Colonic biopsy-associated microbial signatures are predictive of response to anti-TNFα biological therapy in Crohn's disease.

Anti-TNF α colonic biopsy microbiome model predicted treatment response significantly better than random.

• Among six machine learning models trained on ASV-level count data, the anti-TNF α colonic model achieved AUC = 0.90
• 39 patients were on anti-TNF α (infliximab or adalimumab)
• Treatment response was assessed after 26-52 weeks and required ≥50% reduction in simple endoscopic score for CD plus corticosteroid-free clinical or biochemical response
• No other treatment group (VDZ or USTE) or tissue site (ileal) models performed significantly better than random

Anti-TNF α responders had significantly higher pre-treatment α-diversity in colonic biopsies compared to non-responders.

• Higher α-diversity was observed in colonic biopsies of responders prior to anti-TNF α treatment initiation
• 3.9% of β-diversity variation was associated with anti-TNF α response in colonic biopsies
• No major microbial differences in α- or β-diversity were observed for VDZ or USTE treatment groups in either ileal or colonic samples

Mediterraneibacter gnavus ASVs were associated with non-response, whereas Blautia ASVs were associated with response to anti-TNF α therapy.

• Specific ASVs from Mediterraneibacter gnavus were enriched in anti-TNF α non-responders
• Specific Blautia ASVs were enriched in anti-TNF α responders
• These associations were identified from colonic biopsy 16S rRNA gene sequencing data at ASV level

Pretreatment with heat-killed M. gnavus and B. luti reduced anti-TNF α-induced CD14+CD206+ macrophage polarization in mixed lymphocyte reactions, with M. gnavus showing a significantly stronger effect.

• The impact of heat-killed bacteria on anti-TNF α-induced CD14+CD206+ macrophages was tested in mixed lymphocyte reactions (MLRs)
• Both M. gnavus and B. luti led to a reduction in macrophage polarization
• A significantly stronger reduction in macrophage polarization was observed for M. gnavus compared with B. luti
• This mechanistic experiment was conducted to explore how microbial signatures may functionally relate to treatment response

No major microbial differences were observed in VDZ, USTE ileal, or USTE colonic samples between responders and non-responders.

• 47 patients were on VDZ and 39 on USTE
• Clinical features were similar between responders and non-responders across all treatment groups, except for sex in USTE-colon and CRP in USTE-ileum groups
• Mucosal microbiota was profiled by 16S rRNA gene sequencing from pre-treatment ileal and/or colonic biopsies collected endoscopically
• The lack of predictive signal in VDZ and USTE groups contrasts with the significant findings in the anti-TNF α colonic group

A total of 125 adult CD patients initiating biologic therapy were enrolled across three treatment arms.

• 39 patients initiated anti-TNF α (infliximab or adalimumab), 47 initiated vedolizumab, and 39 initiated ustekinumab
• Pre-treatment ileal and/or colonic biopsies were collected endoscopically before treatment initiation
• Response was defined by ≥50% reduction in the simple endoscopic score for CD and either corticosteroid-free clinical response (≥3-point HBI decrease or remission [HBI ≤4]) or biochemical response (≥50% or ≤5 mg/L CRP reduction and ≥50% or ≤250 μg/g faecal calprotectin reduction)