14 Feb 2017

Discovering what Einstein might have described as “spooky action at a distance,” a study published February 8 in Scientific Reports claims that microbes in the gut somehow manage to exacerbate Aβ pathology in the brain. Led by Tristan Bolmont at École Polytechnique Fédérale de Lausanne in Switzerland, the work adds to fledgling evidence implicating gut bacteria in neurodegenerative disease. The researchers reported that APPPS1 mice developed a different throng of gut microbes than their wild-type brethren. What’s more, raising the animals in a sterile environment, without gut microbes, reduced inflammation and Aβ accumulation in their brains. Conversely, colonizing the intestines of these sterile animals with microbes from other mice ramped up their Aβ, even more so if the microbes came from APPPS1 animals. If similar microbial connections happen in people, perhaps one day tailor-made probiotic cocktails could slow the onslaught of AD, the researches proposed.

“There are so many unanswered questions in this field, but this study is another small piece of the puzzle, confirming the connection between gut microbes and neurodegeneration,” said Marco Prinz of the University of Freiburg in Germany.

Several recent studies have drawn connections between intestinal flora and neuropathology in the brain. Last year, researchers reported that treating AD mice with antibiotics substantially reduced the animals’ amyloid burden (see May 2016 conference news). Similarly, others reported that treating Parkinson’s disease model mice with antibiotics, or raising them in a sterile environment, dampened both α-synuclein pathology and movement deficits.

These researchers found that short chain fatty acids (SCFAs) secreted by the gut microbes somehow ramped up neuroinflammation and exacerbated brain pathology (see Dec 2016 news). Along the same vein, another study reported that amyloidogenic peptides secreted by bacteria in the gut did the same (see Oct 2016 news). 

Of course, the microbes aren’t all bad: Researchers led by Prinz reported that SFCAs secreted by the microbes keep microglia ready to respond to threats (see Jun 2015 news). And just as microbes may alter the course of neurodegenerative disease, it appears that disease alters the microbial communities teeming in the gut. Researchers have observed altered microbial profiles in animal models and in people with AD, PD, and other brain diseases (see Cattaneo et al., 2017; Keshavarzian et al., 2015; Scheperjans et al., 2015). 

Against this backdrop of cross talk between brain and belly, first author Taoufiq Harach and colleagues wanted to examine if intestinal microbial communities in APPPS1 mice differed from those in wild-type. They sequenced 16S rRNA from fecal microbes of 1-, 3.5-, and 8-month-old wild-type and APPPS1 mice. The latter start developing Aβ deposits at 1.5 months of age. While gut microbial species in all mice changed with age, their composition changed most drastically in APPPS1 animals. By eight months, Firmicutes, Verrucomicrobia, Proteobacteria, and Actinobacteria taxa plummeted in APPPS1 mice, while Bacteroidetes increased compared to wild-type. The APPPS1 animals also had significantly more of the bacterial genera Rikenellaceae and S24-7, and less of Allobaculum and Akkermansia, as well as a generally more diverse array of species than wild-type mice. 

Micro Milieu. With age, microbial taxa inhabiting the gut change differently in conventionally raised (CONVR) APPPS1 transgenic mice than wild-type. [Courtesy of Harach et al., Scientific Reports 2017.]

Do these microbes have anything to do with Aβ pathology? To find out, the researchers bred and maintained APPPS1 mice in a germ-free environment, and compared the abundance of cerebral Aβ peptides to that in siblings in standard cages. Germ-free and conventionally raised mice were fed sterilized food. The concentrations of Aβ38, 40, and 42 rose as both germ-free (GF) and conventionally raised AD mice aged. However, compared to mice with microbes, GF mice had 42 and 31 percent less Aβ42 at 3.5 and eight months of age, respectively. Histopathological analysis of brain sections revealed that a life without microbes also reduced Aβ plaques by more than half in both the cortex and the hippocampus. Interestingly, the GF mice also had substantially higher levels of the Aβ degrading enzymes neprilysin degrading enzyme (NDE) and insulin degrading enzyme (IDE), offering a potential explanation for the animals’ lowered Aβ loads.

Neuroinflammaton also influences Aβ deposition. Compared to conventional APP/PS1 animals, germ-free mice had half as many Iba1-positive microglia in the brain and steady, rather than increasing, brain concentrations of the inflammatory cytokine IL-1β as they aged. At 3.5 months, the germ-free mice had lower brain levels of three cytokines produced by T cells—IFN-γ, IL-2, and IL-5. 

To determine whether microbiota could exacerbate Aβ pathology, the researchers inoculated four-month-old GF APPPS1 animals with microbes from year-old wild-type or APPPS1 mice that had been raised in conventional environs. Eight weeks later, Aβ42 levels had jumped by 145 percent in animals colonized with microbes from wild-type mice, but by 278 percent in animals incubating bugs from APPPS1 mice. In fact, GF animals colonized with APPPS1 microbes ended up with just as much Aβ42 as conventionally raised APPPS1 mice.

Harach and Bolmont told Alzforum that they are now focusing on how microbes influence Aβ pathology in the brain. They speculated that certain microbial metabolites, including SCFAs, other small lipids, and carbohydrates, could influence the process. This would be in line with recent studies implicating SCFAs in revving up microglia and stoking α-synuclein pathology.

Prinz, whose work implicated SFCAs in maturing microglia, said it would be interesting to test whether the fatty acids play a role in microglial responses to Aβ. “At the end of the day, it’s not clear whether it’s the diversity of bacteria, or a specific strain producing a certain metabolite, that alters Aβ pathology,” he added.

Robert Friedland of the University of Louisville in Kentucky recently reported that amyloids secreted by bacteria in the gut promoted α-synuclein pathology. He said a similar mechanism could account for microbial influence on Aβ pathology. He proposed that different bacterial amyloid strains seed the misfolding of different amyloidogenic proteins—such as α-synuclein and Aβ—either by traveling from the gut or nose to the brain, or via the blood. Interestingly, Friedland also reported that these bacterial amyloids trigger pro-inflammatory responses.

“The gut is our biggest environmental exposure, so the immune system is constantly sampling its contents,” Friedland said. “It is primed to consider bacterial amyloids as dangerous, which could explain why amyloidogenic proteins trigger a neuroinflammatory response.”

Do similar connections between gut microbes and neuropathology occur in humans? Bolmont and Harach recently contributed to a study reporting that people with AD had higher amounts of pro-inflammatory microbial species in their guts (see Cattaneo et al., 2017). For future studies, Bolmont and colleagues will test whether colonization of AD mice with microbes from AD patients exacerbates brain Aβ pathology in the animals. On the flip side, they also want to identify microbial species that can ameliorate the pathology, with an eye toward developing a therapeutic probiotic cocktail.—Jessica Shugart

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References

Research Models Citations

1. APPPS1

News Citations

1. Microbial Hypotheses Intrigue at Zilkha Alzheimer’s Meeting 9 May 2016
2. Do Microbes in the Gut Trigger Parkinson’s Disease? 2 Dec 2016
3. Could Bacterial Amyloid Trigger Parkinson’s Pathology? 14 Oct 2016
4. To Be Hale and Hearty, Brain Microglia Need a Healthy Gut 5 Jun 2015

Paper Citations

1. Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, Ferrari C, Guerra UP, Paghera B, Muscio C, Bianchetti A, Volta GD, Turla M, Cotelli MS, Gennuso M, Prelle A, Zanetti O, Lussignoli G, Mirabile D, Bellandi D, Gentile S, Belotti G, Villani D, Harach T, Bolmont T, Padovani A, Boccardi M, Frisoni GB, INDIA-FBP Group. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017 Jan;49:60-68. Epub 2016 Aug 31 PubMed.
2. Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM. Colonic bacterial composition in Parkinson's disease. Mov Disord. 2015 Sep;30(10):1351-60. Epub 2015 Jul 16 PubMed.
3. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015 Mar;30(3):350-8. Epub 2014 Dec 5 PubMed.

Further Reading

Papers

1. Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, Faßbender K, Schwiertz A, Schäfer KH. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord. 2016 Nov;32:66-72. Epub 2016 Aug 26 PubMed.

News

1. Microbial Hypotheses Intrigue at Zilkha Alzheimer’s Meeting 9 May 2016
2. Like a Tiny Spider-Man, Aβ May Fight Infection by Cocooning Microbes 27 May 2016