Gut microbes and synuclein mice

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Timothy Sampson, Sarkis Mazmanian and colleagues at Caltech (17 authors), with Rob Knight, Marie-Françoise Chesselet, Ali Keshavarzian, Kathleen Shannon, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Viviana Gradinaru and others. Funders named in the paper: the Knut and Alice Wallenberg Foundation and Swedish Research Council (Wittung-Stafshede), a private gift to Keshavarzian, the Heritage Medical Research Institute (Gradinaru, Mazmanian), US National Institutes of Health grant NS085910 (Mazmanian) and a Larry L. Hillblom Foundation fellowship (Sampson).

What happened

The team used Thy1-alpha-synuclein mice, which overproduce the protein and develop movement problems. Raised germ-free (no gut microbes), these mice had milder movement deficits, fewer activated microglia and less synuclein clumping in movement-related brain regions. Antibiotics gave a similar benefit in adult animals, while recolonising with microbes restored the problems. Giving certain microbial products (short-chain fatty acids, byproducts of fibre fermentation) to germ-free mice promoted inflammation and movement symptoms. Transplanting gut microbes from 6 people with new-onset, untreated Parkinson's into the mice worsened their motor impairment more than microbes from 6 matched healthy donors. Cell 167:1469-1480, 1 Dec 2016.

Why it moved us toward a cure

Patients' gut bacteria had been shown to differ from controls' (landmark 217). It gave experimental support for a gut-brain route in disease (landmark 18), and suggested a second, non-neuronal way the gut might affect the brain: via microbial chemicals and immune activation (landmark 52). If microbes modify disease, the microbiome might be a target, though not yet a treatment.

Outcome

Open. The effect is shown in one engineered mouse line, with only 6 donors per group for the human-microbe result. Sampson warned that the long, high-strength antibiotic use in the study is risky for humans and that antibiotics and stool transplants are not yet viable therapies; Mazmanian said translating the work to people would take many years. A 2024 randomised trial of one stool transplant (GUT-PARFECT, Ghent, 46 patients, 12 months) reported off-medication motor scores improving by 5.8 points with healthy-donor stool and 2.7 with the patient's own stool; that is a symptom outcome in one centre, not evidence of slowing the disease. No correction or retraction of the 2016 paper was found; four commentaries accompanied it (Europe PMC).

Sources

• Sampson et al., Cell 2016;167(6):1469-1480, DOI 10.1016/j.cell.2016.11.018, PMID 27912057 (abstract and full text via Europe PMC and PMC5718049; also Caltech record)
• ScienceDaily, Caltech news, 1 Dec 2016 (the authors' cautions)
• Bruggeman et al., eClinicalMedicine 2024, DOI 10.1016/j.eclinm.2024.102563 (abstract via Europe PMC)
• Not yet verified: independent replication of the human-donor transplant result; the full GUT-PARFECT between-group result.