Multiomics Insights into BMI-Related Intratumoral Microbiota in Gastric Cancer

Kang Liu ¹ Zhenchen Jiang ^2,3* Yubo Ma ¹ Ruihong Xia ¹ Yingsong Zheng ⁴ Kailai Yin ⁴ Chuhong Pang ⁴ Li Yuan ^3,5 Xiangdong Cheng ^2,3 Zhuo Liu ² Bo Zhang ^5* Shi Wang ^6*

• ¹ Second Clinical Medical School, Zhejiang Chinese Medical University, Hangzhou, Jiangsu Province, China
• ² Department of Gastric Surgery, Zhejiang Cancer Hospital, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
• ³ Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
• ⁴ Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
• ⁵ Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, University of Chinese Academy of Sciences, Hangzhou, Jiangsu Province, China
• ⁶ Endoscopy division, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China

Body mass index (BMI) is considered an important factor in tumor prognosis, but its role in gastric cancer (GC) remains controversial. There is a lack of studies exploring the effect of BMI on gastric cancer from the perspective of intratumoral microbiota.This study aimed to compare and analyze the differences in and functions of intratumoral microbiota among GC patients with varying BMIs, aiming to ascertain whether specific microbial features are associated with prognosis in low-BMI(LBMI) gastric cancer patients.A retrospective analysis of the clinicopathological features and prognosis of 5567 patients with different BMIs were performed between January 2010 and December 2019. Tumor tissues from 189 GC patients were collected for 16S rRNA sequencing, 64 samples were selected for transcriptome sequencing, and 57 samples were selected for untargeted metabolomic analysis.Clinical cohort analysis revealed that GC patients with a low BMI presented poorer clinical and pathological characteristics than those with a nonlow-BMI(NLBMI). LBMI has as a significant independent risk factor for adverse prognosis, potentially exerting immunosuppressive effects on postoperative adjuvant chemotherapy. 16S rRNA sequencing revealed no significant differences in the alpha and beta diversity of the intratumoral microbiota between the two groups of GC patients. However, LEfSe analysis revealed 32 differential intratumoral microbiota between the LBMI and NLBMI groups. Notably, g_Abiotrophia was significantly enriched in the LBMI group.Further in-depth analysis indicated that genus Abiotrophia was inversely associated with eosinophils, P2RY12, and SCN4B genes, and positively linked withLGR6 in LBMI gastric cancer patients. Metabolomic assessments revealed that LBMI was positively associated with purine metabolites, specifically guanine and inosine diphosphate (IDP).In conclusion, LBMI is an independent risk factor for poor prognosis in gastric cancer patients and may have an inhibitory effect on postoperative adjuvant chemotherapy. Intratumor flora of gastric cancer patients with different BMI levels differed, with different immune cell infiltration and metabolic characteristics. g_Abiotrophia may promote gastric cancer development and progression by regulating eosinophils and purine metabolism pathway, which provides a new idea for precise treatment of gastric cancer.