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NIH grant 1R01DK149061-01: Bacterial Metatranscriptomics from Human Tissues to Resolve Contributions of Host and Microbial Pathways to Health and Disease
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: RUSTEM F ISMAGILOV. Award: $661126.
Start: 2026-08-21T00:00:00.
PROJECT SUMMARY
Tissue-associated microbes play fundamental roles in human health and disease, shaping host immunity, barrier
integrity, and metabolism. Although DNA-level analyses are beginning to shed light on some aspects of the roles
these tissue microbes may play, understanding their true functional significance of host-microbe interactions
requires insights at the gene-expression (RNA) level. However, obtaining these RNA-level insights on microbes
in human tissues has been a formidable challenge because bacterial RNAs are unstable and represent <0.1 %
of total nucleic acids in tissue, their fragile expression profiles are distorted by standard processing, and the field
lacks tools for rigorous and reproducible analysis of low-abundance microbes. Thus, many questions are left
unanswered regarding the molecular mechanism of host-microbe interactions – particularly in complex diseases.
For example, perianal Crohn’s disease (pCD) is a chronic, debilitating inflammatory bowel disease with no cure
and no preventive strategies. Immune and microbial factors are strongly implicated in pCD pathogenesis, but
previous studies struggled to define the drivers of pCD, and none have simultaneously investigated gene
expression of the host and microbes directly in tissues from pCD patients.
This technology-development R01 aims to overcome the current barriers to performing rigorous and reproducible
simultaneous analyses of human and microbial gene expression by developing T-BEAM (Tissue‑associated
Bacteria Enrichment for Analysis by Metatranscriptomics), a tool for stabilizing bacterial and host RNA, removing
>99.9% host nucleic acids, and simultaneously capturing microbial and host transcriptomes from a single biopsy.
We have three Specific Aims: Aim 1: Optimize T‑BEAM in germ‑free tissues spiked with defined bacterial
communities to establish conditions that (i) preserve bacterial transcriptional profiles, (ii) reduce host nucleic
acids >1,000-fold, and (iii) retain bacterial RNA. Aim 2: Rigorously validate and determine limits of detection and
quantification for T‑BEAM in vivo using (i) a monocolonized model and (ii) the human‑relevant hCom2 bacterial
consortium. Aim 3: Apply T‑BEAM to biopsies from patients with subclinical pCD (and matched controls) to
identify microbial and host genes and pathways that are unique to subclinical pCD and that predict radiological
progression of subclinical pCD. This final aim demonstrates the clinical feasibility of the technology and will
produce the first experimentally validated set of microbial and host genes and pathways whose joint expression
patterns are associated with earliest, actionable stage of pCD.
Ultimately, T-BEAM will advance human health by producing validated data that will enable—using both human
intelligence and artificial intelligence—rigorous, reproducible RNA-level analyses of both microbes and the host
in human tissues. Such studies are urgently needed to improve diagnostics and therapeutics for the many
human diseases with poorly understood tissue-associated microbial contributions.document fetched 2026-08-30 02:46