Gut microbiome depletion promotes healthier brown fat and reduces obesity in mice

The white and brown turkey meat from a Thanksgiving dinner

An interesting article from Switzerland was published last week in Nature Medicine.  The scientists reported on a new connection between the gut microbiome and metabolic syndrome (i.e. insulin sensitivity, obesity, etc.)  Whereas most papers observe microbiome disruption and depletion is associated with obesity, this paper describes a different phenomenon: that mice with depleted microbiomes are metabolically healthier than their untouched microbiome counterparts.  As part of the basis for the paper it is important to understand that mammals have two types of fat, brown fat and white fat.  Brown fat is associated with exercise, insulin sensitivity, and health, and white fat is associated with insulin resistance and diabetes.  Brown fat can actually repopulate white fat in a process called browning, and this transition is healthy.  

In the study, the scientists started with either normal mice, germ free mice, or mice that had antibiotics administered to them. They challenged each group of mice with glucose, and noted that antibiotic administration led to improved insulin sensitivity.  When they investigated where the glucose was going, they discovered that it was uptaken by white adipose tissue under the skin.  Then, they compared the normal mice and antibiotic mice, and observed that the antibiotic mice actually had smaller volumes of fat after the glucose uptake.  Interestingly, the fat cells in the germ free and antibiotic mice were smaller and more dense, whereas the normal mice had fewer, larger cells.  The researchers then confirmed that browning of fat was occurring in the germ free and antibiotic mice.  Finally, when the scientists transplanted the microbiome of normal mice into the germ free mice a reversal of many the above described characteristics occurred.  In these mice the fat stopped browning, insulin resistance decreased, and the mice gained weight.

The scientists were able to attribute some of the above phenomena to the release of specific cytokines (molecules that regulate the immune system).  This paper, then, adds to the wealth of research that describes the complex but critical interaction between the gut microbiome, the immune system, and metabolic syndrome.  Although the relationships between these things is yet to be fully understood, this paper may at least change the way you think about the dark and white meat during Thanksgiving dinner this Thursday.

Helminths suppress the immune system by modulating the gut microbiota

The nematode Heligmosomoides polygyrus, which was used in this study, seen into an optical microscope. Taken from the digestive tractus of a rodent.

Helminths, or gut worms, are known to be powerful suppressants of the immune system.  In fact, this is the basis for using helminth therapy for various autoimmune conditions, such as IBD.  Still though, the mechanisms for helminth immunosuppression is unknown.  There have been some studies that suggest the worms are secreting molecules that have this anti-inflammatory effect, but this may not tell the whole story.  Researchers from Switzerland hypothesized that because helminths and our gut bacteria evolved together, it was likely that the helminths were modulating the bacterial gut microbiome, and that this modulation was anti-inflammatory.  They tested and published results that support this idea in the latest issue of Cell Immunity.

The scientists started by showing the efficacy of a mouse helminth, Heligmosomoides polygyrus bakeri (Hpb), in reducing inflammation in mouse models of asthma.  The scientists infected mice with the parasite and exposed those mice, along with non-infected control mice, to dust mites in order to elicit and immune response.  The scientists observed that the Hpb mice had much lower circulating levels of specific cytokines and immune cells after exposure to dust mites than the controls.  Next, the scientist gave the Hpb infected mice antibiotics, which eliminated the gut bacteria but left the helminths intact.  They then exposed these mice and control mice to dust mites to elicit the immune response.  Interestingly, while the helminths alone did decrease the levels of some inflammatory molecules and cells, inflammation still occurred, similar to what was observed in controls.  This meant that the gut bacteria play a role in modulating the helminthic immune suppression.  In order to validate these findings, the scientists then performed fecal microbiota transplants from control mice or helminth infected mice into germ free mice (with no worms).  After, the challenged these mice with house dust mites and discovered that the gut bacteria alone created an immune suppression in the mice, even in the absence of the worms.

The researchers attempted to identify which bacteria may be causing this immune suppression, and measured the microbiomes of the mice.  They noted that higher levels of Clostridiales occurred in the Hpb mice.  They then measured the levels of short chain fatty acids (SCFAs) in the mice’s guts, because Clostridiales are known to produce SCFAs.  They noticed that higher levels of SCFAs, which have previously been linked to immune suppression, did occur in higher levels in mice with Hpb compared to controls.  The scientists then studied this connection between worm infection and increase in SCFAs in pigs and humans.  Remarkably, the increase in SCFAs in helminth-infected subjects compared to controls was observed across species, suggesting the immune suppressing helminth phenomenon is extensible to many mammals.  The researchers even investigated possible mechanisms for why SCFAs were able to suppress the immune system.  They discovered the SCFAs were binding specific receptors that modulate T-cells, and more depth on this issue can be found by reading the paper. 

This study is quite important as it shows that helminths in combination with the bacterial microbiome are important to immune suppression.  This suggests that future therapeutics that may take advantage of helminth-derived molecules may not be as effective.  It does, however, support helminth therapy as an immune suppressant.  However, helminths are also very dangerous and can lead to various diseases.   So, while clinical trials that use helminths are underway, there are still no approved uses for worms.  

Helminths may provide therapeutic benefit to treat brain disorder

We’ve recently talked about a few articles that have studied helminth infection with respect to the microbiome, and how these infections could possibly confer some therapeutic benefits.  Another recent study conducted by researchers at Duke University reinforces these findings.  Autoimmune and inflammatory disorders appear to be more common in developed societies, and many have suggested that the microbiome is a major driver of these changes to our immunity.  These investigators wanted to assess whether or not helminths – which have a lot of influence on the immune system – had any effect in modulating the brain immune system in the context of living conditions and early-life infection, as this has been shown to result in neurodevelopment disorders. 

In this study, male and female rats were infected with a H. diminuta cystercircoid rat tapeworm a few weeks prior to breeding.  The rats were segregated by living conditions, housed in either dirty colonies (or “farm-like” environments), where no water or air filtration was provided) or standard clean pathogen-free laboratory conditions.  The offspring in both environments were delivered helminths, and the males were infected with E. coli early in life. 

Later in adulthood, the immune systems of the progeny animals were challenged by lipopolysaccharide (LPS) inductions in learning tests, and brains were collected shortly after to examine changes in molecular immune responses.  Exaggerated immune responses were observed in rats that were infected with E.coli early in life in the standard clean lab conditions.  Alternatively, the cohort that lived in the farm-like conditions did not experience an increase.  Both groups were infected with helminths.

To narrow down further, the researchers examined the impact of helminths alone in rats housed under clean pathogen-free laboratory conditions.  Indeed, cytokine responses in rats infected with E.coli were reduced in the animals whose mothers were infected with helminths before giving birth.  In addition to immunologic modulation, helminth infections in adult rats where shown to reduce memory deficits that are common following E. coli infection, suggesting helminth infection played a role in modulating developmental disorders due to bacterial infection. 

The helminths also had an effect on the microbiomes of the rodents.  16s rRNA sequencing revealed an average 25% shift in microbiome composition of animals infected with helminths (with a predominant shift of Bacilli to Clostridia).  Rats that were infected with E. coli early in life experienced a microbiome composition shift in adulthood, as more harmful Bacteroidetes species were found in adults.  Interestingly, this observation was not found in those who were E.coli infected but also infected with helminths, suggesting helminths prevented this composition shift. 

Overall, these findings suggest that helminths could provide therapeutic benefit, especially after infection early in life.  It will be interesting to see how this research can translate to human models, especially by narrowing down bacterial infections that could harm or benefit development.  Understanding what drives these developmental complications could have immense health benefits for the public.