Gut Bacteria Enzyme Boosts IBD Drug Response Through Lactate-Histone Pathway
A microbial enzyme from Bifidobacterium enhances anti-TNF therapy efficacy in IBD by reshaping immune regulation via histone lactylation.
Summary
Many patients with inflammatory bowel disease stop responding to anti-TNF drugs over time. Researchers discovered that a bacterial enzyme called phosphoketolase, found in Bifidobacterium, can meaningfully improve how well these drugs work. When this enzyme enters macrophages in the gut, it boosts lactate production. That lactate chemically modifies histones — proteins that package DNA — in a process called lactylation, which switches on a serotonin transporter. The serotonin is then converted into a compound that inhibits TNF-converting enzyme, keeping more TNF anchored to cell surfaces. This strengthens a signaling pathway that expands regulatory T cells, the immune cells that dampen excessive inflammation. A prospective clinical trial confirmed that supplementing with phosphoketolase-producing Bifidobacterium improved patient responses to anti-TNF induction therapy, supporting probiotics as a practical adjunct to standard IBD treatment.
Detailed Summary
Inflammatory bowel disease (IBD) affects millions globally, and anti-TNF biologics are among the most effective treatments available. Yet up to 30–40% of patients fail to respond initially, and many others lose response over time. Finding ways to improve and sustain drug efficacy is a pressing clinical need.
This study from Shanghai Jiao Tong University's Renji Hospital investigated how the gut microbiome influences anti-TNF therapy outcomes. The researchers focused on phosphoketolase, an enzyme present in Bifidobacterium species, and its capacity to act as a functional host enzyme when taken up by macrophages in the gut.
The mechanistic findings reveal a sophisticated molecular cascade: phosphoketolase increases flux through a metabolic pathway that elevates lactate production inside macrophages. This lactate drives histone H4K12 lactylation — an epigenetic modification — which upregulates the serotonin transporter gene. The transporter imports serotonin, which is metabolized into 5-hydroxyindoleacetic acid (5-HIAA). This metabolite inhibits TACE (TNF-alpha converting enzyme), preventing membrane-bound TNF from being shed into the bloodstream. Higher surface transmembrane TNF then activates TNFR2 on regulatory T cells (Tregs), promoting their expansion and immunosuppressive function. This dual effect — more Tregs plus higher serum drug concentrations — amplifies the therapeutic response.
Critically, a prospective clinical trial component validated these findings in human patients: supplementation with phosphoketolase-producing Bifidobacterium during anti-TNF induction therapy improved clinical response rates compared to controls.
These results are significant for clinicians managing IBD, as they suggest a microbiome-based strategy to augment biologic therapy. The epigenetic mechanism linking microbial metabolism to immune regulation also opens new research avenues in gut-immune crosstalk. Caveats include limited access to full trial data and the need for replication in larger, diverse cohorts.
Key Findings
- Phosphoketolase from Bifidobacterium boosts lactate in macrophages, triggering histone H4K12 lactylation to enhance Treg activity.
- Elevated serotonin metabolite 5-HIAA inhibits TNF-converting enzyme, raising surface TNF and amplifying TNFR2-driven Treg expansion.
- Supplementing anti-TNF therapy with phosphoketolase-producing Bifidobacterium improved induction response in a prospective clinical trial.
- The mechanism sustains higher serum anti-TNF drug concentrations, addressing both primary non-response and secondary loss of response.
- Findings position specific probiotic strains as evidence-based adjuncts to biologic therapy in IBD.
Methodology
The study combined mechanistic in vitro and in vivo experiments to map the phosphoketolase-lactylation-Treg axis in macrophages. A prospective clinical trial was conducted using phosphoketolase-producing Bifidobacterium as an adjunct to anti-TNF induction therapy in IBD patients. Full methodological details including trial registration, sample size, and controls are not available from the abstract alone.
Study Limitations
This summary is based on the abstract only, as the full text is not open access; detailed trial design, patient numbers, and statistical outcomes are unavailable. The clinical trial results require replication in larger, ethnically diverse cohorts before broad clinical adoption. The specific Bifidobacterium strains used and optimal dosing regimens are not described in the available text.
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