Revision as of 14:19, 26 October 2012 by Shihyi (Talk | contribs)




Complex Adaptive BioSystems

Human bodies are highly fluctuating complex systems. They detect and integrate the clues from changing environments and their own internal states, making numerous responses after delicate computation and regulation. Traditional routes of drug administration includes oral intake or intravenous injection may be too simplified to promptly fit the real-time condition of the body states. In addition, the frequent and repetitive intake of drugs may be annoying, and sometimes the invasive processes are suffering, bringing inconvenience to our daily lives. Medical instruments or electrical monitors can instantaneously detect and response to some specific physiological or pathological parameters, but they are usually too heavy and bulky to carry, which restrict the mobility of patients while using it. Therefore we aim to program the intestinal microbes to build our novel smart drug delivery systems—PEPDEX.

There are around \(10^{13}\) to \(10^{14}\) microorganisms inhabiting in our gastrointestinal tracts, more than 10 times that of the total number of cells in human bodies. They consist of more than 1000 species, and contain 150 times as many genes as our genomes. Colonizing soon after our birth, these microbes comprise a huge community and closely interact with their hosts, having great influence on our immune systems, endocrine, metabolic states, and even nervous systems, from birth to death, from health to illness. They seem to be tiny natural machines that can be utilize, for carriage of the blueprint of our design and can function adaptively and communicably inside our bodies. Weaving into the fabric of the complexity and adaptability of these intestinal microbial communities, we can achieve desirable medical goals, in our case, production and delivery of peptide drugs. Operation and customization of these complex adaptive biosystems will be an inevitable trend towards the development of systems biology and synthetic bio-techniques.

Peptide-Based Therapies

Bacteria and Immune System

Bacteria and Nervous System

The novel conceptual model “Brain-Gut Axis” has received emerging attention recently. Lots of studies showing evidence that intestinal microbiota have profound impacts on our nervous systems blossom during this 5~10 years. They interact with each other bidirectionally via various pathways. These include neuroendocrine (hypothalamus-pituitary-adrenal axis), immune systems (neuromodulating cytokines), enteric nervous systems and autonomic nervous systems (vagus nerve). Gut microbes produce substance such as tryptophan-related metabolites kynurenic acid, short chain fatty acids, and neurometabolites GABA, noradrenalin, and dopamine that potentially target to and influence functions of our central nervous systems. In the process of neurodevelopment, they modulate the expression level of many critical genes, such as brain-derived neurotropic factor (BDNF), NMDA receptors or 5-HT receptors and communicate with brain regions like striatum, hippocampus, amygdale, hypothalamus, and cingulated gyrus. It has long been known that the colonization of gut flora is related to the stress response of the hosts, changing their states of anxiety and exploratory behavior. Diseases such as inflammatory bowel diseases (IBS) and multiple sclerosis (MS) are also documented to be associated with intestinal microorganisms. New focus has been greatly put on many neuropsychiatric diseases, for instance, autism spectrum disorders (ASD), depression, anxiety disorders, and schizophrenia.

Diagram of brain-gut axis


  1. Collins SM, et al. (2012) The interplay between the intestinal microbiota and the brain. Nature Reviews Microbiology. AOP, published online 24 September 2012, 1-8.
  2. Cryan JF, et al. (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. NatureReviews Neuroscience 13: 701-712.
  3. Rhee SH, et al. (2009) Principles and clinical implications of the brain–gut–enteric microbiota axis. Nature Rev. Gastroenterol. Hepatol. 6, 306–314.
  4. Neufeld KM, et al. (2010) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264.
  5. Bercik, P. et al. (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609.
  6. Lyte M, et al. (2006) Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol. Behav. 89, 350–357.
  7. Bravo, J. A. et al. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055.
  8. Wall, R. et al. (2012)Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota. Am. J. Clin. Nutr. 95, 1278–1287.
  9. Tillisch, K. et al. (2012) Modulation of the brain–gut axis after 4 week intervention with a probiotic fermented dairy product. Gastroenterology 142, S-115.
  10. Mayer EA. (2011) Gut feelings: the emerging biology of gut–brain communication. Nature Rev. Neurosci. 12, 453–466.
  11. Freestone PP, et al. (2008) Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol. 16, 55–64.
  12. Kaper JB, et al. (2005). Bacterial cell to cell signaling in the gastrointestinal tract. Infect. Immun. 73, 3197–3209.
  13. Neufeld KM, et al. (2011). Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264.
  14. Heijtz RD, et al. (2011) Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052.
  15. Gareau MG, et al. (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60, 307–317.
  16. Desbonnet L, et al. (2010) Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188.
  17. Lyte M. (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays 33, 574–581.
  18. Derecki, N. C. et al. (2010) Regulation of learning and memory by meningeal immunity: a key role for IL 4. J. Exp. Med. 207, 1067–1080.
  19. Lyte M, et al. (2011) Stress at the intestinal surface: catecholamines and mucosa– bacteria interactions. Cell Tissue Res. 2431, 23–32..
  20. Lee Y K, et al. (2011) Proinflammatory T cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622.
  21. Berer, K. et al. (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541.
  22. Juárez I, et al. (2008) Ontogeny of altered dendritic morphology in the rat prefrontal cortex, hippocampus, and nucleus accumbens following cesarean delivery and birth anoxia. J. Comp. Neurol. 507, 1734–1747.