Dynamical Modeling Of Antibiotic Resistance In Intestinal Microbiota

Antibiotics are widely used in the treatment of the bacterial infection,but the drug resis-tance caused by the abuse of antibiotics become an increasingly serious problem.Intestinal flora is a complex symbiotic system composed of intestinal microorganisms.A large num-ber of clinical and experimental data has showed that the use of antibiotics can disrupt the balance of various intestinal microorganisms,which is closely related to the occurrence of drug-resistance.However,the underlying mechanism is still unclear.Based on the existed clinical and experimental observations,we established a dynamic model of intestinal flora.By applying numerical simulations and analytical studies,the de-velopment mechanism of antibiotic resistance was revealed.Furthermore,we also explored how the fecal bacteria transplantation take effect in the treatment of drug-resistant infections The main contents include of the following aspectsFirstly,we built a mathematical model to describe the dynamics of intestinal flora and explained the development mechanism of antibiotic resistance.In this paper,we focused on the case where gene sequences of sensitive and resistant pathogens differ only at a few sites.In the second chapter,we roughly divided microbiota into three categories(sensitive pathogens,resistant pathogens and probiotics)and built the mathematical model.The model reproduced the clinical and experimental results well,thus the validity of the model is veri-fied.The stability analysis of equilibriums showed that the main steady-state solutions of the system(healthy stable state,illness stable state,etc.)are not isolated points,but some spatial segments.In the early stage of antibiotic usage,the system state can return to the spatial segment of healthy states after each treatment,yet distinct from the pre-treatment state.The movement on the line segment,where the health steady state solution is located,is the key reason for the development of drug-resistance.In fact,antibiotic can change the proportion of resistant and sensitive pathogens after each treatment.With the increasing number of an-tibiotic treatments,drug resistance emerges when the ratio of resistant pathogens to sensitive pathogens exceeds a certain threshold.We further analyzed the factors that may contribute to the development of drug-resistance.The results exhibit that the number of probiotics,the proportion of intestinal flora composition,and the inter-specific inhibition can affect the oc-currence of drug-resistance.In addition,the responses of different microbiota to antibiotics also have an important influence on the development of drug-resistance.Secondly,we explored how fecal bacteria transplantation take effect in the treatment of drug-resistant infections and optimized the strategy of fecal bacteria transplantation.In the third chapter,our model revealed that fecal bacteria transplantation can help to improve the intestinal flora composition and make the proportion of sensitive pathogens,resistan-t pathogens and probiotics similar to the original healthy state,thus cures drug-resistant infections.Moreover,we analyzed how the survival rate of transplanted bacteria,drug pre-treatment,donor's fecal bacteria composition and the amount of transplantation affect the performance of fecal bacteria transplantation.The simulation results indicates that the in-crease of survival rate of transplanted bacteria,the number of probiotics or the amount of transplantation all favor the recovery of drug-resistant infections.We also found that drug pretreatment is crucial for the effectiveness of fecal bacteria transplantation.In addition,the model predicted that early use of fecal bacteria transplantation could significantly delay the development of drug resistance.Finally,we use piecewise linear approximation to deal with nonlinear ordinary differen-tial equations in chapter 4 and obtain some theoretical results.We proved that the sufficient condition for the generation of infinite non-isolated equilibrium points in the system pro-posed in Chapter 2.And it has been proved theoretically that the fundamental cause of drug resistance is the existence of illness steady states in the continuous drug use systemThe main innovations of this paper are as follows:First of all,based on the consideration that sensitive and resistant pathogens only have a few different sites in gene sequences,steady-state solutions of the system are line segments rather than isolated points.This characteristic of stationary solution is the key factor to explain the mechanism of drug resistanceSecondly,beneficial bacteria are introduced and the inter-specific inhibition between beneficial bacteria and pathogenic bacteria is considered in our model.Our results show that flora structure,especially beneficial bacteria,plays a crucial role in the occurrence of drug resistance.Thirdly,predictive results suggest that early use of fecal bacteria transplantation may effectively delay or even prevent the emergence of drug resistanceThe theoretical studies performed in this thesis revealed the underlying mechanism of drug-resistance upon the abuse of antibiotics,in addition to providing novel design strategies for optimizing the strategy of fecal bacteria transplantation.