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.

Sepsis-like syndrome in a patient after Fecal Microbiota Transplant

Clostridium difficile infection causes pain and diarrhea, is sometimes fatal, and normally occurs after a course of antibiotics leaves the gut in a state of dysbiosis where the C. diff can thrive.  Doctors normally prescribe antibiotics to cure this infection, but this can sometimes exacerbate the problem, making the gut even more prone to infection.  Fecal microbiota transplants (FMT) are the most successful therapy to treat the condition and have been seen to be successful in as many as 95% of treatments. 

A group of doctors in California chronicled the story of a 56-year-old woman who suffered from C. diff after she took a 10-day course of amoxicillin after she became sick with bacterial sinusitis. She went to the doctor after getting very sick and reporting 8-10 bowel movements per day. She was then prescribed various other antibiotic regimes that did not improve her condition over several days and a stool analysis found that she had C. diff.

While admitted at the hospital she was prescribed more antibiotics including metronidazole, vancomycin, and fidaxomicin however this only exacerbated her problems. Finally, her husband was identified as a potential stool donor and on Day 15 she underwent an FMT.

Six hours after the FMT, the woman developed sepsis-like syndrome and had a fever, tachycardia, and hypotension. After the woman was transferred to ICU, it was decided that no further antibiotics would be initiated as this could prevent the FMT from being effective and she did not clinically appear to be severely ill despite her vitals.  The following morning she was recovering and her vital signs normalized. Three days later, she was discharged and six weeks later, her stool frequency had reduced to 2-3 times per day and there was no C. diff recurrence.

Why was it that, this woman suffered from a condition that looked like sepsis after the FMT? The hypotheses included that it could have been a result of another pathogen derived from the donated stool. Second, it could have been a compilation from the procedure such as a perforated colon. Third, the FMT may have been unsuccessful resulting in untreated infection after the cessation of antibiotics the day prior. And finally, it could have been a result of the representation of an immune response as a result of a new gut microbiota.

While this was only an example of one patient and they did not discover the reason for her sepsis-like symptoms, this was an example of the harm that an FMT can cause. The authors state that well designed, executed, and interpreted clinical trials should be conducted if FMTs are to be used for higher risk/benefit conditions.

Fecal microbiota transplants for pouchitis not yet effective

Fecal microbiota transplants (FMTs) are generally accepted as an often-effective treatment for Clostridium difficile infection. To date, this is the only accepted use of FMTs however many scientists and clinicians have proposed other uses of FMTs to treat chronic conditions. One such condition is called pouchitis.

Patients with ulcerative colitis or other diseases often need a total proctocolectomy, the surgical removal of their large intestine and rectum, and have their small intestine connected to the anus to create a pouch to eliminate stools. When this “pouch” becomes inflamed or swells after being irritated, pouchitis results. Approximately half of all patients who need this procedure done get pouchitis in their lifetime and many get it every year.

Researchers in the UK hypothesized that FMTs could be used to treat pouchitis because it is thought that these patients have a dysbiosis. They conducted a trial of 8 patients with chronic pouchitis and published the results in Scientific Reports. After administering the FMT through a nasogastric tube, they analyzed clinical outcomes as well as microbiota composition as well as the immune response. Most importantly, they did not see any significant improved clinical outcomes despite some changes to the microbiome composition and in some individuals, the suggestion of a healthier microbiome as a result in changes in proportion of bacterial species abundance.

This negative result (which is always good to see published) leaves the door open for many further questions in regards to the use of FMTs in IBD including what is the proper route of administration, how often, and what interventions should be conducted prior to treatment. These and many more questions remain as clinicians aim to use FMTs in the treatment of IBD. 

Fecal microbiota transplant as a treatment for MRSA enterocolitis

Fecal microbiota transplants (FMTs) are most commonly used for treating Clostridium difficile infection, an often lethal bacterial infection of the gut. However, there have been many hypotheses that FMTs could be used to treat other conditions that result in a dysbiosis of the microbiota. A new study published in BMC Infectious Diseases suggests that FMTs could be used to treat enterocolitis, infection of the gut, that is a result of Methicillin-resistant Staphylococcus aureus (MRSA).

The most common treatment for this to date has been antibiotic treatment, specifically vanomycin, but the results of how this impacted the microbiota were not measured. In this new study, 5 patients with enterocolitis as a result of MRSA were given FMTs, the infusion of fecal preparation into the GI tract of the patient from a healthy donor. After administration of the FMT, all 5 patients were cured of the MRSA enterocolitis showing no symptoms. MRSA in the feces was also eliminated after FMT.

They also measured the microbiome of patients undergoing the treatment. They found that prior to treatment, patients with MRSA enterocolitis had decreased numbers of species in the gut and S. aureus reached almost half of all intestinal flora.  After the FMT, the microbiome of the recipient trended closer to the microbiome of the donor and alleviated symptoms. 

While there remain concerns with the use of FMTs, there are certain instances where there are few options for treatment and the administration of a new microbiome from a donor fecal sample remain the most promising. While this was only a study of 5 patients at one hospital in Singapore, the investigators suggest FMT as a first-line measure treatment for enterocolitis resulting from MRSA. 

Fecal microbiota transplant as a potential therapy for Crohn's disease

Seattle Children's Hospital

Clinicians at Seattle Children’s Hospital have found that fecal microbiota transplants (FMTs) may be a therapeutic option for patients with Crohn’s disease. Crohn’s disease (CD) is an inflammatory disease of the GI tract that is marked by an immune attack on a person’s own body, specifically in the gut.  The microbiome of CD patients is altered compared to healthy indivduals, but it is not clear if this is a cause or effect of the immune attack.  The group at Seattle Children’s Hospital hypothesized that if they could alter the microbiome of these patients that they would promote less inflammation resulting in fewer symptoms. 

The successful results were published in the journal Inflammatory Bowel Disease. They conducted fecal microbiota transplants in 9 individuals with pediatric Crohn’s disease between the ages of 12 and 19.  Patients received transplants from their parents, 7 from their mother and 2 from their father.  After two weeks, 7 of the 9 patients were in remission and at weeks six and twelve, 5 of the 9 patients were still in remission.  While the patients did have some side effects, almost all of them were mild.

The investigators looked at the differences in the microbiome between donor and recipient and what impact this had on disease.  They found that the individual who received the transplant of a microbiome that was most similar resulted in the smallest change of clinical course and the FMT recipient whose microbiome was the most different resulted in the greatest change in clinical course. They also found that increased levels of Escherichia coli correlated with increased clinical symptoms and inflammatory markers.  While it is not likely that E. coli is the cause of CD, it is an interesting observation that could be investigated to better understand what impact it has on disease progression.

This study provided evidence that the microbiome plays and important role in Crohn’s disease.  The results of this small study were promising and show that fecal microbiota transplants were generally safe and should be further investigated as a potential therapeutic option for individuals with this inflammatory disease. Further longitudinal studies are important to understand the entire impact that the FMT has on an individual.  As we have seen in previous blog posts, while it may cure the disease it is aiming to treat, there can also be other unintended consequences. 

Revisiting FMTs, and the patient that was cured of C. diff but became obese

Happy Valentine's Day to all our readers!  We will be back blogging on Tuesday, February 17, after we take off Monday, February 16 for President's Day.

Clostridia difficile infections can be nasty to deal with.  They cause pain and diarrhea, and are sometimes fatal.  They normally occur after a course of antibiotics, which leaves the gut in a state of dysbiosis where the C. diff can thrive.  Doctors normally prescribe antibiotics to cure this infection, but this can sometimes exacerbate the problem, making the gut even more prone to infection.  As we have discussed, fecal microbiome transplants (FMTs) have been successful in curing over 95% of C. diff infections.  Practically speaking, FMTs involve transferring the stool of a donor into the bowels of an infected patient.  While they are highly effective in treating C. diff, this practice is not without controversy.

The microbiome donor is generally a healthy person who is related to the patient and lives in the same household, generally a husband or wife.  The logic behind this is that these people share a similar microbiome, and some evidence supports this.  There are other ways to identify donors including the much publicized OpenBiome which has a stool repository which functions much like a blood or sperm bank.  These transplants come from ‘healthy’ strangers.  In most cases of FMTs, the stool is screened similarly to the way blood is screened, for specific diseases such as AIDS or hepatitis, and a few microbial pathogens (like C. diff).  The problem is, the microbiome is SO much more complex than blood, and as we learn every day on this blog, its impact on health and disease is not fully understood.  In fact, the promise of the microbiome is that it is connected with such far ranging diseases and phenotypes, from depression, to obesity, to arthritis.  We have numerous examples in mice where FMTs are actually able to transfer specific phenotypes, even unexpected ones such as anxiety.  What happens in humans though?  When we transplant feces between humans do phenotypes carry over?

Unfortunately, because the practice is mostly new, mostly unregulated, mostly isolated, and generally not a part of scientific studies, the long term impacts of FMTs are largely unknown.  The people who should and would know most about this, OpenBiome, have not published their findings, or at least are not talking about them.  We know that FMTs are really, really, good at curing C. diff, and may be the best solution to this debilitating disease, but at what cost is unknown, a classic bioethics dilemma.

Enter a healthy, 32 year old 136 pound woman from Rhode Island.  She had taken antibiotics for a vaginal infection and came down with a nasty C. diff infection which progressed over the course of a few months.  After antibiotics failed she opted for an FMT from her 16 year old, healthy daughter.  Fortunately, the FMT cleared the infection.  Unfortunately, over the ensuing year, the patient gained 34 pounds, and now weighs 170 pounds.  These are the kinds of results that make people nervous about FMTs.  We notice the weight gain because it is outward-facing and easy to measure, but what else has changed that we can’t notice, both physically and emotionally?  We need to be thinking about when we consider FMTs, especially when other, less complicated methods for treating C. diff are passing clinical trials.

FMTs exemplify both the promise and repercussions of the microbiome.  If the microbiome is as important and powerful as we think it is, then we need to investigate its clinical uses with deliberateness and care.