Microbiomics-based Investigation Of The Regulation And Intervention Of Gut Microbiota In Enteropathy

There are trillions of bacteria in the human gut,which co-exist with humans to form a complex and changeable ecological environment.These gut microbes,known as gut microbiota,participate in various metabolic pathways and signal transduction during human physiology while maintaining the stability of the gut barrier and the balance of the gut environment.The gut microbiota has adapted to human hosts over a long period of time,gradually forming a relatively stable dynamic equilibrium relationship.In this process of two-way communication,humans provide a nutrient-rich gut environment for the microbiota,which in turn provides humans with a diverse and highly adaptive metabolite.However,this balance can be upset in some enteropathic situation,such as colon cancer or colitis,resulting in a dysbiosis of the gut microbiota.This can cause a variety of symptoms of the body and even aggravate the disease condition.Therefore,it is very important to understand the changes of intestinal microflora on the regulation of host homeostasis in various intestinal diseases and to study the intervention and treatment methods mediated by gut microbiota.In recent years,with the development of computer technology and high-throughput sequencing,bioinformatics approaches have taken an important place in microbiology research,giving rise to microbiomics,a research direction that has allowed the physiological functions of gut microbes to be discovered and confirmed at the genetic level through 16 S amplicon sequencing and metagenomics sequencing.Through microbiome tools and bioinformatics approaches,this thesis investigates the dynamics of the gut microbiota compartment,the impact of specific microorganisms,and the microbially mediated therapeutic interventions using a colon cancer mouse model and an dextran sodium sulfate(DSS)-induced colitis mouse model.In the study of colon cancer,we established an orthotopic model of colon cancer by inoculating a tumor mass onto the colon.Then,the 16 S rDNA sequencing technique was used to screen out the microbiota which showed obvious changes during the development of colon cancer.The abundance of Akkermansia muciniphila(A.muciniphila)was significantly increased in the model group.A.Muciniphila is known for its ability to break down mucins,which are an important component of the intestinal barrier and play an important role in maintaining intestinal barrier homeostasis.In recent studies,the effect of A.Muciniphila on human intestinal health is remain controversial.Therefore,in order to elucidate the role of A.muciniphila in the development of colon cancer,we established an A.muciniphila over-colonization mouse model to investigate whether the over-colonization of A.muciniphila would have an adverse effect on the intestinal barrier when intestinal homeostasis was disrupted.As it turns out,the over-colonization of A.muciniphila reduced mucin content and tight junction protein expression,suggesting that its over-degradation disrupts the Dynamic equilibrium between mucin production and breakdown,which undermines the integrity of the intestinal barrier.Subsequently,to investigate gut microbiota-mediated disease interventions,we treated mice with DSS-induced colitis using a natural plant polysaccharide drug,Lycium barbarum glycopeptide(LbGP),and explored the effect and mechanism of LbGP treatment for acute colitis from the perspective of gut microbiota at multiple time points using 16 S rDNA sequencing technology.The results showed that the composition of gut microbitoa in the model group changed obviously during the development of colitis,and the LbGP treatment could rapidly relieve the symptoms of colitis and restore the destroyed intestinal microflora homeostasis.Harmful bacteria,such as Lachnoclostridium and Parabacteroides＿distasonis,were suppressed during the course of treatment;while probiotic bacteria,such as Bacteroides＿acidifaciens,Lactobacillus,and Alistipes,were increased during LbGP treatment,suggesting that LbGP can improve the intestinal environment by regulating the balance of harmful and probiotic bacteria.In addition to this,to identify key biomarkers during LbGP treatment,we identified a family called Muribaculaceae through a randomized forest analysis,whose abundance changed with the progression of LbGP treatment,suggesting that Muribaculaceae play an important role in the development and recovery of colitis.This thesis provides insight into the regulatory mechanisms of gut microbiota-host interactions in disease settings and effective modalities of external intervention from the above aspects,providing new insights into the etiology and clinical treatment modalities of intestinal inflammation and colon cancer.