Integrated multi-omics reveal gut microbiota-mediated bile acid metabolism alteration regulating immunotherapy responses to anti-α4β7-integrin in Crohn’s disease

ABSTRACT

Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn’s disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn’s disease, and the response to anti-α4β7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn’s disease initiating anti-α4β7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4β7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4β7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4β7-integrin in Crohn’s disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.

KEYWORDS:

• Gut microbiota
• bile acid metabolism
• biomarker
• Crohn’s disease
• immunotherapy responses
• Anti-α4β7-integrin

Acknowledgments

We would like to acknowledge Figdraw (www.figdraw.com) for their assistance in creating Figure 13 for this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Bing Han, Daiyuan Tang, and Xiaoping Lv conceived the project and designed the experiment. Bing Han, Daiyuan Tang, Xiaodan Lv, Junhua Fan, Shiquan Li, Hui Zhu, Jiatong Zhang, and Shang Xu conducted the experiment. Xiaofang Xu, Ziqian Huang, Zhixi Huang, and Guangfu Lin contributed the clinical cases. Bing Han and Daiyuan Tang sorted out the findings. Bing Han wrote the manuscript. Xiaoping Lv and Lingling Zhan revised the manuscript. All authors read and approved the final manuscript.

Data availability statement

The data obtained from whole-genome shotgun metagenomics and 16S-rDNA gene high-throughput sequencing were uploaded to the NCBI SRA (www.ncbi.nlm.nih.gov) and can be accessed using the following BioProject numbers: PRJNA1022859, PRJNA1024074, PRJNA1024099, and PRJNA1024450. The data generated from non-targeted metabolomics and targeted BA metabolomics were deposited in the MetaboLights (www.ebi.ac.uk/metabolights) and can be accessed using the following numbers: MTBLS8700 and MTBLS8702.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2310894

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [81860104]; Natural Science Foundation of Guangxi Zhuang Autonomous Region [2023GXNSFDA026024]; Innovation Project of Guangxi Graduate Education [YCBZ2022079].