Obesity and the daily cycle of the microbiome

We recently wrote a blog about an article discussing how sleeping patterns affected the microbiome and may contribute to obesity, but what about eating patterns?  A paper published last week in Cell Metabolism aimed to answer this question. 

Three groups of mice were used in the experiment.  The first group of mice was given unlimited access to a high fat diet.  These mice ate their food all day and night.  The second group of mice mice was given a high fat diet but restricted to eat for only 8 hours per day.  The final group of mice was given unlimited access to normal food.  These mice tended to eat for only 8 hours per day, so they were actually no different than a group of mice restricted to eating normal food for 8 hours per day.  The researchers measured all of the mice’s microbiomes, weights, cholesterol, and other metabolites at various time points throughout the day.

Most shockingly, they found that by restricting the mice to a high fat diet for only 8 hours per day decreased their obesity and cholesterol and these mice were indiscriminant from mice eating normally.  The mice that ate the high fat diet at all hours were obese, and had high cholesterol.  When investigating the mice’s stool, the scientists discovered that the stool of mice with restricted eating times was of higher caloric density than mice eating a high fat diet at all times.  This means that mice that eat the high fat diet at any time extract more calories from their food than those mice that restrict their eating.  They also discovered that while all mice that ate a high fat diet had similar microbiomes, the mice that only ate for 8 hours had many cyclic bacteria that would flourish and dissipate depending on the feeding schedule, whereas there were less cyclic bacteria in the mice that ate at all times.  Furthermore, there seemed to be a decrease in one bacteria associated with obesity, Lactococcus, in the mice with restricted eating times, even with the high fat diet, whereas these bacteria flourished in mice that ate the high fat diet at all times. 

From a microbiome science standpoint, this study demonstrates the need to consider diurnal cycles when making microbiome measurements.  From a nutrition standpoint it makes one reconsider the benefits of eating many small meals a day versus fasting.   If nothing else, the study demonstrates how complex the microbiome, diet, and obesity puzzle really is, and how much we have yet to understand.

We've domesticated chickens and cows, how about probiotics?

Domesticated pig

Desended from wild boar

I recently came across an interesting article from Nature's Scientific Reports that discusses the ongoing domestication of bacteria by humans.  We are all well aware of domestication of animals and plants, but have we ever considered domesticating bacteria? One consequence in animals is that the domestic versions does not resemble their wild counterparts.  Striking examples are the large, white domestic ducks that are actually originally descended from the common mallard, or sheeps, which do not resemble the wild mouflon.  Another consequence is that the domesticated animals lose genetic diversity.  You may have heard stories about bananas which are at extreme risk for disease because of their monogenetic cultivation, or how many farm breeds across the world are going extinct putting the entire population of that animal at risk.  In the article researchers investigated how Lactobacillus acidophilus has changed since being used in dairy foods and probiotics.

 L. acidophilus is a unique bacteria because it can convert carbohydrates to lactic acid.  Humans then, harness the bacteria to create fermented foods like yogurt.  Because of its use in yogurt, and its general recognition as being safe by the FDA, many Lactobacillaea are used in probiotics, and we have written about the results of studies using them before.  The researchers in this study examined many different strains of L. acidophilus from all over the world and dating back to 1922 to see how the species has changed.  As it turns out, much like the domesticated plants and animals, all the strains tested had incredible genetic homology, with each strain being incredibly similar to the next.  The authors believe that this strain is very robust, and that it sits in a very advantageous place in evolutionary space, so that it is difficult for mutations to take hold.  This species can be thought of as an evolutionary bottleneck.  This may have given this strain an upper hand in being selected by early manufacturers, who did not want variation between batches and starter cultures.

 One may wonder though, does this put L. acidophilus at risk for disease?  As it turns out the bacteria appears to be very resistant to disease.  While it is attacked by many phages, these do not seem to affect the overall reliability of the species.  Again, this resiliency speaks to its use in manufacturing.  So the next time you are downing some delicious greek yogurt, remember that it likely tastes the same as when the ancient greeks were eating it too!

Treating severe nickel allergies with probiotics

Buffalo nickel, made of 25% nickel.

Systematic nickel allergy syndrome (SNAS) is a severe reaction to nickel, a metal that is found in nature and most human food sources. An allergic reaction to nickel can manifest cutaneously, causing inflammation and irritation of the skin, or it can be gastrointestinal, causing diarrhea. Studies in which balanced diets are used as a way of reintroducing nickel to SNAS patients have been conducted to find possible treatments of this allergy; however no cure has been found. Research by a group in Italy was published last month in the Journal of Applied Microbiology that examined the use of probiotics such as Lactobacillus reuteri to treat SNAS patients.

A double blind study was performed using twenty-two adult women who had both systematic and cutaneous reactions to nickel. A control group received a placebo, while an experimental group received the L. reuteri probiotic. Fecal sampling and clinical evaluations were performed at the start of the study, before any pills were taken, as well as after two weeks of supplementation and two weeks after the end of the trial. Throughout the entire evaluation period the patients followed a low-nickel diet.

Both groups prior to experimentation had low diversity of lactic acid bacteria (LAB) communities in their gut.  After the trial, they found that the control group had stable LAB communities while the experimental group resulted in greater diversity of LAB than prior to the study. They found that only the experimental group showed the presence of L. reuteri meaning that the bacteria in the probiotic had successfully colonized and survived in the gut, an essential feature if a probiotic is to be used in a clinical setting.

They also found a significant improvement in cutaneous symptoms after two weeks in both the group being given the probiotic with a low-nickel diet, as well as the strictly low-nickel diet patient group, however the improvement was more pronounced in the group getting the probiotic. Only patients receiving the supplementary L. reuteri showed a significant reduction in gastrointestinal symptoms. Eating a diet low in nickel will cause less averse reactions than an uncontrolled diet; however, this study strongly suggests that probiotics can significantly decrease the severity of allergy symptoms in SNAS patients. The study also suggests that a combination of diet and probiotics could increase bacteria’s ability to colonize in the intestines. Further long-term studies on the prolonged effects of probiotic use in treating SNAS and other conditions will allow us to better understand how to use probiotics to manipulate the microbiome and treat disease. 

A possible new treatment for Lupus by modulating the microbiome

Sweet potatoes are a natural rich source of Vitamin A.

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Lupus is a well-known autoimmune disease that causes inflammation in several organs and can sometimes be fatal.  Its cause is still unknown, but it has recently been implicated with the microbiome, and we have written about it before on this blog.  New research out of Virginia Tech has provided further evidence of this link by showing specific microbiome differences between control and Lupus affected mice.  They also showed that Vitamin A may help improve the the Lupus mice’s conditions.

The researchers tested two groups of mice, one a healthy control group and the other that had a genetic mutation that causes Lupus-like symptoms.  When they studied the microbiomes of these mice they discovered that the Lupus mice had a significant reduction in Lactobacillaceae and increase in Lachnospiraceae.  The researchers then connected the severity of lupus symptoms directly with the levels of these two bacteria (worse symptoms with higher Lachnospiraceae abundance and lower Lactobacillaceae abundance).  Interestingly, Lupus affects almost 10 times more females than males.  These researchers showed that while there was little difference between genders in the control group microbiomes, there was a much higher diversity in the microbiomes of female Lupus mice as compared to male Lupus mice. 

Vitamin A has been shown in humans to relieve the symptoms of Lupus, so the researchers fed the Lupus mice both retinol (pure vitamin A), as well retinoic acid (a metabolite of vitamin A).  While the retinol did not seem to help the Lupus mice, the retinoic acid restored populations of Lactobacillaceae, and relieved symptoms in the Lupus mice.

We know that mice are not a perfect model for humans, but this research shows that the microbiome may be an important factor in Lupus.  As such, it also shows a potential prebiotic, retinoic acid, for the treatment of Lupus.  Lupus is a complex disease, and we do not expect it to be completely understood through the lens of the microbiome, but research like this is important in elucidating possible connections between the two.

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Proton pump inhibitors may increase susceptibility to Clostridium difficile infection

Individuals who produce too much gastric acid in their stomach are often are prescribed proton pump inhibitors (PPIs), a group of drugs that prevent the production of acid for the treatment of ulcers, gastroesophogeal reflux disease (GERD), and other conditions related to acid production. Scientists at the Mayo Clinic in Arizona and Minnesota published a study last week in the journal Microbiome that found that the prolonged use of PPIs resulted in a reduction in gut microbiome diversity. The authors hypothesized that this reduced gut diversity is predisposing patients using PPIs to Clostridium difficile infection, an often-fatal bacterial infection that we have written about extensively on the blog.

Previous observational studies had shown a correlation between PPI usage and C. diff infection, however this study set out to identify what was actually causing this link.  The scientists took fecal samples from 9 healthy subjects before, during, and after they were given either a high or low-dose PPI treatment. They also took fecal samples from 5 patients with untreated C. diff infections and compared the bacteria in the fecal samples between the healthy patients and untreated patients infected with C. diff.

After taking PPIs, the healthy individuals’ gut microbiomes started looking very similar to those of patients with untreated C. diff. The number of bacterial species was significantly reduced from before they were exposed to PPIs, and the reduction was independent of dosage. This reduction of bacterial diversity in the gut doesn’t mean that patients on these medications will definitely become infected with C. diff, but it does likely predispose patients to the infection and more easily allow the bacteria to colonize the gut. 

The study found that after 28 days of PPI treatment the reduced gut diversity can be reversed, however it is not clear what prolonged PPI usage does to the gut microbiome.  This study included only a small number of subjects and future studies will hopefully be expanded and include patients who are prescribed PPIs for treating a specific condition. Better understanding the impact that PPIs have on the gut microbiome may also allow for the development of probiotics that could help counteract the effects of PPIs and help keep the gut microbiome diversity stable. 

Promoting your dog’s microbiome through functional food

Dogs are man’s best friend, but did you know that they can suffer from digestive diseases and inflammatory bowel diseases too?  A new study published in the British Journal of Nutrition aimed to investigate how dog foods could be ‘functionalized’ by the addition of potato fiber.  This prebiotic promoted the production of many important molecules and shifted the microbiome in ways that may be critical to gut health.

In the study, numerous dogs had their feces sampled for their microbiome in addition to metabolites.  A control group was fed a normal diet and an experimental group was fed the normal diet with the different amounts of potato fiber.  All of the dogs’ microbiomes were richest in Firmicutes, regardless of diet.  However, dogs given potato fiber had an increase in Firmicute abundance, as well as Bifidobacterium spp. and Lactobacillus spp.   Both Bifodobacterium and Lactobacillus are common probiotics that are shown to promote gut health in humans.  In addition, one particular bacterium, Faecalibacterium prausnitzii, was shown to proliferate after the potato fiber was added to the diet.  This bacterium has also been related to decreases in IBD in humans.  Finally, the dogs that ate potato fiber had an increase in butyrate, short chained fatty acids (SCFAs), and an overall decrease feces pH.  Each of these has been implicated with lower incidence of IBD.

This study was one of the first to investigate prebiotics in dog food.  The simple addition of potato fiber, a complex carbohydrate, had important changes on the microbiome, including the production of SCFAs which we have blogged about in the past.  Potato fiber may be an easy, inexpensive dog chow additive for all dog owners and lovers to help their pets lead happier, healthier lives.