Bacterial Microbiome

Improvements in technology for identifying microbes by DNA sequencing have resulted in an explosion of interest in the populations that associate with the human body. Particular attention has focused on the microbes that inhabit human guts because of the profound effects they can have on health and disease.

Specific assemblies of gut microbes can act as an environmental factor contributing to obesity in susceptible hosts, a research area previously explored by Dr. Ruth Ley at Cornell University. Dysbiosis of the microbiota has been observed in irritable bowel syndrome, ulcerative colitis, and Crohn’s disease. Beneficial microbes modulate the immune system and help defend us against pathogenic organisms. Symbiotic microbes in the intestine result in enriched capacities for polysaccharide, amino acid, and xenobiotic metabolism and the biosynthesis of vitamins and isoprenoids.

The largest immunological organ in the body is the gut-associated lymphoid tissues, which produce molecules involved in immune defense and signaling, including cytokines and chemokines.

The bacteria that reside in the human gut communicate with intestinal epithelial cells and modulate their action, and vice versa. Nutrients and signals from intestinal cells affect which microbes thrive. Dr. Ley’s group discovered that antibodies secreted into the gut can signal to motile microbiota to cease their motility, in a process that may be fundamental to gut homeostasis.

ME/CFS patients exhibit both chronic activation and dysfunction of their immune systems. Cross-talk is known to occur between intestinal immune cells and the microbes that reside in the gut. An altered community of gut microbes due to a dysfunctional immune system could be responsible for some ME/CFS symptoms and contribute to chronic immune activation by affecting mucosal immunity and disrupting intestinal integrity, thus allowing translocation of bacteria from the gut into blood.

While the intestinal epithelium normally bars passage of bacteria, disturbances in its function can allow microbial translocation that results in the presence of lipopolysaccharide (LPS) in the serum. LPS can trigger immune responses and itself could be a factor responsible for some ME/CFS symptoms. ME/CFS patients have been reported to have increased IgA and IgM to LPS of enterobacteria.

A symptom often reported by ME/CFS patients is gastrointestinal disturbance. Because of the possibility that the gut microbiome could be altered, and that intestinal integrity might be compromised, Maureen Hanson’s group collaborated with Ruth Ley’s lab. Postdoctoral associate Ludovic Giloteaux spent time in both labs to complete the project.

DNA was isolated from fecal samples from subjects identified by Dr. Susan Levine. 16S rDNA sequencing was performed and the taxonomic groups present in each sample were identified by consulting a database. The number of different types of bacteria present in the ME/CFS patients’ samples was lower than in healthy individuals. Lower species diversity is also seen in inflammatory bowel disease.

Twenty-four families and genera were differentially abundant in patients and controls, with 18 groups less abundant in patients. Some of the bacterial groups that are less abundant in patients are known to produce anti-inflammatory molecules. Loss of those species may contribute to immune activation in patients.

Analysis of blood from the same patients provided evidence for increased microbial translocation and loss of integrity of the intestinal epithelium. Higher levels of LPS, LPS-binding protein, and sCD14, a receptor that detects LPS, were observed in the patients.

One conclusion that cannot be made from these findings is that dysbiosis of the gut is the cause of ME/CFS. A plausible hypothesis is that disturbances in gut function are contributing to the symptoms of the illness. The underlying cause of the abnormal microbiome and increased microbial translocation remains unknown.

An important message from this study is that there are quantifiable biological differences between an ME/CFS patient population and healthy individuals. Other biological differences have also been reported in the past, but the incorrect hypothesis that the disease is psychological continues to persist. Publicity about such findings is necessary to inform the public as well as health professionals that ME/CFS is a real, serious, and disabling physical illness.

Publications

Hanson MR, Giloteaux L. 2017. The gut microbiome in Myalgic Encephalomyelitis. Biochemist. 2017 Apr;39(2):10-13.

Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. 2016. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 4(1):30.

Articles About the Microbiome Study in the Lay Press

• A scientifically correct article published in a number of other locations:
  Gut bacteria may hold clues to chronic fatigue syndrome
• A well-written article, despite being illustrated by a sleepy cat:
  What Causes Chronic Fatigue Syndrome? This Study Sheds Light on a New Direction of Research
• An article that mentions evidence against the psychological concept of ME/CFS, but also includes a problematic exercise-recovery video based on the now-discredited PACE trial:
  Chronic fatigue syndrome and gut bacteria
  Background on the now-discredited PACE trial.
• An accurate article that includes an appropriate video about a severely ill ME/CFS patient:
  Chronic fatigue and gut bacteria
• The New York Times health blog:
  Gut Bacteria Are Different in People With Chronic Fatigue Syndrome
• An article that includes a video from the Swedish National Association for ME illustrating the severity of the disease:
  Labroots: Chronic Fatigue Syndrome biomarkers linked to gut microbiome

Eukaryotic Microbiota

The human gut microbiome is composed of bacteria, eukaryotes, and viruses. Gut eukaryotes typically consist of protozoa and fungi and are mainly commensal; nevertheless, the role such microbes play in healthy individuals is not well understood.

While most studies of the gut microbiota have focused on bacterial components, methods have been developed to examine eukaryotes through 18S rDNA sequencing.

Graduate student Alexandra Mandarano in Maureen Hanson’s group carried out a pilot study of the eukaryotic microbiota using a subset of the samples provided by Dr. Susan Levine for the bacterial microbiome study. The majority of identified eukaryotes in the gut microbiome were fungal and belonged to the phyla Basidiomycota or Ascomycota. Individual subjects were observed to have a unique composition of eukaryotes in their gut microbiome.

The Gut Virome

Although viruses that attack human cells are sometimes present in the human gut microbiome, by far the majority of viruses present are ones that attack bacteria.

High-throughput DNA sequencing is beginning to be applied to characterize the bacteriophages present in the human gut. Differential abundance of such bacteriophages in healthy versus ill individuals may result from gut dysbiosis that alters bacterial populations. It is also possible that bacteriophages may sometimes be responsible for altering the relative abundance of particular bacterial types.

Postdoctoral Research Associate Ludovic Giloteaux in Maureen Hanson’s lab used Illumina sequencing to characterize the enteric virome of ME/CFS patients who participated in the bacterial microbiome study. The predicted hosts of the identifiable phages and prophages were members of the Firmicutes and Bacteroidetes. These phyla, and in particular the families Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae, constituted the most abundant bacterial families in the sampled fecal microbial communities, as defined by 16S rRNA gene analysis.

Like the gut microbiome, the bacteriophage virome is abnormal in comparison with healthy individuals.

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