Changes in Gut Microbiota and Pathological Analysis of Chronicinflammation in HIV-1 gp120tg Mice in a Proinflammatory State

Backgrounds: Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) remain significant global health challenges, contributing to substantial morbidity and mortality worldwide. Since the first HIV was registered it has infected millions of people in a worldwide pandemic. Nowadays, people with HIV (PWH) are living longer than before in the era of combination antiretroviral therapy (cART). However, HIV-1 causes a range of comorbidities to become a problem and causes significant morbidity and mortality among PWH in modern society. Therefore, PWH has an increased risk of HIV-associated comorbidities that need to be addressed to improve their health and lives. Especially, gastrointestinal symptoms are often noted in PLWH and are also highly prevalent in the ART era. HIV causes significant changes in the gut microbiota, structure and immunological function of the gastrointestinal environment, which has a profound local on gastrointestinal disorders, moreover systemic effects on other HIV related disorders. In the gut, altered microbiota induces pro-inflammatory immune responses and increased risk of inflammatory disease. Methods: Large intestine samples from 25 gp120 tg mice aged 6, 9, and 12 months, along with 15 wild-type (WT) mice, were analyzed. Gut microbiota was analyzed using 16S rRNA high-throughput sequencing technology. Inflammatory markers and cell populations were evaluated through microscopic analysis and ELISA. Statistical analyses were performed using SPSS version 25.0, and histological images were analyzed using ImageJ software. Results: HIV-1 gp120 mice exhibited increased proportions of Firmicutes, and specific microbial taxa compared to controls. At the order levels, Erysipelotrichales was the most abundant in fecal microbiota in gp120tg mice. There was a statistically significant difference in specific bacterial taxa between the two groups by comparing the levels. P value was less than 0.05 in specific bacterial relative abundance at the levels. Inflammation scoring revealed significant differences between gp120 mice and WT controls (p = 0.018). The mean density of colon lymphoid tissue aggregates of HIV-1 gp120 mice was higher than WT (P<0.005). HIV-1 gp120 mice demonstrated elevated levels of eosinophils (t(98)= 4.7, p=0.00002 in mucosa and t(98)= 6.6, p=0.00002 in the submucosa, eosinophils positive for major basic protein, within colon tissue samples. Additionally, IL-1β expression levels were elevated in gp120 mice compared to WT controls (P<0.05). Conclusions: This study highlights associations between alterations in gut microbiota and markers of inflammation in the gastrointestinal tract of HIV-1 gp120 tg mice. In our study, we investigated the impact of altered gut microbiota in HIV-1 gp120tg mice during the proinflammatory state on the development of chronic inflammation. Our findings reveal that changes in gut bacteria can indeed induce the inflammatory process and stimulate immune cell recruitment, including eosinophils, within the large intestine. Specifically, we observed a pronounced inflammatory process characterized by increased eosinophil levels and the presence of positive major basic protein. A significant increase in IL-1 beta was detected, these results were indicating a localized proinflammatory state. These findings underscore the intricate relationship between gut microbiota and immune responses, emphasizing the need for further research to elucidate underlying mechanisms and implications for gastrointestinal health and disease. (Acknowledgements:This study was supported by National Natural Science Foundation of China, No. 82172259 to H. Cao and Natural Science Foundation of Guangdong, China, No. 2024A1515010606 to H. Cao and Grant from School of Public Health of Southern Medical University, China, Grant No. GW202431 to H. Cao; Corresponding author: Hong Cao, gzhcao@smu.edu.cn)