MIMIC
We carry ~100x more microbial genes than human genes (~3.3M vs ~20,000), and we already know microbes signal to us in chemistry — SCFAs->GPR43, bile acids->FXR/TGR5, tryptophan->AhR, some even mimicking our own ligands (
Core trick
Co-folds gut miniprotein families against 25 human receptors plus fold-matched decoys, keeping only interfaces that beat the decoy null and overlap the native ligand site.
Description
We carry ~100x more microbial genes than human genes (~3.3M vs ~20,000), and we already know microbes signal to us in chemistry — SCFAs->GPR43, bile acids->FXR/TGR5, tryptophan->AhR, some even mimicking our own ligands (Cohen 2017). The open question is the secreted proteins: do microbes also signal in protein, and we've simply never looked? We built a structure-first screen to find out.
The pipeline, one candidate. Starting from 965 million GMSC smORFs across 75 habitats, four filters narrow to 2,187 gut-only secreted family representatives, then a signal-peptide-aware mature-form refold collapses to 297 mature families. Each was co-folded against 25 targets — 15 human immune/cytokine/GPCR/barrier receptors plus 10 fold-matched decoys (the null every hit must beat) — 7,408 of 7,425 peptide x receptor interfaces folded with ESMFold2 in a single session. One candidate survives: MIMIC.
Six independent computational lines of evidence:
Interaction — folds a confident interface on IL7R, on the exact surface where interleukin-7 binds (~65% overlap) — co-location with the functional interface, not enrichment.
Specificity — picks IL-7Ralpha out of its own gamma-c receptor family, clearing the five closest paralogs; AlphaFold3 agrees independently (two engines, same call).
Not a sequence mimic — no sequence homology to IL-7. A structural mimic, not a captured human gene.
Mobility — rides a Tcp/ArdA conjugative (Tn916/ICE) element across 239 gut species in two phyla (Bacillota + Actinomycetota), including 15 Clostridioides difficile strains (MGE-enrichment p = 0.003, #2 of 592 families).
Conservation across that spread; and 6. alternatives ruled out.
Why it matters. Leading hypothesis (of two): MIMIC mutes IL-7 to keep its microbe immune-invisible — a shield the mobile element can trade from commensals into a pathogen like C. difficile. That reframes the microbiome as a mobile library of human-receptor ligands — immune invisibility a microbe can acquire by transfer, not only evolve. Disease stakes are direct (IL-7 immune signaling; C. difficile colitis). Every panel is computational and none measures binding — this is a testable structural hypothesis, and one week settles it: add MIMIC + IL-7 on T cells and read pSTAT5 (suppressed = antagonist/shield; drives it alone = agonist).
README excerpt
# MIMIC **A mobile microbial peptide that engages a human cytokine receptor.** *A structure-first screen of the gut secretome against human immune receptors.* **Kenneth Loi, Zhaojun Wang** · Built with Claude Science **▶ [Live site](https://kenloi.github.io/mimic-gut-secretome/)** — hub linking the full mini-paper, the interactive deck, and the co-fold database browser. --- ## What this is The human gut microbiome encodes far more protein than the human genome. Most of its secreted miniproteins (<100 aa) are uncharacterized. Some may mimic host ligands and engage human receptors directly — protein signaling, alongside the well-mapped metabolite signaling (short-chain fatty acids, bile acids). We built a structure-first screen to look for them: co-fold gut-secreted miniprotein families against a frozen panel of human immune receptors plus decoys, and score each interface against a null. The unit of observation is a peptide–human-protein pair. The output is a ranked list of structurally supported candidate interactions — hypothesis prioritization, not causation. ## The headline finding **MIMIC-078** (family representative `078_038_456`, mature 45 aa) folds a confident interface on **IL-7Rα** — iPTM 0.911, interface PAE 7.4 Å, z 6.0 against decoys — and lands on the exact surface where interleukin-7 binds, with no sequence homology to IL-7 (a structural mimic, not a captured gene). The interaction is specific: MIMIC selects IL-7Rα (0.91) over all five γc-family paralogs