Colorectal cancer is highly associated with inflammatory bowel disease , and the dysbiosis of intestinal microbiota has been recognized as one of the drivers of inflammatory bowel disease  that alters the interactions between microbes and the mucosal immune system [3, 4]. Therefore, intestinal microbes have been successfully developed as a clinical approach for colorectal cancer risk detection in recent years [5-9]. Gut microbes dynamically interact with intestinal epithelial cells [10, 11]; therefore, microbial communities are likely altered with the development of colorectal cancer. In addition, microbial communities may also have adaptive strategies to resist lesion shocks and maintain the completeness of communities and functions. Previous studies reported that intestinal microbial aggregates are sex-dependent [12-14], but the response mechanism during colorectal cancer development is still unclear.
Gut microbial communities can remain homeostatic in normal individuals ; however, this homeostasis will be broken by the development of colorectal cancer, which weakens the plastic adjustment of normal communities. Previous studies have demonstrated that the microbial communities in colorectal cancer patients deviate from those in normal individuals [16-18], and some studies have revealed how gut microbes change in healthy individuals compared to colorectal cancer patients at the taxonomic scale. However, the conclusions of these studies have not been consistent; for instance, microbes belonging to the Firmicutes phylum were detected with lower abundance in colorectal cancer patients in a previous study , whereas Firmicutes dominated in colorectal cancer patients in a recent study . Moreover, the genera Bacteroides  and Fusobacterium [9, 22] were enriched, whereas Ruminococcus  and Bacteroides  were depleted in patients with colorectal adenoma or cancer. Unlike gastric cancer, which is probably solely derived from a single pathogenic bacterium, such as Helicobacter spp., colorectal cancer is involved in multiple microbial changes [16-18]. The gut microbiota is influenced by the age , diet style [24, 25]and genetic background of the host ; therefore, it is difficult to capture the full picture of microbial changes if we only focus on which taxon increased or decreased. Ecological insights concern microbial changes at the community scale, which may help us move beyond the current situation and reveal ecological response strategies of microbial communities to colorectal cancer.
Sexual divergences must be taken into account when detecting microbial changes during the development of colorectal cancer because sexual maturation, hormones, and the differences in the immune system and function profoundly affect microbe colonization in the gut [12-14]. Differences in initial colonization represent historic factors that likely contribute to how the microbial community responds to colorectal cancer, while sexual dimorphism may serve as a crucial long-term selection pressure that determines how microbial species aggregate . Recent studies revealed that the gut microbial communities in males are distinguished from those in females in the face of external environmental pressures [28, 29], suggesting that males and females have distinct microbial aggregation strategies in the gut. Studies focusing on abdominal obesity-related disease , type I diabetes [31, 32], and major depressive disorder  have also demonstrated that sex-specific differences are important for shaping the gut microbial community with the development of related diseases. These results imply that sexual divergence is a primary factor in shaping the gut microbial community. Gut microbial changes and disease are highly associated with sex differences [12, 13]; however, the mechanism of species assembly with the development of colorectal cancer in males and females, with respect to ecological insights, is unknown.
Community assemblies describe microbial responses to environmental changes at the community scale and have been successfully applied in the microbial ecology of natural ecosystems . Microbial community assembly is associated with both deterministic and stochastic processes . Deterministic processes are involved in the ecological selection of both biotic and abiotic factors, which influence microbial assembly by changing the fitness between organisms and the environment and eventually altering community composition and species abundance . Stochastic processes include dispersal, random birth, death and ecological drifts, which result in communities that are close to those produced by chance . The balance between these two ecological processes could reflect how intestinal microbes respond to the development of colorectal cancer at the community scale; however, these processes have not been used to explain the variation in microbial communities with the development of colorectal cancer in males and females. A recent study indicated that colorectal cancer might influence microbial assembly indirectly by altering niche differentiation . In soil microbial ecological research, lineages of bacteria can easily branch from a more extreme environment to colonize a more temperate environment, causing adapted lineages to colonize or accumulate in temperate environments, further resulting in greater diversity and higher stochastic assembly . The gut microbiota is essential to complex ecological communities that have little fundamental difference from other ecological communities in nature, such as soils and lakes. However, whether ecological forces that shape gut microbial communities and the development of colorectal cancer are discrepant between males and females is unclear.
Gut microbes in communities mutually interact to form stable networks to serve specific ecological functions [39, 40]. The enrichment or depletion of specific lineages in local communities might break the balance of the entire microbial ecosystem if these species are essential components in the ecological function network. Co-occurrence patterns are ubiquitous and particularly important in understanding microbial community structure, offering new insights into potential interaction networks among microbes at the system-level scale and revealing niche spaces shared by lineages in local communities [41-43]. Taxonomic changes that are induced by the development of colorectal cancer likely alter the topological features of the co-occurrence network and further change microbial ecological function profiles. By identifying the lineages with high topological importance in the network using topology-based analysis of large networks, it is likely that novel indicators that cannot be detected with traditional methods can be found. Comparing the topological properties of nodes (a node represents a species in network analysis) and networks can provide insights into the response mechanism of gut microbial communities to cancer-inducing environmental changes.
In this paper, we compared the response mechanism of the gut microbial community at the community scale with the development of colorectal cancer in males and females using high-throughput sequencing data from the study of Zackular et al. (2014). Specifically, we downloaded 90 high quality fecal samples from public databases to represent the time series of colorectal cancer (healthy, colorectal adenoma and carcinoma). Two basic questions have been addressed: (i) Are the responses of the gut microbial community to colorectal cancer development gender-dependent? (ii) How is the microbial response to colorectal cancer development at the community scale determined based on ecological insights in males and females?