Microbial signals emanating from the bowels of mice somehow worsen tau pathology and neurodegeneration. This, according to a study that used microbe-nixing protocols to connect bacteria teeming in the gut, ApoE genotype, and tau-mediated neurodegeneration. Led by David Holtzman at Washington University in St. Louis, scientists found that tau transgenic mice raised in germ-free conditions harbored less tau pathology, and suffered less neurodegeneration, than their microbe-replete counterparts. Briefly killing off gut microbes with a round of antibiotics also fended off tau-mediated damage, but only in males, and more so in those expressing ApoE3 than ApoE4. The scientists tied short-chain fatty acids churned out by some gut microbes to cytokine production by innate immune cells that may stoke damaging glial responses. The findings, published in Science on January 13, support the idea that strong ties exist between the throngs of microbes living in the gut, and neuroinflammatory conditions in the brain.
- Raising them sans microbes protects tau-transgenic mice.
- Antibiotics only protect males, especially those expressing ApoE3.
- Short-chain fatty acids produced by gut bacteria revved cytokines, riled glia in brain.
“Overall, these exciting results highlight the potential to harness the gut microbiota to prevent or slow the progression of AD and other tauopathies, and raise awareness about the potential long-term effects of early life diet,” wrote Tanya Jain and Yue-Ming Li of Memorial Sloan Kettering Cancer Center in New York in an editorial accompanying the paper in Science.
Besides tau, other neurodegenerative culprits, including Aβ and α-synuclein, are reportedly goaded by the diverse bacterial inhabitants of the gut (Dec 2016 news; Feb 2017 news; Apr 2020 conference news). Exactly how the bacteria manage to accelerate brain pathology is not entirely clear, however, studies suggest that microbial metabolites, including short-chain fatty acids, influence the state of peripheral immune cells as well as glia in the brain (Jun 2015 news).
First author Dong-Oh Seo and colleagues studied how these microbiome-microglia interactions might play out in the context of tauopathy. Previously, Holtzman’s group found that microglia were centrally involved in wreaking neuronal havoc in response to tau pathology, and that ApoE4 made things worse (Sep 2017 news). To find out if signals from the gut microbiome fit into this picture, the researchers raised P301S-tau/ApoE4 transgenic (TE4) mice, in germ-free conditions from birth. Remarkably, a life without gut microbes lessened the burden of tau tangles and protected the TE4 mice from neurodegeneration. Both males and females benefited, but not when the mice were fed a generous helping of gut bacteria—in the form of poop—from 40-week-old TE4 mice.
When the researchers intervened more transiently with the microbiome, by giving 2-week-old mice a week-long round of antibiotics, only male mice benefited, and P301S-tau/ApoE3 knock-in (TE3) males were more protected than TE4 males. At 40 weeks of age, they had much less tau pathology and neurodegeneration in their brains than untreated controls. Antibiotics did nothing to fend off tau pathology or neurodegeneration in female mice, regardless of ApoE genotype. Notably, female mouse microbiomes are different from male microbiomes. As reported previously, ApoE knockout, “TEKO” mice, were protected from both tau pathology and neurodegeneration.
Antibiotics Fend Off Tau. Hyperphosphorylated tau (brown) packed the hippocampi of male TE3 and TE4 mice (top). Treatment with antibiotics dramatically reduced tau burden in TE3, but less so in TE4 mice (bottom). Tau mice without ApoE have little pathology, with or without antibiotic treatment (right). [Courtesy of Seo et al., Science, 2023.]
Might the differential effect of the microbiome based on sex and ApoE genotype come down to glia? Using single-cell RNA sequencing, the researchers found that in response to tau pathology, astrocytes and microglia expanded and dramatically shifted their gene expression profiles. Treatment with antibiotics dampened this shift in male TE3 mice, but not in male TE4 mice, or in females of either genotype. The findings align with previous work from the Holtzman lab and other groups, which indicated that both female sex and ApoE4 genotype promote damaging responses in microglia (Oct 2019 news; Jul 2019 conference news). “Perturbing the microbiome with antibiotics may be insufficient to overcome the effects of sex and ApoE genotype on microglia,” Holtzman said.
Next, the researchers looked for signals from the microbiome that could explain the responses to antibiotics. Treatment with this cocktail in early life stripped the gut of microbes temporarily, and a different complement grew back into adulthood. Fewer Helicobacter, Ruminococcus, and Butyricicoccus populated the intestines at 40 weeks of age. Members of the latter two genera are known to churn out short-chain fatty acids (SCFAs). In line with this, concentrations of these fatty acids dropped in the gut in response to antibiotics, but only in males. Untreated females already have less SCFAs in their gut than do untreated males, perhaps explaining why the females did not respond to antibiotics. When the researchers added a cocktail of microbial SCFAs—acetate, butyrate, and proprionate—to the drinking water of the male TE4 mice that were raised in germ-free conditions, the mice developed substantial tau pathology and gliosis.
Glia do not express SCFA receptors, so why do the cells respond to the metabolites? The scientists hypothesized that SCFAs might activate glia indirectly, via peripheral immune cells that do express SCFA receptors, such as those that patrol the meninges. In support of this idea, they found that antibiotic-treated male mice had fewer meningeal γδ T cells and plasmacytoid dendritic cells. The latter produce most of the interferon in the body, Holtzman noted, and this inflammatory molecule is known to incite neuroinflammation in the brain. The findings hint that interferon cranked out by pDCs in the meninges could provide a pathogenic link between microbes in the gut and microglia in the brain.
Microbiome-Microglia Convergence. Gut microbes (bottom) release numerous metabolites, including short-chain fatty acids (SCFA). These interact with peripheral immune cells (center), which influence glial activity in the brain (top). [Courtesy of Seo et al., Science, 2023.]
Daniel Erny of the University of Freiburg in Germany noted that while SCFAs may indirectly transform microglia by activating peripheral immune cells, a direct pathway also exists. Previously, Erny reported that the acetate, a microbial SCFA, enters the CNS, where it is readily taken up by microglia (Erny et al., 2021). He found that while acetate worsened Aβ accumulation in 5xFAD mice, it was also essential for proper microglial maturation and homeostasis in healthy mice. Notably, SCFAs can be anti-inflammatory in other disease settings, such as multiple sclerosis (Melbye et al., 2019). “The role of SCFAs is health and disease-context dependent,” Erny said.
For Erny, the most important message from the paper is that the two hallmark pathologies of AD—amyloid plaque and now neurofibrillary tangles—are similarly exacerbated by the microbiome via microglia.
Steven Estus and Diana Zajac of the University of Kentucky in Lexington noted that SCFAs may also act independently of microglia in the brain by, for example, dampening levels of amyloid clearing enzymes (Harach et al., 2017).—Jessica Shugart
- Do Microbes in the Gut Trigger Parkinson’s Disease?
- Microbes in the Gut Egg on Aβ Pathology in Mice
- ‘Working from Home’: Do Gut Microbes Hold Sway Over Glia, Aβ?
- To Be Hale and Hearty, Brain Microglia Need a Healthy Gut
- ApoE4 Makes All Things Tau Worse, From Beginning to End
- In Tauopathy, ApoE Destroys Neurons Via Microglia
- Down to Sex? Boy and Girl Microglia Respond Differently
Research Models Citations
- Tau P301S (Line PS19)
- APOE4 Knock-In, floxed (CureAlz)
- APOE3 Knock-In, floxed (CureAlz)
- 5xFAD (C57BL6)
- Erny D, Dokalis N, Mezö C, Castoldi A, Mossad O, Staszewski O, Frosch M, Villa M, Fuchs V, Mayer A, Neuber J, Sosat J, Tholen S, Schilling O, Vlachos A, Blank T, Gomez de Agüero M, Macpherson AJ, Pearce EJ, Prinz M. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab. 2021 Nov 2;33(11):2260-2276.e7. PubMed.
- Melbye P, Olsson A, Hansen TH, Søndergaard HB, Bang Oturai A. Short-chain fatty acids and gut microbiota in multiple sclerosis. Acta Neurol Scand. 2019 Mar;139(3):208-219. Epub 2018 Dec 3 PubMed.
- Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fåk F, Jucker M, Lasser T, Bolmont T. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017 Feb 8;7:41802. PubMed.
No Available Further Reading
- Seo DO, O'Donnell D, Jain N, Ulrich JD, Herz J, Li Y, Lemieux M, Cheng J, Hu H, Serrano JR, Bao X, Franke E, Karlsson M, Meier M, Deng S, Desai C, Dodiya H, Lelwala-Guruge J, Handley SA, Kipnis J, Sisodia SS, Gordon JI, Holtzman DM. ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science. 2023 Jan 13;379(6628):eadd1236. PubMed.