The role of circulating metabolomics in linking metabolic dysfunction, inflammation, and risk of diverticulitis outcomes

BACKGROUND: Obesity and chronic inflammation are associated with an elevated risk of diverticulitis. However, the underlying mechanisms, particularly the role of circulating metabolites are not well understood. METHODS: We derived metabolomic signatures of metabolic dysfunction (body mass index, waist circumference, C-peptide, and adiponectin) and inflammation (C-reactive protein, interleukin 6, and tumor necrosis factor receptor superfamily 1B). We then predicted metabolomic signatures among 7888 participants who were free of diverticulitis at blood collection in Nurses' Health Study (NHS), NHSII, and Health Professional Follow-up Study (HPFS) and evaluated their association with risk of diverticulitis incidence, recurrence, and surgery. FINDINGS: Metabolomic signatures explained 32% of the variation in the metabolic dysfunction markers and 29% of the variation in inflammation markers. Both signatures were significantly associated with an increased risk of diverticulitis. The multivariable-adjusted hazard ratio (HR) for incident diverticulitis comparing participants in the highest quartile to those in the lowest was 1.97 (95% confidence interval [CI]: 1.52-2.54; P-trend<0.0001) for the metabolic dysfunction signature and 1.40 (95% CI: 1.08-1.81; P-trend = 0.02) for the inflammation signature. Metabolic dysfunction signature was additionally associated with an increased risk of diverticulitis recurrence (extreme-quartile HR: 1.80; 95% CI: 1.10-2.96; P-trend = 0.004) and surgery requirement (HR: 2.99; 95% CI: 1.56-5.70; P-trend = 0.005). INTERPRETATION: Both metabolomic signatures of metabolic dysfunction and inflammation were significantly associated with incident diverticulitis. The metabolic dysfunction signature showed a more robust association with diverticulitis recurrence and surgery requirement. Our results suggest a role of circulating metabolites in metabolic and inflammatory pathways in diverticulitis pathogenesis. FUNDING: This study was supported by grants from the National Institutes of Health (UM1 CA186107, R01 CA49449, U01CA176726, R01 CA67262, U01 CA167552). ATC is an American Cancer Society Research Professor. WM is supported by the National Institutes of Health (K01DK135854-01A1), American Gastroenterological Association (AGA2021-13-01), and MGH Claflin Distinguished Scholar Award. ATC, ELG, and LLS are supported by National Institutes of Health (R01 DK101495). MD is supported by the National Institutes of Health/National Cancer Institute (NIH/NCI K00CA274714, K99CA297022). LLS is supported by National Institute of Health (NIDDK 1 R01DK131694). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.