Bacteria may play a significant role in inflammatory disease

According to research from Stellenbosch University and the University of Manchester, bacterial cell wall mopping agents could treat chronic inflammatory diseases like type 2 diabetes

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Recent academic research news indicates that bacteria may be responsible for more kinds of disease than has thus far been suspected, particularly in terms of inflammatory diseases like type 2 diabetes (T2D).
More specifically, Prof. Resia Pretorius from Stellenbosch University (SU) in South Africa and Prof. Douglas Kell from the University of Manchester have conducted a series of studies that “are drastically changing the way scientists think about the effect bacteria have on a number of diseases including Alzheimer’s disease, Parkinson’s disease, sepsis, rheumatoid arthritis and most recently type 2 diabetes,” according to the University of Manchester.
As The New Scientist noted in September 2016 of earlier and similar research by Pretorius and Kell, “Researchers have found that bacteria in the blood of healthy people may help trigger strokes and heart attacks, and perhaps also contribute to conditions like Alzheimer’s disease, diabetes and arthritis. All of these disorders involve inflammation ... [they] are also all linked to overactive blood clotting, excessive levels of iron in the blood and sheets of abnormally folded proteins ... To see if bacteria could be playing a role in all this, [Kell and Pretorius] have been looking at their ability to disrupt clotting.”
As the University of Manchester points out, Pretorius and Kell have previously established that many chronic inflammatory diseases have a microbial origin. But there is a catch that has hampered that realization coming about earlier. “If the bacteria were active, or replicating, as in the case of infectious diseases, we would have known all about that,” explained Kell. “But the microbes are not replicating, they’re mainly actually dormant.”
This “dormancy” meant that bacteria didn’t show up under standard microbial test conditions—also, bacteria had been thought to be absent from human blood, the university notes. However, high levels of iron in blood (typical of inflammatory diseases) can effectively bring these bacteria back to life. Previous research suggested that under these conditions, the bacteria start replicating and secreting lipopolysaccharides (LPS), leading to increased inflammation.
As Pretorius and Kell had already established, anomalous amyloidogenic blood clotting, a cause of inflammation, is linked to and can be experimentally induced by bacterial cell wall constituents such as LPS and lipoteichoic acid (LTA), which are components of gram-negative and gram-positive bacteria, respectively.
“These coagulopathies (adverse blood clotting) are also typical of inflammatory diseases, and the researchers have long shown that they lead to amyloid formation, where the blood clotting proteins (called fibrinogen) are structurally deformed from a-helixes to a flat b-sheet-like structures, potentially leading to cell death and neuro-degeneration,” noted the University of Manchester. As a result, the fibrin fibers of blood clots in diseased individuals are distinctly different from those of healthy individuals.
“In normal blood clots, these fibers would look like a bowl of spaghetti,” explained Pretorius. “But in diseased individuals, their blood clots look matted with large fused and condensed fibers. They can also be observed with special stains that fluoresce in the presence of amyloid.”
The researchers found that this changed clot structure is present in all inflammatory conditions studied, now including T2D.
In their 2017 study, recently published in Scientific Reports, Pretorius and Kell, along with student Sthembile Mbotwe from the University of Pretoria, investigated the effect of LPS-binding protein (LBP), which is normally produced by all individuals. They added LBP to blood from T2D patients (and also to healthy blood after the addition of LPS). Previously they had showed that LPS causes abnormal clot formation when added to healthy blood, and that this could be reversed by LBP. In this publication they showed that LBP could also reverse the adverse clot structure in T2D blood. This process was confirmed by both scanning electron microscopy and super-resolution confocal microscopy, leading to the conclusion that bacterial LPS is a significant player in the development and maintenance of T2D and its disabling sequelae.
“In an inflamed situation, large amounts of LPS probably prevent LBP from doing its work properly,” explains Pretorius. “We now have a considerable amount of evidence, much of it new, that in contrast to the current strategies for attacking T2D, the recognition that it involves dormant microbes, chronic inflammatory processes and coagulopathies, offer new opportunities for treatment.”
Or, as the University of Manchester put it: More work on therapeutics for inflammatory conditions may need to look at whether there any molecules that may “mop up” LPS or LTA that might be circulating in the blood of people with inflammatory diseases.
In other recent work at the University of Manchester on bacteria and inflammation, researchers reported in May 2016 that tests on the mucus lining of the intestine, performed in mice, found changes in bacteria that could lead to inflammatory bowel disease 12 weeks earlier than previously possible through looking at stool samples, leading to the possibility of earlier diagnosis and better management of the disease in humans.
Diagnosis of inflammatory bowel diseases like Crohn’s Disease and ulcerative colitis is often only made once the patient has symptoms, and it has been shown that once they are ill they often have changed bacteria in their stools. But as the university noted, it had never been clear whether bacterial changes cause the inflammation or happen as a result of inflammation.
However, the bacteria commonly found in stool samples have a different profile to those found in the mucus lining which protects the intestinal tissue. It is this mucus layer that the University researchers tested.
Dr. Sheena Cruickshank, who led the research, said: “Stool samples do not fully replicate the complex picture of the microbiota in the gut which lives in communities in discrete locations within the gut. We took mucus samples which are found right next to the cells of the gut and therefore closer to where the problems develop. As a result we could see changes in the microbiota twelve weeks before they were detectable in the stool samples.
“The bacteria in the gut usually live in a carefully balanced system, and this is incredibly useful for digestion and keeping us healthy. However, for some reason, this balance can be disturbed. Being able to observe what is upsetting this balance earlier and understanding the bacteria involved will give us much greater opportunities to understand the causes of some of these painful diseases and better help patients.”

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