotic at weaning age fixes a lot of the gut issues.  Does it also reverse some of the behavior impairments associated with autism?

The short answer is yes!  Autistic mice fed B. frag were less anxious, less obsessive, more communicative and interacted more with other mice.  The test for obsessive behavior was kind of cute.  The mice were put in a cage filled with sand with marbles sitting on top.  The autistic-like mice bury a greater percentage of the marbles, demonstrating a stereotyped behavior.

Yogurt from everyone!

If I had an autistic child and read this paper, I would start them on probiotics right away.  I mean probiotics are good for everyone, right, so it definitely seems worth trying.  In fact, the authors say that B. fragilis is depleted in human ASD children compared to matched controls.  Furthermore, probiotics have already been shown to be beneficial in treating chronic fatigue syndrome.   

The authors end their paper with this bold statement: “We propose the transformative concept that autism, and likely other behavioral conditions, are potentially diseases involving the gut that ultimately impact the immune, metabolic, and nervous systems, and that microbiome-mediated therapies may be a safe and effective treatment for these neurodevelopmental disorders.”

This is why pre-meds have to learn about fungi

By now we all know there are tons of bacteria living in our guts (we are made up of 10x more bacteria than human cells!)  The bacteria help us digest food and make new molecules.  If our microbiome gets disrupted it can lead to serious digestive problems.  It has also been suggested that our bacteria help us fight infections by interacting with the immune system.  Bacteria aren’t the only microorganisms living inside us, though.  It turns out there is a diverse population of fungi living in our intestines, as reported by Iliev et al. in Science last week.

Fungus like mushrooms?

When we think of fungus, most people think about mushrooms.  I can almost guarantee you no one is growing mushrooms in their colons.  There are lots of other types of fungi, though, including single-celled creatures like Saccharomyces “yeast”.  Fungi are one phylogenetic group, so they have characteristics in common with each other, including many of their DNA sequences. 

In order to test for fungi in animal guts, the authors did PCR to test mice for the presence of a certain fungus-only DNA sequence.  They found fungus throughout the entire mouse gastrointestinal tract, with the highest density towards the end of the colon (or large intestine).  They also found fungi in rat, guinea pig, rabbit, pig, dog and human feces!  I’m glad humans weren’t left out of this fungal bounty.

The authors isolated the DNA from mouse feces and sequenced all the fungal DNA they could find.  They identified over 100 different known fungal species and more than 100 potentially new species of fungi!  Most of these fungi were found in low concentrations, except for Candida tropicalis which accounted for 65% of all the fecal fungi.  Candida tropicalis is an opportunistic pathogen, which only causes a problem when it grows out of control in people with suppressed immune systems.

Candida.  Image source

Fungal receptor

Our immune systems are trained to seek out and destroy foreign invaders like bacteria, viruses and fungi.  How does the immune system recognize fungi?  They have a cell wall (human cells do not) that has the molecule B-1,3,-glucans (a sugar polymer).  Macrophages in our immune system express a receptor called Dectin-1, which can recognize B-1,3-glucans and initiate an immune attack.  Since we have potentially pathogenic fungi living in our guts, our immune systems are probably always keeping them in check, so they don’t grow out of control and make us sick.  In fact, some of the diseases that cause inflammatory bowel disorders might be caused by fungi, and not bacteria, inducing an inflammatory response. 

To test this idea, the authors chemically induced colitis (inflammation of the colon) in mice (I’ll spare you a photo).  These mice were found to have circulating antibodies against fungal proteins, which implies that fungi have something to do with the pathology of colitis.  The authors wondered what would happen to mice which do not have the Dectin-1 receptor.  Since they can’t detect fungi, their immune systems would not be able to mount any attack.  Sure enough, the mutant mice had much worse colitis symptoms.  They had way more C. tropicalis (and other pathogenic fungi) in their guts than the wildtype mice which also had colitis.  In other words, missing the fungal receptor didn’t necessarily cause colitis, but it made the symptoms much worse. 

To further prove that colitis is aggravated by the native fungal population, the authors gave the mutant mice an antifungal drug during the induced colitis session.  These mice were much healthier than their siblings who did not receive the drug.  As long as something, an antifungal drug or the functioning immune system, can control fungal growth, then colitis is much milder.

Relevance to human disease

The inability to control fungi in the gut leads to more severe colitis in mice.  What about in humans?  Could a similar mutation be responsible for human colitis?  The authors focused on patients who have ulcerative colitis.  This comes in various forms; 30% of the patients have a severe form that does not respond to medical therapy.  They sequenced the gene for the fungal receptor and found that patients with the severe form were more likely to have a particular gene sequence compared to patients with a more mild type of colitis.  Though this doesn’t prove anything, it is in line with the idea that fungal growth can aggravate the inflamed colon.  Perhaps this sequence difference in the severe patients prevents their fungal receptor from working at full efficiency.

To summarize all this, we have fungus living in our intestinal tract.  Some of these fungi are totally harmless and I bet they help us with some physiological function (yet to be determined).  Other native fungi, including C. tropicalis, are potentially pathogenic, but are controlled by the immune system normally.  If the immune system cannot recognize fungal cells because the fungal receptor is defective, then the fungi will begin to grow out of control, which can upset the natural order in our guts.  Inflammatory bowel diseases will become more severe when the fungi are able to grow unchecked by the immune system. 

I have to say I don’t like the idea of a bunch of pathogenic fungi living in my intestines and just waiting for my immune system to let down its guard.  Stay vigilant macrophages!

Check out this excellent article by Carl Zimmer in the NY Times about the human microbiome.