Lua Labs Report — Specific prebiotics that modulate the estrobolome and progesterobolome

Date: 2026-05-19 Researcher: Lua Labs Classification: Microbiome · Nutrigenomics · Metabolomics Line: L1 — Gut-hormonal axis (estrobolome) Sub-topic: 1.5 — Specific prebiotics that support the estrobolome (inulin, FOS, resistant starch, polyphenols, LATAM fibers)

External sources

1. Geng et al. (2025). "Gut Microbiota Modulation by Inulin Improves Metabolism and Ovarian Function in Polycystic Ovary Syndrome". Advanced Science. PMC12120758. https://pubmed.ncbi.nlm.nih.gov/40192074/
2. Bian et al. (2023). "Dietary Supplementation of Inulin Contributes to the Prevention of Estrogen Receptor-Negative Mammary Cancer by Alteration of Gut Microbial Communities and Epigenetic Regulations". International Journal of Molecular Sciences. PMC10218871. https://pubmed.ncbi.nlm.nih.gov/37240357/
3. Li et al. (2024). "Resistant starch intake facilitates weight loss in humans by reshaping the gut microbiota". Nature Metabolism 6:578–597. https://www.nature.com/articles/s42255-024-00988-y
4. Yang et al. (2024). "Gut microbial features and dietary fiber intake predict gut microbiota response to resistant starch supplementation". Gut Microbes. PMC11197919. https://pmc.ncbi.nlm.nih.gov/articles/PMC11197919/
5. Remes-Troche et al. (2024). "A Randomized, Double-Blind, Placebo-Controlled Trial: Efficacy of Opuntia ficus-indica Prebiotic Supplementation in Subjects with Gut Dysbiosis". Nutrients. PMC10934938. https://pubmed.ncbi.nlm.nih.gov/38474715/
6. Salas-Salvadó et al. (2024). "The Effect of Opuntia ficus Mucilage Pectin and Citrus aurantium Extract Added to a Food Matrix on the Gut Microbiota of Lean Humans and Humans with Obesity". Foods 13(4):587. https://www.mdpi.com/2304-8158/13/4/587
7. Hu et al. (2023). "Gut Microbiota and Critical Role of the Estrobolome — β-glucuronidase Enzyme as Potential Therapeutic Target in Breast Cancer". PMC10535898. https://pmc.ncbi.nlm.nih.gov/articles/PMC10535898/
8. Mendoza-Pérez et al. (2017/2024 update). "Nixtamalization Process Affects Resistant Starch Formation and Glycemic Index of Tamales". J Food Sci. https://pubmed.ncbi.nlm.nih.gov/28398614/
9. Honda et al. (2024). "Supplementation with a Probiotic Formula Having β-Glucuronidase Activity Modulates Serum Estrogen Levels in Healthy Peri- and Postmenopausal Women". Journal of Medicinal Food. PMID 38742994.
10. García-Mantrana et al. (2018, cited by 2024-2025 studies). "Phytoestrogen Metabolism by Adult Human Gut Microbiota". Molecules 21(8):1034. PMC6274073.
11. Verediano et al. (2024). "Effect of green banana and pineapple fibre powder consumption on host gut microbiome". PMC11378528.
12. Bendiks et al. (2024). "Frontiers Editorial: Resistant starch: advances and applications in nutrition for disease prevention". PMC12223771.

Baseline knowledge (what I know before searching)

Prebiotics are not a homogeneous class — they are differential substrates for distinct microbial sub-ecosystems, each with its own chemistry, taxonomy, and metabolic output. The question "does this prebiotic help the estrobolome" is poorly framed; the correct question is which bacteria it feeds and which enzymes are induced as a consequence.

Inulin and FOS (fructans, β(2→1) fructosyl-fructose). Preferred substrates for Bifidobacterium spp. (β-fructosidase), Faecalibacterium prausnitzii via cross-feeding (they do not ferment inulin directly — they consume acetate and lactate produced by Bifidos), Bacteroides (with some specificity for long-chain inulin). Main output: acetate + propionate + butyrate (via cross-feeding). Short chain (FOS, DP 2-8): rapid proximal fermentation, a lot of gas, a lot of acetate. Long chain (native inulin, DP 10-60): more distal fermentation, more butyrate, fewer symptoms. Typical effective dose: 5-10 g/day induces a measurable bifidogenic shift in 14 days; ≥15 g/day starts with significant flatulence in sensitive responders.

For the estrobolome specifically: most Bifidobacterium have low gmGUS activity compared with Bacteroides fragilis or Lactobacillus brevis KABP052. That is — inulin/FOS are NOT direct prebiotics of the classic estrobolome. Their hormonal mechanism is indirect: (a) propionate/acetate via cross-feeding → butyrate → HDAC inhibition at the ESR2 promoter (same mechanism we documented in L1.4 with nixtamal); (b) reduction of systemic LPS (Geng 2025: inulin lowers LBP in PCOS) → less TLR4 → less follicular atresia (L1.3 mechanism); (c) it could support Bifidobacterium animalis, associated with more stable hormonal profiles in perimenopause.

GOS (galacto-oligosaccharides, enzymatically extended lactose). Similar to FOS but more selective for Bifidobacterium infantis/longum. Less evidence of hormonal modulation.

Resistant starch — four classic types + RS5 (amylose-lipid complex):

• RS1: physically inaccessible (whole grains, intact seeds). Slow and distal fermentation. Broad substrate, not very selective.
• RS2: resistant crystalline native granule (green banana, raw potato, high-amylose maize starch). Selective substrate for Ruminococcus bromii (keystone species) → releases oligosaccharides for Faecalibacterium prausnitzii and Eubacterium rectale → butyrate. Output: 8→12 mmol/kg fecal butyrate with 30-40g/day dose. Huge variability: 20-30% "non-responders" without baseline R. bromii.
• RS3: retrograded starch (cooked and cooled: cold potato, cold rice, nixtamalized tortilla). Preferred substrate of Bifidobacterium adolescentis and Roseburia intestinalis. Central mechanism for the LATAM effect documented in L1.4.
• RS4: chemically modified (little relevance for a natural diet).
• RS5: amylose-lipid complex, abundant in nixtamalized tortilla through amylose-corn oil binding. Slow fermentation, mixed profile.

Polyphenols as "third-generation prebiotics." They are not fibers, but they modify microbial composition by inhibiting pathobionts (succinate producers, Enterobacteriaceae) and supporting Akkermansia muciniphila (especially flavonoids and ellagitannins). More importantly: they require microbial biotransformation to become active. Resveratrol → dihydro-resveratrol (more bioactive than the original). EGCG → 4'-O-methyl-EGCG and pyrogallol metabolites. Isoflavones (daidzein) → equol (ERβ affinity >> ERα, only 25-30% of Western women are producers; 50-60% in Asian cohorts). Ellagitannins (pomegranate, raspberry, walnut) → urolithin A (mitochondrial autophagy → oocyte mitochondrial quality, connects with L9 NAD+). Lignans (flaxseed, chia, whole grains) → enterolactone (moderate ERβ affinity, almost all women are producers but at different rates).

Accessible LATAM fibers:

• Nopal (Opuntia ficus-indica): mucilage (branched polysaccharides with arabinose, galactose, xylose, rhamnose) + pectins. It is not a classic fermentable fiber — it acts more like a viscous gel. But mucilage-derived oligosaccharides (MO) and pectin-derived oligosaccharides (PO) are validated prebiotics in vitro: +24% lactobacilli, +25% bifidos, +50% propionate/butyrate.
• Beans (black/pinto): resistant starch (RS1+RS2), soluble fiber (partial β-glucans), oligosaccharides (raffinose, stachyose). Broad fermentation → significant production of acetate, propionate, butyrate. Associated polyphenols (condensed tannins, anthocyanins) modulate composition in parallel.
• Chia: mucilage (similar to nopal, high in β-D-xylopyranose and α-D-glucopyranose), 30% total fiber, lignans (enterolactone precursor).
• Jicama: main source of natural inulin in the LATAM diet (10-12% fresh weight), does not require industrial supplementation.
• Green plantain: practically pure RS2, 50-55 g RS per 100 g dry flour.

Critical operational difference: "supporting bifidobacteria" is a trivial finding; almost any fermentable fiber does it. "Specifically modulating estrobolomic gmGUS activity" requires measuring fecal β-glucuronidase quantified by hydrolysis of 4-methylumbelliferyl-β-D-glucuronide (MUG) or urinary levels of 2-/4-/16-hydroxyestrones (2:16 OH-E1 ratio as a proxy for estrogen detoxification) — and almost no prebiotic studies do this. Most report alpha diversity, SCFAs, and taxonomic changes. This is a critical methodological gap in the literature.

Findings from recent papers

Inulin and ovarian function (Geng 2025, Advanced Science — first serious human + animal trial):

• Clinical PCOS cohort + PCOS mice. Inulin improved hyperandrogenism and glucolipid metabolism in both.
• Identified mechanism: inulin increased "co-abundance group 12" (Bifidobacterium spp. + SCFA producers) → ↑ fecal acetate/propionate/butyrate → ↓ plasma LBP → ↓ systemic LPS → ↓ ovarian inflammation.
• FMT from PCOS patients treated with inulin into gnotobiotic mice reproduced the effect: ↑ insulin sensitivity, ↓ lipid accumulation, ↓ hyperandrogenism, ↓ ovarian inflammation.
• Human dose used: 10 g/day x 12 weeks. Minimum time to measurable effect: 8 weeks.

Inulin, ER- cancer, and epigenetics (Bian 2023, Int J Mol Sci):

• Murine model. Dietary inulin reduced development of ER-negative mammary cancer.
• Epigenetic mechanism: ↓ HDAC2, ↓ HDAC8, ↓ DNMT3b. ↓ Akt/PI3K/NF-kB.
• Connection with L1.4: the "butyrate → HDAC inhibition" mechanism is confirmed. Even more relevant: inulin affects DNMTs (DNA methyltransferases), not only HDACs. This can modulate ESR1 methylation (silenced in ER-) → reactivation of estrogen receptor α in sensitive tissues. Mechanism COMPLEMENTARY to butyrate → ESR2.
• Limitation: animal model. Human validation pending.

Resistant starch (Li 2024, Nature Metabolism — n=37 overweight humans, crossover RCT):

• 40 g/day RS2 (high-amylose maize) x 8 weeks. Significant weight loss, ↑ insulin sensitivity, ↓ hepatic steatosis.
• Enriched bacteria: Ruminococcus bromii, Bifidobacterium adolescentis, Faecalibacterium prausnitzii, Eubacterium rectale.
• Fecal butyrate: 8 → 12 mmol/kg in responders.
• Individual asymmetry: three groups — "enhanced", "high", "low" responders. Group predictor: baseline abundance of R. bromii. Without R. bromii → no primary degradation of RS2 → no cross-feeding → no butyrate.

Yang 2024 (PMC11197919) confirms: baseline composition and habitual dietary fiber predict >40% of the variance in response to RS. The same 30 g/day produces opposite responses depending on background.

Nopal — human RCT (Remes-Troche 2024, Salas-Salvadó 2024):

• 300 mg/day Odilia™ extract (Opuntia ficus-indica) x 8 weeks in n=80 with dysbiosis.
• Firmicutes/Bacteroidetes ratio ↓, ↑ Bacteroides + Clostridium_XIVa (butyrate producer), ↓ pro-inflammatory pathobionts.
• ↓ GI discomfort score.
• Important limitation: 300 mg is a minimal extract dose. A real serving of nopal (100 g) provides ~3-4 g of fiber including ~1.5 g mucilage — an order of magnitude greater than the extract. Implication: the effect of real nopal is probably much greater than reported.
• First positive RCT of a native LATAM prebiotic in humans.

Green banana (Verediano 2024): 14 days, 5 g fiber/day (low dose). Increase in 7 key species: F. prausnitzii, B. longum, B. bifidum, B. adolescentis, B. pseudocatenulatum, B. obeum, R. inulinivorans. Shows that with modest doses (1/4 of a medium green plantain) there is already a shift.

Polyphenols (Most 2024, PMC11346568):

• 12-week trial EGCG + resveratrol (282 + 80 mg/day) in overweight.
• Sex-specific changes in microbiome + fat oxidation.
• Women responded differently from men — suggests hormonal modulation of the polyphenol-microbiome effect.
• Limitation: supplemental dose, not dietary. Difficult to replicate with a normal diet (you would need 7-10 cups of green tea + 1 kg of grapes with skin/day).

Equol and urolithin (García-Mantrana et al. review + ASJPC 2025):

• Capacity to produce equol: 25-30% Western women, 50-60% Asian women, not characterized in LATAM (gap).
• Equol significantly improves vasomotor symptoms in producers vs non-producers.
• Equol-production capacity is associated with microbial diversity — more diversity → higher probability of producing equol.
• Urolithin A (ellagitannin metabolite) induces oocyte mitophagy — first concrete bridge between prebiotic-polyphenol and oocyte quality (anticipated L9).

Complete molecular/endocrine mechanism

PREBIOTIC              TARGET BACTERIA                     METABOLITE             HORMONAL EFFECT
─────────────────────────────────────────────────────────────────────────────────────────────────────
Inulin (10g)      →    Bifidobacterium adolescentis   →    Acetate + propionate → ↓ LBP/LPS → ↓ TLR4
FOS (5g)          →    Bifidobacterium infantis       →    Lactate (cross-feed) →    in granulosa → ↓ atresia
                                                                      ↓
                                                           Faecalibacterium prausnitzii
                                                                      ↓
                                                           Butyrate → HDAC1/2/8 inhibition
                                                                      ↓
                                                           ↑ H3K27 acetylation at ESR2 promoter
                                                                      ↓
                                                           ↑ ERβ expression → ↑ functional estrogenic sensitivity
                                                                      ↓
                                                           Butyrate → DNMT3b inhibition
                                                                      ↓
                                                           ↓ ESR1 methylation → partial ERα reactivation
                                                                      (Bian 2023 mechanism, ER- breast cancer)

RS3 (nixtamal)    →    R. bromii + B. adolescentis    →    Direct butyrate    →    ↑ ESR2 via epigenetics
RS2 (green plantain)→  R. bromii (keystone)           →    Oligosaccharides   →    F. prausnitzii → butyrate
                                                                                   (depends on baseline R. bromii)

Lignans (chia)    →    Bacteroides, Clostridium      →    Enterolactone      →    Moderate ERβ affinity
Isoflavones (soy) →    Slackia, Adlercreutzia         →    Equol (25-30% women) → ERβ >> ERα; vasomotor symptoms
Ellagitannins     →    Gordonibacter, Ellagibacter   →    Urolithin A        →    Oocyte mitophagy (L9 bridge)
                                                                                   ↓ SASP in granulosa (L10 bridge)

Nopal mucilage    →    Bacteroides + Clostridium XIVa →   Propionate+butyrate →   ↓ systemic inflammation
Bean pectins      →    Faecalibacterium + Roseburia  →    Butyrate           →    ↑ ESR2 + ↓ LPS

           ────────────────── CLASSIC ESTROBOLOME (gmGUS) ──────────────────
           Which prebiotics modulate it DIRECTLY?
                  Almost none of the above act specifically on gmGUS.
                  Only *Bacteroides fragilis* (high GUS) responds to complex fibers (pectins, arabinoxylans).
                  KABP052 probiotic is the documented direct intervention (not prebiotic).

Central insight: the available modern prebiotics do NOT primarily modulate the classic estrobolome (gmGUS) — they modulate the adjacent sub-ecosystems that sustain hormonal sensitivity through epigenetic pathways (butyrate → ESR2/ESR1) and by reducing inflammatory load (LPS → TLR4). This rewrites the simple hypothesis "prebiotic = more estrogen recycling".

Cross-synthesis with previous findings

With L1.1 (classic estrobolome): KABP052 supplementation maintained E2 for 12 weeks, but the probiotic only colonizes if the intestinal environment allows it. Prediction: co-administering KABP052 with inulin 10 g/day enhances the effect because (a) inulin lowers LPS and reduces the inflammation that hinders colonization; (b) the bifidobacteria generated by inulin coexist with KABP052; (c) the resulting butyrate upregulates ESR2 while KABP052 maintains E2 — a compound effect. No trial has tested this combination yet.

With L1.2 (progesterobolome): Parabacteroides responds poorly to inulin (it consumes pectins and mucins better). The real substrate of the progesterobolome may be nopal + chia mucilage (branched heteropolysaccharides) + bean pectins. This changes the L1.2 formulation: "progesterobolome rescue" is not done with inulin/FOS — it is done with viscous LATAM fibers. Important repositioning.

With L1.3 (dysbiosis and early menopause): the "critical microbial window" (0-12 years) means that adult prebiotic responder potential is partially determined in childhood. Derivable prediction: women born by C-section + formula have a lower probability of having robust baseline R. bromii → lower response to adult RS2. Mode of birth (C-section + formula) as a predictive variable, already noted in L1.3, gains concrete value here.

With L1.4 (LATAM fermented foods): the model closes. LATAM fermented foods provide β-glucosidases (phytoestrogen aglycones) + lactic acid (acidifies colon → supports bifidobacteria). Nixtamal provides RS3 + RS5 → butyrate. The "Mesoamerican Ancestral Buffer" works because both elements are synergistic: fermented food activates phytoestrogens, nixtamal sustains butyrate production, butyrate upregulates ESR2 that receives the phytoestrogens. The synergy is bidirectional and simultaneously prebiotic-probiotic-epigenetic. No isolated component replicates it.

Anticipated connection with L9 (NAD+): urolithin A is produced by gut microbiota from ellagitannins → induces mitophagy. Mitophagy in oocytes = mitochondrial quality = preserved ovarian function. A new hypothesis emerges here: fertility/ovarian longevity partially depends on the urolithin-producing enterotype. Natural connection between L1 and L9.

Connection with L7 (progesterone): the progesterobolome uses biliary cortisol as substrate. Prebiotics that support Eggerthella lenta and Gordonibacter are not classic — they are low-molecular-weight fibers + polyphenols (Gordonibacter is known for metabolizing ellagitannins). Pomegranate and walnuts (ellagitannins) could be specific prebiotics of the progesterobolome via 21-dehydroxylation. New hypothesis.

Lua Labs hypotheses

Hypothesis 7: "Prebiotic-probiotic synergy directed at the estrobolome"

Statement: Co-administration of inulin 10 g/day + L. brevis KABP052 for 12 weeks in perimenopausal women maintains serum E2 ≥10% higher than KABP052 alone, because inulin (a) reduces LPS/LBP that inhibits probiotic colonization, (b) generates butyrate that upregulates ESR2, amplifying functional estrogenic sensitivity, (c) creates a co-permissive bifidogenic environment. The effect is multiplicative, not additive.

Proposed mechanism: Previously described compound pathway. Three parallel pathways converging on increased functional estrogenic tone without requiring high absolute serum levels.

Confidence level: Medium — the mechanistic logic is solid, but only Honda 2024 (12 weeks, n=70 women, no co-prebiotic) and Geng 2025 (inulin alone, no co-probiotic) support the components. The interaction has never been tested in humans.

How to validate:

• With a formal study: 2x2 RCT (KABP052 ± inulin) n=160 perimenopausal women, 12 weeks, endpoints serum E2, urinary 2:16 OH-E1, fecal MUG (gmGUS), Greene Climacteric Scale.

Limitations: dependence on KABP052 (only available via Akkermansia Biosciences/Kaneka); the link "inulin → less LPS → better KABP052 colonization" has not been measured directly.

Hypothesis 8: "Urolithin-A enterotype as a marker of ovarian longevity"

Statement: Women who produce urolithin A (~40% of the general population according to metabotypes) have a significantly slower AMH/age decline than non-producers, controlling for age, BMI, and diet. Urolithin A produced by microbiota from dietary ellagitannins induces mitophagy in oocytes → preserves mitochondrial quality → slows follicular atresia.

Proposed mechanism: Pomegranate/raspberry/walnut/strawberry → ellagitannins → Gordonibacter urolithinfaciens / Ellagibacter isourolithinifaciens → urolithin A → nuclear translocation → ↑ PINK1/Parkin → mitophagy in granulosa → reduction of ovarian SASP (direct bridge to L10 senolytics).

Confidence level: Low-Medium — urolithin A induces mitophagy is well established (Ryu Nat Med 2016, Andreux Nat Metab 2019), but the specific effect in human oocytes in vivo has not been demonstrated. There is only one study of urolithin A in murine ovarian function (not replicated).

How to validate:

• With a formal study: observational cohort n=300, urolithin phenotyping by urine after ellagitannins, 2-year AMH follow-up.

Limitations: major confounder — urolithin A producers may have a more diverse microbiota = healthier overall. Difficult to isolate the specific effect of urolithin.

Hypothesis 9: "Stratified prebiotic prescription — the Microbiome Boot Strap before RS"

Statement: In women with a history of multiple antibiotics or loss of Prevotella copri (acculturated LATAM women), direct supplementation with RS2 (40 g green plantain / day) fails because there is no baseline R. bromii. A 2-week boot strap with inulin 5g/day + nopal 100g/day BEFOREHAND restores the bifidogenic base and diversity necessary for RS2 to work.

Proposed mechanism: inulin/nopal support acidic luminal pH + mucin/oligosaccharide production → permissive ecosystem for R. bromii (which requires amylose + pH 5.5-6.5 + no competition with E. coli). Once R. bromii is present, RS2 ferments correctly.

Confidence level: Medium — Yang 2024 demonstrates that microbial background predicts response to RS, but nobody has tested this sequenced "boot strap".

How to validate:

• With a formal study: 3-arm RCT (RS2 alone, boot strap+RS2, control), n=120, 12 weeks, endpoints fecal butyrate + perimenopausal symptoms.

Limitations: not validatable without baseline microbiome sequencing; it requires directly measuring microbial composition before and after the intervention.

Candidate formulation: "Personalized Estro-Buffer by Enterotype"

Compounds:

• Path A (non-equol producers + ~70%): L. brevis KABP052 (5×10⁹ CFU) + long-chain inulin (10g) + ground chia (15g, lignans) + nopal (100g/day) → estrobolomic activation + enterolactone production + mucilage.
• Path B (equol producers + high diversity): inulin (10g) + chia + green plantain (1/2 unit ≈ 20g RS2) → maximize butyrate and equol; skip KABP052.
• Path C (post-antibiotics / acculturated): boot strap inulin+nopal 2 weeks → KABP052 + RS3 (nixtamal) → ramping to Path A or B.

Target population: Carmen (perimenopausal), partially Sofía (active cycle with PCOS — Path A reduces LPS), not Rosa (postmenopausal requires adding DHEA and peripheral aromatization — outside L1).

Complementary mechanisms: direct estrobolome (KABP052) + epigenetic estrobolome (butyrate ESR2) + selective ERβ phytoestrogens (chia+lignans+equol) + inflammation reduction LPS (inulin+nopal) + enterolactone production (lignans+microbiota).

Regulatory status: all components are foods or GRAS. KABP052 commercially available. No prescription required.

Requires validation: 2x2 trial KABP052±inulin (Hyp. 7); equol phenotyping before stratification; minimum 12 weeks for detectable signal.

Individual variability

Genetics:

• UGT1A1, UGT2B15: rapid vs slow estrogen glucuronidators. Slow (variant *28) recycle more estrogen → more dependent on a healthy estrobolome to avoid accumulating estrogen dominance.
• COMT (Val158Met): slow methylators generate more 4-OH-E1 (genotoxic) → need more intestinal detoxification via bile β-glucuronidation + balanced microbial reabsorption.
• CYP1A1, CYP1B1: 2-OH/16α-OH ratio partially determined by these. Polyphenols (crucifers, DIM) induce CYP1A1 → favorable ratio.

Microbial:

• Equol producers (25-30% West, 50-60% Asia, LATAM?): respond ~3x better to soy/isoflavones for vasomotor symptoms. Capacity correlates with alpha diversity.
• Urolithin-A producers (~40%): extra benefit from ellagitannins in mitophagy. They can move from "non-producer" to "producer" with an ellagitannin-rich diet for 4-6 weeks in some but not all women.
• R. bromii present/absent: determines response to RS2. Predictor: recent antibiotics, chronic low-fiber diet, high processed-food load.

Epigenetics:

• Baseline methylation of the ESR2 promoter — women with hypermethylated ESR2 have lower baseline expression, so upregulation via butyrate may be proportionally greater (low-floor effect).

Cultural/regional:

• LATAM has a data gap: what % of Mexican women are equol producers? what % are urolithin producers? The traditional diet rich in beans+chia+regional fruits could predict higher rates than European cohorts (hypothesis).

Mandatory falsifiable prediction (close)

Prediction L1.5: In a cohort of women aged 35-55 with ≥90 days of continuous dietary records, participants in the top quartile of epigenetic-type prebiotic density (regular consumption of jicama, green plantain, nopal, nixtamalized beans, and chia) will report a Greene Climacteric Score ≥1.0σ below the bottom quartile, after adjusting for age, self-reported hormonal stage, and estimated BMI.

Falsifiable: if the difference is <0.5σ or the effect disappears after adjusting for confounders, the hypothesis "LATAM prebiotics modulate perimenopausal symptoms via butyrate → ESR2 epigenetics" is significantly weakened.

Time to result: 90 days in a cohort with a complete dietary diary and biomarkers/symptoms defined by the protocol.