MIMICS: Model Intestinal Microflora In Computer Simulation

A research project initiated by the International Study Group for New Antimicrobial Strategies

Staff

Principal researcher:Dr M.H.F. Wilkinson
PhD student Ir D.J. Kamerman
Visualisation by: Drs. J. Kraak

Aims

The MIMICS project is the first research project within the framework of the research programme of the International Study Group for New Antimicrobial Strategies (ISGNAS). Its aim is to provide new insight into the workings of the intestinal microflora by combining data from in vitro measurements of the metabolic properties of bacteria into a large scale computer simulation. The chief research aim is to study which parameters have the most profound effect on the colonization resistance, i.e. the difficulty with which newcomers colonize the intestine.

Progress

A set of programs has been developed to model transport, metabolism (host and bacterial), food supply, etc., on the Cray J932 of the Centre for High Performance Computing . The model intestine consists of an axisymetric tube, with varying diameter, and incorporates up to 6 species of bacteria, food substrate, oxygen, transport (bulk motion and diffusion). Food enters through the oral end, either continously, or intermittently, and through the intestinal wall (mucus production). Oxygen is supplied along with the food. Bacteria are modelled through Monod equations. Visualization of the results is done using AVS. A pilot study has been performed in which the initial colonization and consequent competition between aerobic and anaerobic bacteria within the model gut were studied. The results show that even in a model which does not include the immune system, a reasonable ratio of aerobes to anaerobes was established (approximately 1:1000). This suggests that the ratio of food to oxygen, rather than selection by the immune system is responsible for the anaerobic nature of the intestinal microflora. Furthermore, strict anaerobic bacteria could only colonize the sterile, oxygen rich environment of a "newborn's" intestine after aerobes, or facultatively anaerobic bacteria (which can switch from aerobic to anaerobic metabolism) had reduced the oxygen level.
The results were presented at the Tenth Old Herborn University Seminar: New Antimicrobial Strategies, and will be published in the proceedings.


Animation of colonization

Figure 1. Distribution of bacteria through small and large intestine, 6 days after colonization of sterile intestine. The unit of the scale is 10log of the number of bacteria/g. The length of the intestine is 6 m, the diameter varies from 3 cm in the small intestine through 10 cm in the cecum, back to 6 in the colon. Radial scale has been exagerated for display purposes.

Future plans

Future plans include adding more species, improved realism of the fluid dynamics, toxin and metabolite production, etc.

Background

The human gut is host to a vast number of microorganisms, predominantly anaerobic bacteria. It is thought that these bacteria play a vital role in the normal metabolism, and as a first line of defense against potentially pathogenic (harmful) bacteria. However, the complexity of this ecosystem, and the anaerobic nature of most of the inhabitants (i.e. they don't grow in air!), means that the population dynamics is both hard to observe and to understand. Since this ecosystem is part of the natural defenses against invading bacteria, better understanding of this "colonization resistance" may lead to ways to prevent infections, reducing the need for treatment with antibiotics. Given the growing concern about antibiotic resistance in bacteria, such new antimicrobial strategies are urgently needed.
In recent years there has been quite some progress in developing better methods to observe the microflora, especially through the development of identification techniques which do not require culturing. However, theoretical understanding has not kept pace with the new observations.

Funding

This project is funded through generous donations of The Symbiogroup, Herborn-Dill, Germany.

Publications

  1. Journal Papers

    1. M.H.F. Wilkinson. Decoys in predation and parasitism. Comments on Theoretical Biology (2003) 8:321-338.

    2. M.H.F. Wilkinson. Model intestinal microflora in computer simulation: a simulation and modelling package for host-microflora interactions. IEEE Trans. Biomed. Eng., in press. PDF (296 kB) preprint version available.

    3. M.H.F. Wilkinson. Predation in the presence of decoys: an inhibitory factor on pathogen control by bacteriophages or bdellovibrios in dense and diverse ecosystems. J. Theor. Biol., (2001) 208:27-36. Pre-print version available in PDF (292 kB). Note: may differ from final version; ALWAYS check final version when citing.

    4. H. Boureau, L. Hartmann, T. Karjalainen, I. Rowland and M.H.F. Wilkinson. Models to study colonisation and colonisation resistance. Microb. Ecol. Hlth. Dis. (2000) 12 sup. 2:247-258.

  2. Conference Papers

    1. D.J. Kamerman and M.H.F. Wilkinson. In silico modelling of the human intestinal microflora. Lecture Notes in Computer Science Vol. 2329 Proc. ICCS 2002, (P.M.A. Sloot et al eds), April 2002, Amsterdam, The Netherlands, pp. 117-126. PDF (201 kB) preprint version available.

    2. M.H.F. Wilkinson. Nonlinear dynamics, chaos-theory, and the "sciences of complexity": their relevance to the study of the interaction between host and microflora. In: "Old Herborn University Seminar Monograph 10: New Antimicrobial Strategies" (P.J. Heidt, V. Rusch and D. van der Waaij, eds.) pp. 111-130, Herborn Litterae, Herborn-Dill, Germany, 1997. PDF (842 kB) version available.

  3. Technical Reports

    1. M.H.F. Wilkinson. MIMICS Technical Report: MIMICS Cellular Automaton Progam Design and Performance Testing. PDF (411 kB) version available.

    2. M.H.F. Wilkinson. MIMICS Technical Report: Ordinary Differential Equations for Modelling Bacterial Interactions in the Gut. PDF (291 kB) version available.