Science

The microbiome is part of the regimen.

A practical account of how Fusobacterium nucleatum and the broader gut community shape both the efficacy and the toxicity of colorectal-cancer chemotherapy — and where a defined microbial molecule can intervene.

The biology of chemoresistance.

Colorectal tumors are not sterile. A subset of them — particularly those of the right colon and the consensus molecular subtype CMS1 — harbor Fusobacterium nucleatum, a Gram-negative anaerobe that travels with the malignant cells from primary tumor to liver metastasis and persists through cycles of cytotoxic therapy.¹

Mechanistically, F. nucleatum activates Toll-like receptor signaling through TLR4 and MYD88, induces the autophagy machinery via ULK1 and ATG7, and selectively suppresses microRNAs (miR-18a*, miR-4802) that normally restrain it. The downstream effect is a tumor cell that survives 5-fluorouracil and oxaliplatin at concentrations that would otherwise be lethal.² Patients whose tumors carry high Fn burden have measurably worse recurrence-free survival.

The implication is structural: chemoresistance, in this setting, is not only a property of the cancer cell — it is a property of the cell-and-its-microbe together. Therapies that ignore the microbe cannot, by construction, address it.

The biology of chemotherapy-induced GI toxicity.

The cytotoxic regimens used in colorectal cancer were designed to kill rapidly-dividing cells. The intestinal crypt — turning over every three to five days — is among the most rapidly-dividing tissues in the body. The toxicity profile is therefore not incidental but inevitable.

Mucositis begins as crypt apoptosis, progresses through villous blunting and barrier loss, and presents clinically as diarrhea, dehydration, and bacterial translocation. Irinotecan adds a distinct pharmacologic insult: its active metabolite, SN-38, is glucuronidated by the liver into an inactive form (SN-38G) and excreted into bile — only to be regenerated in the gut lumen by bacterial β-glucuronidases and re-presented to the epithelium at high local concentration.³

Severe (Grade 3+) GI toxicity occurs in 15–40% of patients on 5-FU–based therapy and a comparable fraction on irinotecan-containing regimens. For a meaningful share of those patients, the toxicity — not the cancer — is what determines whether they finish the course.

Three axes, one molecule.

i. Recondition the tumor microenvironment ii. Suppress microbial drug reactivation iii. Restore the epithelial barrier

Recondition the tumor microenvironment.

The primary aim of the program is to interrupt the F. nucleatum–autophagy axis that allows colorectal tumor cells to survive cytotoxic therapy.

Our lead postbiotic is selected for activity against the host pathways that Fn exploits — TLR4/MYD88-driven autophagy, suppression of tumor-restraining microRNAs, and the inflammatory milieu that surrounds the bacterium within the tumor — without requiring direct antibiosis against the organism itself. The intended clinical readout is restored sensitivity to standard-of-care 5-FU and oxaliplatin in Fn-high tumors.

ii.

Suppress microbial drug reactivation.

A second arm of the program targets the bacterial enzymes that convert inactivated chemotherapy metabolites back into their toxic forms inside the gut lumen.

Bacterial β-glucuronidases — distributed across multiple commensal and opportunistic taxa — regenerate active SN-38 from biliary SN-38G and so convert irinotecan's hepatic detoxification into a sustained intestinal re-exposure. Selective small-molecule inhibition of this enzyme class attenuates GI toxicity in animal models without disturbing the broader commensal community, and is the cleanest available point of leverage on the toxicity arm of the axis.³

iii.

Restore the epithelial barrier.

The third arm is mucosal: preserve the epithelium that holds the rest of the system together.

Defined microbial metabolites — short-chain fatty acids, indole derivatives, and related postbiotic species — support tight-junction integrity, accelerate crypt regeneration, and dampen the innate-immune cascade that converts mucosal injury into clinical mucositis. In our preclinical models, this axis is what translates biochemical activity into a tolerable, patient-level outcome.

Pipeline.

Program	Indication	Stage
TB-001 Postbiotic small molecule targeting F. nucleatum-mediated chemoresistance and chemotherapy-induced GI toxicity in colorectal cancer.	Colorectal cancer (1L mCRC)	Lead optimization
TB-002 Discovery-stage second-generation candidate broadening activity across additional cytotoxic regimens.	CRC, undisclosed	Discovery