Sexual dimorphism of gut microbiota in colorectal cancer
Colorectal cancer(CRC)represents a significant public health challenge globally,ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide.Recent cancer statistics indicate that the average annual incidence and overall mortality rates of CRC are higher in men than in women,highlighting pronounced sex differences in both the risk and prognosis of the disease.These differences may be attributed to variations in sex hormone levels.Emerging evidence suggests that the gut microbiota associated with CRC exhibits sexual dimorphism,and its interaction with sex hormones—primarily estrogen and androgen—may contribute to these sex differences.The gut microbiota plays a crucial role in the tumor microenvironment,with intestinal microbial dysbiosis identified as a risk factor for CRC.Recent findings have established the concepts of the'microgenderome'and the'sex hormone-gut microbiome axis',which elucidate the bidirectional interactions among gut microbiota,sex hormones,and the immune system.These novel terms provide a foundation for exploring the intricate relationships between gut microbiota,sex hormones,and CRC.However,research on the interactions between sex hormones and gut microbiota that may influence sex differences in CRC remains limited.The gut microbiota constitutes a vast and complex ecosystem,and the role of sex hormones in CRC is still debated.Both factors are influenced by environmental conditions and exhibit significant individual variability.This complexity underscores the challenges in investigating the mechanisms by which intestinal microbiota and sex hormones may contribute to gender differences in CRC,necessitating more robust evidence to substantiate existing conclusions.In this manuscript,we primarily present indirect evidence from two perspectives:inflammation and the immune microenvironment,which supports the notion that interactions between sex hormones and intestinal microbes contribute to sex differences in CRC.Specifically,regarding the inflammatory microenvironment,estrogen can sustain the balance of intestinal microecology by enhancing the diversity of intestinal microbiota and increasing the relative abundance of commensal bacteria while reducing the relative abundance of pathogenic bacteria,thereby alleviating intestinal inflammation.Inflammation and oxidative stress can hinder the progression of colitis-related cancers.Conversely,androgens may induce intestinal microbial dysbiosis,facilitating the malignant progression of intestinal inflammation and increasing the risk of tumors.Concerning the immune microenvironment,estrogen can counteract the immunosuppressive microenvironment and bolster the body's anti-tumor immunity by downregulating the expression of PD-L1,modulating the number of infiltrating immune cells,and preserving the balance of intestinal microecology.In contrast,androgens may adversely affect anti-PD-Ll therapy,and reducing testosterone levels may alter the composition of the CRC gut microbiota,thereby enhancing the efficacy of immunotherapy.These findings suggest that sex hormones and gut microbiota may serve as key regulators of CRC immunotherapy,with estradiol and certain specific probiotics emerging as potential targets for improving anti-PD-Ll efficacy.Furthermore,sex hormones can influence the composition and diversity of the intestinal microbiota,which in turn plays a role in regulating the circulation and metabolism of sex hormones.This bidirectional interaction is crucial in understanding the development of sex differences in CRC.However,the effects of estrogen and androgens are closely linked to their receptor status and exhibit dual roles in the pathogenesis of CRC.This paper aims to review the sexual dimorphism of gut microbiota in CRC.It will elucidate the phenomenon of sexual dimorphism in gut microbiota associated with CRC and provide an in-depth analysis of the regulatory mechanisms through which sex hormones and intestinal microbiota influence colon inflammation and the immune microenvironment.Additionally,the study will explore the bidirectional interactions between sex hormone signaling and intestinal microbiota,thereby offering a scientific reference for therapeutic strategies that leverage both intestinal microbiota and sex hormones.
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