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Diabetic neuropathy caused by gut microbes?

For a decade or more, evidence has implicated the gut microbiota in the pathogenesis of type 2 diabetes. Transfer of fecal bacteria from an obese, insulin resistance mouse causes the rapid induction of insulin resistance in recipient mice, for instance. More recent work by Thaiss et al. published in Science demonstrates a causal role for an altered gut microbiota in diabetes, showing impaired gut barrier function and increased microbial dissemination to be key events in the pathogenesis of the disease.

In addition, observational studies suggest that the gut microbiota plays a role in diabetes complications such as diabetic retinopathy and diabetic neuropathy, both degenerative nerve diseases. Recent findings by Forsyth et al. indicate a causal role for gut microbes interacting with the immune system in neurologic disorders such as diabetic neuropathy and Parkinson’s disease. Another study showed that metabolic syndrome – insulin resistance, inflammation, and blood lipid abnormalities that often accompany diabetes – occurs after gut microbiota undergo a pathologic change and after enteric (gut) neuropathy appears.

Do gut microbiota attack enteric neurons in diabetes and Parkinson’s disease? I became interested in this topic after hearing UCLA gastroenterologist Emeran Mayer talk about his experience seeing patients in the GI clinic with gut motility and constipation problems, years before they were diagnosed with Parkinson’s disease. In the movement disorder Parkinson’s disease, pathological alpha-synuclein immunoreactivity occurs first in peripheral neurons in the gut, prior to their appearance in the substantia nigra in the brain. These intriguing observations raise the possibility that some neurological disorders may have their origin in the gut, and that the ENS (enteric nervous system) is a target of gut pathogens.

For the host, gut motility, or peristalsis, moves the products of digestion through the digestive tract and it also prevents a dangerous overgrowth of gut microbes. In the setting of bowel obstruction, where the forward movement of digesta and microbes becomes impossible, gut microbes produce gut ischemia, perforation, and lethal sepsis. More commonly, hosts are engaged in a tug of war over motility with harmful gut microbes. Gut microbes capable of slowing the movement of the gut can gain an advantage by increasing their numbers or prolonging their stay in the intestine. They may gain also access to dietary nutrients otherwise inaccessible to them, resulting in a fitness advantage. Hosts, conversely, have an interest in preventing bacterial overgrowth – bile acids, lysozyme, and motility protect hosts against harmful overgrowth. Various protective microbes also antagonize gut pathogens, and their products, e.g., butyrate, can have the effect of speeding gut motility.

How could microbes slow motility?  Sulfate reducing bacteria produce hydrogen sulfide, a neurotransmitter gas, that slows motility.  Microbial produced nitric oxide is another molecule that reduces gut motility. Another candidate molecule is phenylacetylglutamine, PAG. PAG is a neurotoxic metabolite that is similar in structure to a catecholamine. A recent unstructured metabolomic study showed it to be enriched in diabetics with neuropathy and a likely cause of neuron loss in those patients.

Endotoxin also reduces gut motility. Reichardt et al showed that giving mice a Western diet rich in saturated fatty acids alters the gut microbiome in a way that increases endotoxin interacting with TLR4, disrupts motility, and induces loss of nitrergic neurons. These are the same neurons that are lost in diabetic neuropathy. Overstimulation of nitrergic neurons by endotoxin causes a kind of cell death, pyroptosis, in those neurons that prevents colon smooth muscle from relaxing and impairs colonic motility. 

So, is it possible that diabetic neuropathy result’s from gut pathogens gaining an advantage by damaging gut neurons? If true, antibiotics that target gut pathogens should tend to increase gut motility and could be helpful in treating constipation. When I was a resident in the intensive care unit, we often used the antibiotic erythromycin to induce gut peristalsis, which was useful when we were trying to advance feeding tubes into the small intestine of our patients. Because of their effect on gut bacteria, antibiotics would be expected to influence motility via the gut-brain axis. However, antibiotics have also been shown to have direct pro-motility effects. Similar findings are reported for diet-derived compounds that kill gut pathogens. Quercetin, a plant flavonoid, was shown by Xie and colleagues to reverse dysbiosis linked with gut neuropathy. Quercetin in this study boosted the densities of beneficial microbes and diminished the numbers of pathogens, while also protecting against neuropathic changes in gut neurons. If this effect is generalized, we would expect that a great many plant flavonoids and polyphenols might have similar effects. This is because we evolved with those dietary compounds that had predictably beneficial effects on the microbiome when they are consumed. 

Categories: Uncategorized

Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine

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