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.

The microbiome of the international space station

Characterization of the microbial composition of the International Space Station (ISS) is a topic that currently interests the National Aeronautics and Space Administration (NASA). The ISS is an interesting environment because it is a built environment that experiences constant human contact, microgravity and space radiation. Understanding the ISS microbial community would help with help and safety concerns as well as proper maintenance of the ISS. Scientists across the United States combined their efforts to properly characterize the microbial community of the ISS, and compared it to cleanrooms on Earth. The results were published by Microbiome.

         Samples were collected from ISS high-efficiently particulate arrestance (HEPA, vacuum cleaner bag components from the ISS, and two cleanrooms at the Jet Propulsion Laboratory (JPL) in Pasadena, CA. Cleanrooms are closed rooms with little human traffic and filtered air. Bacterial and fungal samples were cultured and sequenced using next generation sequencing techniques in order to determine identities. Sixteen fungal strains were isolated from the ISS samples compared to the three strains from JPL samples, with most strains being associated with the phylum Ascomycota. Bacterial samples from the ISS were dominated by Actinobacteria, Bacilli, and Clostridia, while samples from the JPL were dominated by Alphaproteobacteria and Gammaproteobacteria. On a genus level, the two sample environments were completely distinct as well.

         This study shows that the International Space Station has a very distinct microbial community that must be monitored. As we know that the microbiome is so influential on health, it is important that the ISS bacteria are characterized in order to ensure the health and safety of those on board. This is just another important example that the microbiome has a great influence on humans, even from out in space.         

The microbiome’s response to the flu and its treatment

In 2013 there was an avian flu (H7N9) outbreak in China that affected 140 people, killing 46 of them.  During the outbreak doctors from one of the major hospitals in China treated 40 of these patients by giving them antivirals and antibiotics, amongst other first line treatments.  In addition, they gave probiotics along with the antibiotics to restore the gut microbiome.  All the while, they measured the patients’ microbiomes to track how they changed throughout the course of treatment.  The results of this study were published last week in the journal Nature Scientific Reports.

Twenty six patients were enrolled in the study, and each of them was given antibiotics within 6 hours of admission to the hospital.  In addition, each one was given Clostridia probiotic capsules along with the antibiotics.  Thirty one healthy control stool samples that represented the demographics of those undergoing flu treatment were also measured as a part of the study.  Before the antibiotics were taken, the patients with the flu already had altered microbiomes that were low in diversity and had lower abundances of Bacteroidetes and higher levels of Proteobacteria.  After antibiotics were given there was a dramatic shift in the microbiomes, that was characterized by a relative increase in the abundance of Escherichia coli.  In addition, the scientists noted that the probiotics were in fact increasing the amounts of Clostridia in the guts of patients who took them, and that the probiotics may have led to better clinical outcomes.  In their hospital only 20% of patients died of the flu, whereas 40% died in the rest of China.

The major takeaway from this study is the changes that the flu has on the microbiome, decreasing diversity and altering the levels of certain phyla.  The fact that the probiotics did appear to take hold and improve clinical outcomes is interesting, but the study was extremely small and limited in its scope to reach any statistically significant conclusions.  Overall though, this study suggests that if you come down with a flu that it may be wise to feed and nourish your microbiome because it is ‘getting sick’ right alongside you.

Microbiome metabolite in urine predicts severity of graft versus host disease

Molecular structure of indoxyl-sulfate

People that suffer from blood cancers, such as acute myeloid leukemia, often times receive hematopoietic stem cell transplants (HSCT) as part of their therapy.  This procedure typically replaces the sick person’s white blood cells with those of a healthy donor.  While this is a life-saving procedure it does carry a type of transplant ‘rejection’ risk.  While in a normal organ transplant a person’s own white blood cells will attack the foreign organ, in this case the new, donor white blood cells begin attacking parts of the recipient’s body.  This is called graft versus host disease (GvHD), and can often times be fatal.  One of the primary areas that are attacked by the new blood cells is the gut microbiome.  This is not surprising because the ‘replacement’ immune system is not programmed to tolerate and accept the bacteria in the gut, because they are so different from the bacteria it was originally adapted for.  Therefore, GvHD, is often considered a microbiome disease, and there have even been studies to investigate whether matching microbiomes decreases risk for the disease. 

An important area of research is focused on detecting GvHD before it begins so that it can be treated early.  While normally GvHD is diagnosed by symptoms, it may be possible to use the microbiome itself for early detection of the disease.  A group out of Germany recently showed that by monitoring a specific metabolite produced in the gut, indoxyl sulfate, one could predict the severity of GvHD.  This molecule is only produced by bacteria, mostly in the gut, by breaking down the amino acid tryptophan.  Moreover, indoxyl sulfate is an important signaling molecule that is thought to modulate the gut epithelial function, and may cause inflammation.  They published the results of their study in the journal Blood last week. 

The scientists measured the indoxyl sulfate concentration in the urine of 131 individuals undergoing HSCT over the course of 28 days following the treatment.  After, the ranked the patients in terms of indoxyl sulfate level during the first ten days after transplant, and compared their outcomes.  Remarkably, the people that had the lowest levels of indoxyl sulfate had a statistically significant higher risk of dying of GvHD after 12 months.  Next, the scientists attempted to relate the gut microbiome composition of the patients with the indoxyl sulfate levels.  They realized higher diversity microbiomes were related to higher indoxyl sulfate levels, and healthier outcomes.  In addition, higher levels of Clostridia and lower levels of Bacilli led to higher indoxyl sulfate.

This study may go a long way in informing clinicians about GvHD risk in their patients.  Not only does it show that monitoring indoxyl sulfate may predict GvHD severity, but it also points to specific bacteria that may be important in controlling its levels.  HSCTs are a highly effective treatment for blood cancer, that often times have a higher efficacy/safety profile compared with traditional cancer therapies.  Understanding the microbiome’s role in GvHD, one of the most important risks of HSCT, will hopefully lead to improved therapies and better overall cancer outcomes.

Red wine and coffee modulate the microbiome

Prebiotics are foods that alter the microbiome.  They are important to many potential microbiome therapeutics because they could be used to shift the microbiome from a dysbiotic, or unhealthy state, to a normal healthy state.  Most scientists that study prebiotics investigate indigestible fiber, because these are known to survive digestion are broken down by specific microbes, thus predictably selecting for specific organisms’ growth.  Recently though, other prebiotics are being studied.  A major class of these are polyphenolic compounds, which provide the antioxidant characteristics of plant material.  Last week researchers from Spain studied the shift in the microbiome that may be induced by red wine and coffee in particular.  They published their results in the journal Food & Function.

The researchers studied 23 patients that had allergic rhinosinusitis or asthma as well as 22 age-matched controls.  They chose individuals with autoimmune diseases because of the promise of prebiotics affecting their diseases.  They asked all of the individuals to fill out a food survey of what they had eaten in the past year, and how often they ate it.  After, the scientists took samples of their feces and measured the bacteria within it.  The scientists found that the abundance of Clostridium, Lactococcus and Lactobacillus was directly associated with polyphenol intake from coffee, and that Bacteroides was positively associated with red wine consumption.  Unfortunately, they noted that these did not differ between allergic people and healthy ones.

This study was certainly lacking in its scope and rigor.  It did not attempt any interventional studies to controllably reproduce these effects, and it did not identifiy specific polyphenols that are responsible.  Nonetheless, it does begin to define how alternative prebiotics may affect our microbiome.  Polyphenols in particular are linked to all sorts of health benefits, normally attributed to their anti-oxidation, however perhaps they positively impact the microbiome as well. 

The anorexia nervosa gut microbiome differs from healthy controls and is related to mental health

Two photographs, before and after treatment for anorexia

Anorexia nervosa is devastating condition in which an individual purposely starves themselves leading to severely low weight.  In addition, most patients with anorexia have depression, and there is a definitely mental aspect to this disease.  The disease then, has both dietary and mental components, making it extremely interesting to microbiome scientists, because the microbiome is implicated with both of these facets.  Scientists from UNC recently conducted a preliminary study on both of these aspects of the disease by comparing the microbiomes and mental state of anorexic patients before and after treatment, along with healthy controls.  They published there results last week in the journal Psychosomatic Medicine.

Sixteen patients with anorexia nervosa who sought treatment for their disease had stool samples collected at admission to the hospital as well as their mental health assessed.  Ten of these individuals that made partial recoveries (improved body mass index) were discharged from the hospital and donated stool samples and had their mental health assessed upon leaving.  The researchers discovered that the patients’ microbiomes severely lacked diversity compared to aged matched controls, and that was true for both admission and discharge from the hospital.  The scientists noted though, that the patients that left the hospital had microbiomes that more resembled the control individuals than when they entered.  For example, the anorexic patients had very little Clostridia when they entered the hospital, but these populations rebounded during treatment.  In terms of the mental health aspect of anorexia and the microbiome, the researchers found a direct association between eating disorder psychopathology and microbiome diversity, with lower diversity corresponding to worse eating disorder psychopathology.  The same was true for depression, as the degree of depression was inversely correlated with bacterial diversity.  In terms of individual families of bacteria, a lack of Ruminococcaceae had the strongest association negative mental state.

This study shows that a lack of eating decreases gut flora diversity and negatively impacts the microbiome.  While not surprising, this lack of diversity will almost certainly cause a dysbiosis that detriments many other aspects of health.  One of these, in the case of anorexia, may be mental health, but of course it is not clear which causes which, or if there is any causation or merely just correlation.  In any event, disorders that have both mental and dietary components are extremely fascinating to investigate, as it is possible the microbiome is of primary importance to these diseases.