Gut. 2024 Nov 11;73(12):1953-1964. doi: 10.1136/gutjnl-2024-332475.

Jonathan P Jacobs ^1 2 3, Elizabeth A Spencer ⁴, Drew S Helmus ⁵, Julianne C Yang ^6 3, Venu Lagishetty ⁶, Gerold Bongers ^7 8, Graham Britton ^7 8, Kyle Gettler ⁹, Pamela Reyes-Mercedes ⁵, Jianzhong Hu ⁷, Amy Hart ¹⁰, Esi Lamousé-Smith ¹⁰, Jan Wehkamp ¹⁰, Carol Landers ¹¹, Philip Debbas ¹¹, Joana Torres ^5 12, Jean-Frederic Colombel ⁵, Judy Cho ⁹, Inga Peter ⁷, Jeremiah Faith ^7 8, Jonathan Braun ¹¹, Marla Dubinsky ⁴

Author information

¹Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA JJacobs@mednet.ucla.edu.

²Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.

³Goodman-Luskin Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

⁴The Division of Pediatric Gastroenterology and Nutrition, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

⁵The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

⁶Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

⁷Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

⁸Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

⁹Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

¹⁰Janssen, Spring House, Pennsylvania, USA.

¹¹F. Widjaja Inflammatory Bowel Disease Institute, Cedars Sinai Medical Center, Los Angeles, California, USA.

¹²Hospital da Luz, Lisboa, Portugal.

Abstract

Objective: IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives).

Design: Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed.

Results: Microbial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied by marked shifts in the faecal metabolome and, to a lesser extent, the serum metabolome. Faecal and serum metabolomics dysbiosis indices were validated in an independent cohort. Dysbiosis was associated with elevated antimicrobial serologies but not with faecal calprotectin. Dysbiosis metrics differentiated IBD from non-IBD comparably to serologies, with a model combining calprotectin, faecal metabolomics dysbiosis index and serology score demonstrating highest accuracy.

Conclusion: These findings support that dysbiosis exists as a pre-disease state detectable by faecal and serum biomarkers for IBD risk prediction. Given the expansion of disease-modifying agents and non-invasive imaging, the indices developed here may facilitate earlier diagnoses and improved management in at-risk individuals.