Intestinal group 1 innate lymphoid cells drive macrophage-induced inflammation and endocrine defects in obesity and promote insulinemia

ABSTRACT

Hypercaloric diets overactivate the intestinal immune system and disrupt the microbiome and epithelial cell functions, impairing glucose metabolism. The origins of this inflammatory cascade are poorly characterized. We investigated the involvement of intestinal proinflammatory group 1 innate lymphoid cells (ILC1s) in obesity progression and metabolic disruption. In obese mice, we studied longitudinally the ILC1s response to the diet and ILC1s depletion to address its role in obesity. ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s. ILC1s depletion induced the ILC3-IL-22 pathway, increasing mucin production, antimicrobial peptides, and neuroendocrine cells. These changes were translated into higher gut hormones and reduced insulinemia and adiposity. ILC1s depletion was also associated with a bloom in Akkermansia muciniphila and decreases in Bilophila spp. Intestinal-ILC1s are upstream activators of inflammatory signals, connecting immunity with the microbiome, the enteroendocrine system, and the intestinal barrier in the control of glucose metabolism and adiposity.

KEYWORDS:

• Microbiota
• obesity
• ILC1s
• metabolism
• high-sucrose high-fat diet
• Akkermansia muciniphila

Acknowledgments

We thank I. Noguera and the technicians of the Animal Facilities of the SCSIE-UV for their expert technical assistance. We also acknowledge the valuable help of S. Norte and A. Flores from the Flow Cytometry service of SCSIE-UV. The assistance of P. Coll of the IATA microscopy service and the staff of Patologika S.A. are also well appreciated. We thank our laboratory colleagues Dr. M. Romaní-Pérez and L. Perales for their intellectual contribution and assistance in the experimental tasks of this work, respectively.

Disclosure statement

The authors declare that there is no duality of interest associated with this manuscript.

Author contributions

RL-G, MO and YS conceived and designed the study, RL-G and MO performed the in vivo experiment and analyzed the samples, CF-C analyzed the 16S rRNA data; TR and GQ analyzed the metabolic data; VR: contributed to the immune analysis and critically reviewed the manuscript. RL-G, MO, and YS wrote the manuscript. All authors reviewed and agreed with the final version.

Data availability statement

The sequences corresponding to the analyses of the gut microbiota composition are uploaded in the ENA (project number PRJEB53615; https://www.ebi.ac.uk/ena/browser/view/PRJEB53615). The non-targeted metabolic data used in this study is available in the Zenodo repository (https://zenodo.org/record/7104987#.Y_OwfR_MJdg, doi:10.5281/zenodo.7104987).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2181928

Additional information

Funding

This study has been supported by the Spanish Ministry of Science and Innovation (MICINN) (grant PID2020-119536RB-I00). An PFU contract to RL-G from the Spanish Ministry of Universities (PFU 18/02026) and a Marie Sklodowska Curie Actions (MSCA-IF) ”MicroILCs” (GA: 8905454) contract to MO are acknowledged. The grant of Spanish Ministry of Science and Innovation (MCIN/AEI) of Center of Excellence Accreditation Severo Ochoa (CEX2021-001189-S/ MCIN/AEI / 10.13039/501100011033) is also acknowledged.