The gut microbiome may contribute to susceptibility to developing alcoholic liver disease

Alcoholic liver disease (ALD) is a major public health issue, yet the underlying mechanisms between ethanol consumption and injury to the liver are poorly understood.  Alcoholics vary in their susceptibility to developing ALD and alcoholic hepatitis (AH) despite consuming similar amounts of alcohol.  Taken together, this evidence suggests that other factors contribute to the onset and progression of ALD other than direct toxicity of alcohol.  Intestinal inflammation and pro-inflammatory bacterial products have also been observed in ALD patients and preclinical mice models, and intestinal dysbiosis has been observed in patients with alcohol dependency.  With this in mind, a team of European researchers devised a strategy to demonstrate microbiome dysbiosis as a casual driver of liver injury. 

The researchers transplanted human gut microbiota into germ-free mice, and the mice were then placed on a high-alcohol diet.  Microbiota were harvested from human alcoholic patients with or without AH (or low severity AH).  Mice transplanted with AH-microbiota had marked increases in symptoms of liver disease as compared to those mice that received microbiota transplants from non-AH alcoholic patients.  These include severe liver inflammation (including increases in T lymphocytes and natural killer cells), more necrosis in the liver, and higher intestinal permeability.  Enterobacteria counts were high in sever-AH patients and faecalibacterium genus was associated with AH-microbiota with low severity.  In an interesting spin, the researchers also transferred microbiota from an alcoholic patient without AH to mice with liver lesions.  Interestingly, mice who had received these microbiota displayed a reduction in serum alanine aminotransferase levels and a decrease in liver regeneration, suggesting that these microbiota could even possibly reverse alcohol-induced liver lesions. 

These findings not only support an association between the gut microbiome and susceptibility to developing alcoholic liver disease, but also provide evidence that these bacteria may drive disease onset.  These were important findings that support microbiota-causal effect rather than dysbiosis as a consequence of liver disease.  This data could perhaps promote development of novel diagnostic techniques that assess the gut microbiome or bacterial metabolites of alcoholic patients.  Methods such as manipulating the microbiome as a therapeutic approach for these patients could also be explored. 

Melanoma cancer therapy’s efficacy may depend on the existence of specific gut bacteria

Ipilimumab is a monoclonal antibody (mAb) that binds to, and activates T-cells. (Technically, the drug binds to the CTLA-4 receptor on T-cells, which decreases T-cell suppression)  It is currently an approved therapy for the treatment of metastatic melanoma.  Unfortunately, activation of the immune system can damage the microbiome, and taking iplimumab often results in adverse side effects in the gut, such as diarrhea.  Scientists from France were studying the effect of the drug on the microbiome when they discovered that its efficacy was actually dependent on the presence of certain gut bacteria.  They published their results in the journal Science.

First, the scientists administered the ipilimumab to three groups of mice that had been given cancer through an established model.  One group of mice had a normal microbiome, the second group was germ-free, and the final group had a normal microbiome, but then were given antibiotics.  Surprisingly, the mAb activated much fewer T-cells and was much less effective in destroying the cancer in the mice that were germ free and had been given antibiotics compared to the normal mice.  In addition, the scientists noted that intestinal inflammation occurred in the normal mice, but less so in the others.  Next, the scientists measured the microbiome changes as a result of administration of the mAb, and observed a rapid decrease in Bacteroidales, Burkholderiales, and an increase in Clostridiales.  The scientists then inoculated cancerous mice with specific bacterial species prior to administration of the drug, and then measured the drug’s efficacy.  Remarkably, specific species, such as Bacteroides thetaiotaomicron were able to reestablish the drug’s therapeutic potential and decrease inflammation.

The microbiome’s complex dynamic with the immune system once again presents itself, this time by modulating the efficacy of ipilimumab.  The scientists did do some work on humans, and they noted that not all human patients suffering from melanoma and taking ipilimumab have those beneficial bacteria in their stool.  The scientists did not discuss whether their existence was associated with the cancer’s progression in humans, although it would be interesting to see.  Ipilimumab is just one of many drugs that use the immune system to attack cancer.  Continued research is needed on the microbiome’s impact on these drugs.

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. 

Gastric bypass surgery alters microbiome which possible contributes to weight loss

Schematic of Roux-en-Y anastomosis.

Roux-en-Y gastric bypass surgery and vertical banded gastroplasty are two types of bariatric weight loss surgeries that are highly effective in promoting weight loss.  The mechanisms for their efficacy are complex and not completely known, but both surgeries are shown to reduce caloric intake, suppress hunger and increase gastric emptying.  Little is known about how the microbiome changes during these surgeries, and how this change may effect subsequent weight loss.  A team of Swedish scientists investigated this topic and showed the gut microbiota undergo important changes.  They published their results in the journal Cell Metabolism.

The researchers compared the microbiomes of women that were obese and hadn’t had surgery with those who were of similar BMI presurgery, but had undergone surgery at least nine years earlier.  They observed some major differences in the women’s microbiomes, with the post-operative women had much higher levels of Gammaproteobacteria and lower levels of Firmicutes.  When the scientists looked at actual genetic variations they found many differences.  Some notable differences were a decrease in short chain fatty acid (SCFA) and in increase in trimethylamine N-oxide (TMAO) creation in women who had surgery.  As we have written about in this blog before, SCFAs are often associated with health, while TMAO is a risk factor for some cardiovascular diseases.  Interestingly, when they took the microbiomes from both groups of women and transferred them into germ-free mice, the mice receiving microbiomes of women that had undergone surgery gained less weight than the mice that received microbiomes of obese women.

Gastric bypass surgery is often a last resort for folks that have severe obesity.  While not normally considered, the microbiome is drastically affected by this procedure. The microbiome is certainly altered by the procedure, and it appears that it may even be helping keep the weight off.  However, there may be some negative microbiome-mediated consequences as well, derived from alterations to micrbiome metabolism, such as an increased level of TMAO.  Like all surgeries, folks undergoing this one need to balance the risks and rewards of the procedure, and hopefully after this study, the microbiome will be considered.

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. 

New info on fecal microbiota transplants for C. difficile and ulcerative colitis

"Fecal bacterial communities of recurrent [C. diff]  patients shift towards [healthy] fecal bacterial communities after FMT. Pre-FMT patient samples (red circle); post-FMT patient samples (green circles); trajectory of patient fecal communities after FMT (blue line)."
Image and caption from the C. diff paper: Weingarden et al. Microbiome 2015 3:10   doi:10.1186/s40168-015-0070-0

Two important papers regarding fecal microbiota transplants (FMTs) were published last week.  The first was an examination of a patient’s microbiome over time after he or she undergoes an FMT to treat C. difficile.  The second showed the results of clinical trials that used FMTs in an attempt to treat ulcerative colitis.   The FMT papers, which are described below, improve our understanding of this procedure, which holds promise to treat various microbiome-based diseases.

The C. diff paper, published in the journal Microbiome, attempted to answer the question: Do the microbiome changes that occur after FMT remain long after the procedure?  We know that FMTs are highly effective in treating C. diff because they install a healthy microbiome that can crowd out the infection.  However, it is unknown if these new bugs that take hold are transient, or if they become permanent members of the gut.  The researchers sampled the microbiomes of FMT donors and recipient patients before and up to 84 days after an FMT procedure to treat C. diff.  They discovered that the recipients’ dysbiotic microbiomes stabilized quickly, and after just one day they closely resembled the donors’ microbiomes.  Continued measurements showed that the microbiomes deviated over the next few weeks, but that they remained healthy.

The colitis clinical trial, published in the journal Gastroenterology, attempted to discover if FMTs could treat ulcerative colitis.  Ulcerative colitis is widely considered to somehow be related to a dysbiosis in the microbiome, so can FMTs from healthy donors treat this disease?  The study was a double blind randomized clinical in which 48 people suffering from ulcerative colitis either received stool from healthy donors (treatment) or just an FMT of their own stool (control).  7/23 patients who received stool from a healthy donor were in remission after 12 weeks, while 5/25 patients who received their own stool were in remission at that time.  Unfortunately, this is not a clinically significant result based on the number of patients involved.  The researchers measured the bacterial abundance in all of the patients microbiomes before and after treatment.  Before treatment the microbiomes all had some baseline similarity.  After treatment, though, the patients who responded to treatment from a healthy donor all had an increase in certain Clostridia, and the patients who responded to treatment from their own stool all had in increase in certain Bacilli, Proteobacteria and Bacteriodetes.  The researchers feel that this information warrants further study.

FMTs are an exciting new therapy that may be important in treating some really nasty diseases.  We do want to remind people, though, that it is still an unproven technique that should only be performed under the guidance of a doctor.  As we have written about before, the promise of the microbiome is what makes FMTs both attractive, but potentially dangerous at the same time.