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Evidence that the perinatal maternal microbiome mediates metabolite signaling programs that drive sex-specific microglial metabolic alterations and Alzheimer’s disease susceptibility
Saha P, Slimmon N, Nadgauda A, Patel P, Mishra D, Poli PB, Inukai A, Fernandez A et al.. Research Square, 2026-10-23
Topic: Gut, metabolism and diet
Maternal microbiome-dependent programming of neuroimmune and metabolic pathways during early development may critically shape sex-specific susceptibility to Alzheimer’s disease (AD) later in life. We have documented that in mouse models of Aβ deposition, broad-spectrum antibiotic (ABX)-mediated perturbations of the gut microbiome postnatally (P14-P21) selectively reduces Aβ pathology only in male, but not in female animals. Here, we shift the developmental window upstream to test whether perinatal maternal microbiome perturbations shapes the pathological trajectories of offspring. Dams were treated with the broad-spectrum ABX from preconception through gestation, without direct exposure of the offspring. Strikingly, maternal microbiome disruption selectively reduced cortical Aβ burden in female offspring, with no effect in males, effectively reversing the sex bias observed following postnatal ABX manipulations. To explore the mechanisms underlying this effect, we now report that female offspring exhibited coordinated shifts in microbial composition and amino acid metabolism, that are coupled to cortical transcriptional programs enriched for GPCR signaling and Rho GTPase pathways. As many microbial metabolites and amino acid-derived ligands signal through GPCRs that are expressed by microglia, these transcriptional changes suggest enhanced GPCR-mediated nutrient sensing in microglia of female animals. These systems level changes in microglia drive a metabolically engaged amyloid clearing phenotype, providing a mechanistic link between maternal microbiome disruption and enhanced Aβ clearance in females. Together, these findings demonstrate that maternal microbial inheritance and developmental timing critically shape sex specific AD susceptibility and position temporal microbiome modulation as a potential precision strategy for disease prevention.
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APA 7th
Saha, P., Slimmon, N., Nadgauda, A., Patel, P., Mishra, D., Poli, P. B., et al. (2026). Evidence that the perinatal maternal microbiome mediates metabolite signaling programs that drive sex-specific microglial metabolic alterations and Alzheimer’s disease susceptibility. Research Square. https://doi.org/10.21203/rs.3.rs-11307065/v1
Vancouver
Saha P, Slimmon N, Nadgauda A, Patel P, Mishra D, Poli PB, et al. Evidence that the perinatal maternal microbiome mediates metabolite signaling programs that drive sex-specific microglial metabolic alterations and Alzheimer’s disease susceptibility. Research Square. 2026. doi:10.21203/rs.3.rs-11307065/v1.
BibTeX
@article{saha2026-847bc61d,
author = {Saha, P. and Slimmon, N. and Nadgauda, A. and Patel, P. and Mishra, D. and Poli, P. B. and Inukai, A. and Fernandez, A. and others},
title = {{Evidence that the perinatal maternal microbiome mediates metabolite signaling programs that drive sex-specific microglial metabolic alterations and Alzheimer’s disease susceptibility}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11307065/v1},
url = {https://doi.org/10.21203/rs.3.rs-11307065/v1}
}
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Key findings
- Together, these findings demonstrate that maternal microbial inheritance and developmental timing critically shape sex specific AD susceptibility and position temporal microbiome modulation as a potential precision strategy for disease prevention.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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