Gut microbiome dysbiosis: The chicken/egg scenario

November 6th, 2017 by Amy Proal
The gut microbiome expresses over 9 million genes (Image: Medium Magazine)

The gut microbiome expresses over 9 million genes (Image: Medium Magazine)

Just ten years ago the human body was assumed to be largely sterile. Today, molecular technologies have revealed complex microbial ecosystems in nearly every human organ/niche. These microbiome communities persist in blood, tissue, the brain, the liver, the amniotic fluid, the placenta and beyond.

To date, the gut microbiome is the most widely studied human microbiome ecosystem. For one thing, the gut harbors a tremendous number of microbes (the gut microbiome alone expresses over 9 million genes!). Also gut microbiome composition can be evaluated by collecting fecal samples. These fecal samples are easy and relatively cheap to obtain.

When it comes to the gut, an increasing number of studies report a common trend: most inflammatory disease states is associated with imbalance of the gut microbiome. This imbalance, or dysbiosis, is characterized by decreased gut microbiome species diversity.

If the gut microbiome reaches a state of dysbiosis, a second trend is often observed: the lining of the gut becomes “leaky,” or worn down. This allows infectious agents to more easily cross the intestinal lining into bloodstream. There, increased inflammation may be generated in response to their presence.

While gut dysbiosis and “leaky gut” contribute to symptoms and chronic inflammation, the phenomena beg an important question: Is gut microbiome dysbiosis the CAUSE of chronic inflammatory disease, or does it RESULT from immune dysfunction initiated inside the cells of the immune system?

I’ll describe research on HIV/AIDS to clarify the situation. Several studies show that the gut microbiome is imbalanced in HIV/AIDS. However, the disease is also connected to an easily identified pathogen; a pathogen able to survive inside the cells of the immune system. Once inside these cells, HIV is able to “hijack” and dysregulate human pathways that control the immune response. The result: patients with the virus become extremely immunocompromised, to the point where controlling infection at other body sites (like the gut) becomes a serious challenge.

Gut microbiota alterations during HIV infection and their potential effects on the host (Elinav et al)

Gut microbiota alterations during HIV infection and their potential effects on the host (Elinav et al)

With the above in mind, gut microbiome dysbiosis in HIV/AIDS is largely believed to be a SECONDARY or downstream result of the overall disease process. In effect, immune dysfunction caused by HIV intracellular infection (often in the blood/tissues) comes first. Gut microbiome dysbiosis comes second, as immune cells in the gut progressively lose the ability to correctly target/manage the billions of microbes in their vicinity.

Does this chicken/egg situation apply to other inflammatory disease states? It might. Take ME/CFS. Several research teams have reported gut microbiome imbalance/decreased species diversity in patients with the disease. This has raised the possibility that gut microbiome dysbiosis may initiate the ME/CFS disease process.

While this is possible, gut microbiome dysfunction in ME/CFS may actually be quite similar to that of HIV/AIDS. Consider that recent analyses have detected thousands of “new” microbes in human tissue/blood. Are any of these uncharacterized microbes capable of slowing the immune response by infecting the cells of patients with ME/CFS? If yes, then ME/CFS gut microbiome dysfunction may also be a downstream result of systemic intracellular infection.

Research on other inflammatory conditions supports this possibility. For example, the gut microbiome of patients with Alzheimer’s disease is characterized by decreased microbial diversity. However, central Alzheimers pathology occurs outside the gut (eg. amyloid beta accumulates in the brain in response to infection). Parkinson’s is also characterized by gut microbiome imbalance. But the disease is connected to other infectious processes, including prion build-up in the central nervous system (CNS). This led Parkinson’s researcher Haydeh Payami to ask the million dollar gut microbiome question:

“At this point, researchers do not know which comes first. Does having Parkinson’s cause changes in an individual’s gut microbiome, or are changes in the microbiome a predictor or early warning sign of Parkinson’s?”

Alzheimer's disease is characterized by gut microbiome dysbiosis (Image: Kerafast blog)

Alzheimer’s disease is characterized by gut microbiome dysbiosis (Image: Kerafast blog)

I think Payami’s first suggestion is most probable. In Parkinson’s, infection of immune cells in the brain/blood/CNS may cause a system-wide drop in immune function. Gut microbiome composition/balance may suffer as a result of this immunosuppression (it doesn’t help that immune cells in the gut can also become infected). 

Also, under these and similar conditions, gut microbiome dysbiosis CAN be a useful warning sign. Gut microbiome imbalance may serve as a predictive marker of increasing systemic immune dysfunction.

I’ll give another example. A recent study found that patients with more diverse gut microbiomes responded better to a cancer immunotherapy treatment. Based on this data, the research team concluded that diverse gut bacteria might “help” the treatment function correctly. But what if the opposite association is true? It’s very possible that subjects with higher gut microbiome diversity were simply less immunocompromised. Aka, the immune system of a person with less severe cancer would be able to better keep the gut microbiome in a state of balance. If this second possibility holds true, no wonder the patients with more diverse guts responded better to a therapy that requires the immune system to work (immunotherapy).

Gut microbiome studies should subsequently be accompanied by analyses that continue to study intracellular pathogens capable of slowing the human immune response. We must also study the numerous strategies these pathogens employ to infect host cells.  As I’ve published many times, intracellular pathogens can directly alter human DNA transcription, translation and metabolic activity. This makes them uniquely suited to drive inflammatory disease processes.

Screen Shot 2017-11-06 at 10.49.51 AMIf you follow me on Twitter (@microbeminded2), you’ll see I’ve shared many recent studies that better clarify how pathogens survive inside human cells. In fact, intracellular survival could be considered a pre-requisite for any human pathogen able to drive a persistent disease. One study found that Zika virus slows T cell activity by infecting human macrophages. By surviving inside human cells, S. aureus maintains greater control over nasal microbiome composition. Mycobacterium tuberculosis can persist for decades inside the acidic lysosomes of human cells.  A range of bacteria can use flagella (a motor-like tail) to better colonize and attack host cells. E.coli rapidly evolve to invade white blood cells in order to evade the immune response. 

E.coli (in blue) inside the phagosomes of human white blood cells

E.coli (in blue) inside the phagosomes of human white blood cells

 

I don’t mean to suggest that gut microbiome dysbiosis isn’t a major issue in its own right. Even if imbalance is a downstream result of intracellular infection, it still “feeds into” pathways increasing symptoms and illness progression. An imbalanced gut may begin to harbor new pathogens, or allow chronic pathogens to re-activate. This causes additional suffering, inflammation, and disease. 

So dietary interventions and other treatments aimed at improving gut microbiome function are still very important. Let’s just make sure these therapies are accompanied by research on intracellular infection, immunity, and microbial persistence in tissue/blood.     

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