View source for Microbial drug delivery

[[File:Lactococcus lactis.jpg|thumb|''Lactococcus lactis'', a species used in microbial drug delivery]]
'''Microbial drug delivery''' is an emerging form of drug administration characterized by the use of [[Commensalism|commensal]] [[Microorganism|microbes]] that have been [[Genetically modified organism|genetically modified]] to produce medications for [[Chronic condition|chronic diseases]] in [[human]]s.<ref name=":0">{{Cite journal|last=Hamady|first=Zzr|date=2013-05-01|title=Novel xylan-controlled delivery of therapeutic proteins to inflamed colon by the human anaerobic commensal bacterium|journal=Annals of the Royal College of Surgeons of England|volume=95|issue=4|pages=235–240|doi=10.1308/003588413X13511609958217|issn=0035-8843|pmc=4132495|pmid=23676805}}</ref><ref name=":1">{{Cite journal|last1=Steidler|first1=Lothar|last2=Rottiers|first2=Pieter|date=2006-08-01|title=Therapeutic Drug Delivery by Genetically Modified Lactococcus lactis|journal=Annals of the New York Academy of Sciences|language=en|volume=1072|issue=1|pages=176–186|doi=10.1196/annals.1326.031|pmid=17057198|bibcode=2006NYASA1072..176S |s2cid=21052633 |issn=1749-6632|url=https://biblio.ugent.be/publication/351510/file/2935297|url-access=subscription}}</ref><ref name=":2">{{Cite journal|last1=Braat|first1=Henri|last2=Rottiers|first2=Pieter|last3=Hommes|first3=Daniel W.|last4=Huyghebaert|first4=Nathalie|last5=Remaut|first5=Erik|last6=Remon|first6=Jean–Paul|last7=Deventer|first7=Sander J.H. van|last8=Neirynck|first8=Sabine|last9=Peppelenbosch|first9=Maikel P.|title=A Phase I Trial With Transgenic Bacteria Expressing Interleukin-10 in Crohn's Disease|journal=Clinical Gastroenterology and Hepatology|volume=4|issue=6|pages=754–759|doi=10.1016/j.cgh.2006.03.028|pmid=16716759|date=June 2006}}</ref> Only proteinaceous [[drug]]s can be produced by microbes, as [[DNA]] encodes for [[protein]]. Research into microbial drug delivery refers to this [[route of administration]] as [[Topical medication|topical]], since the microbes release the drug directly to the surface of affected [[Tissue (biology)|tissues]], namely the [[Intestinal epithelium|gastrointestinal (GI) epithelium]].<ref name=":0" /><ref name=":1" /> Microbial drug delivery is not currently used as a standard route of drug administration due to its experimental nature. During [[clinical trial]]s, it has been used to treat forms of [[inflammatory bowel disease]] (IBD).<ref name=":1" /><ref name=":2" /> The most prominently studied vehicles of microbial drug administration are the [[bacteria]]l [[species]], ''[[Lactococcus lactis]]'' and ''[[Bacteroides ovatus]].''<ref name=":0" /><ref name=":1" /><ref name=":2" />

== Medical usage ==
The usage of [[Recombinant DNA|recombinant]] microbes (i.e. microorganisms designed to contain DNA from two or more different species) has applications in treating chronic diseases.<ref name=":0" /><ref name=":1" /><ref name=":2" /> In 2006, Braat ''et al''. implemented microbial drug delivery with ''L. lactis'' in clinical trials, successfully treating [[Crohn's disease]] (CD), a form of IBD that causes [[inflammation]] and [[Ulcer (disambiguation)|ulceration]] in the [[Gastrointestinal tract|intestines]]. In this study, a recombinant strain of ''L. lactis'' containing [[complementary DNA]] (cDNA) for the human [[Interleukin 10|interleukin-10]] (IL-10) [[gene]] was used to treat CD with IL-10, an anti-inflammatory [[cytokine]].<ref name=":1" /><ref name=":2" /> Patients consumed capsules containing the microbe to populate the intestines and received therapeutic doses of IL-10 directly from the recombinant bacteria.<ref name=":2" /> As this route of administration is experimental, it is currently not available as a standard treatment option.

In a 2013 [[Animal testing|animal study]] with ''B. ovatus'' as the vehicle for microbial drug delivery, researcher Zaed Hamady suggested that recombinant strains of ''B. ovatus'' containing [[Transforming growth factor beta|transforming growth factor-beta]] (TGF-β) and [[keratinocyte growth factor]]-2 (KGF-2) are ready for clinical trials.<ref name=":0" />

== Mechanism of drug administration ==

=== ''L. lactis'' mechanism ===
The ''L. lactis'' mechanism of microbial drug delivery described in the 2006 study of Braat ''et al.'' uses a form of recombinant ''L. lactis'' (LL-Thy12) which has replaced the gene, Thy12, with the gene for human IL-10. Removal of Thy12, which encodes for the production of [[thymidine]], causes ''L. lactis'' to become dependent on dietary thymidine to maintain live colonies in the gut.<ref name=":1" /><ref name=":2" /> The addition of the IL-10 gene allows for the production of human IL-10 to decreases gut inflammation.<ref name=":2" /> [[Secretion]] of IL-10 from ''L. lactis'' in the gut is considered to be a topical administration of the drug to the epithelium, permitting healing in local tissues damaged by inflammation.<ref name=":1" /><ref name=":2" /> The administration of IL-10 topically avoids [[systemic effect]]s, such as [[immunosuppression]] in non-target tissues.<ref name=":1" /> When using LL-Thy12, IL-10 secretion is dependent on the quantity of live LL-Thy12 in the GI tract. As the presence of dietary thymidine increases the quantity of LL-Thy12, the drug production increases proportionately. Reductions in dietary thymidine kill LL-Thy12, decreasing the production of IL-10.<ref name=":1" /><ref name=":2" /> There is a delay of approximately 72-hours between a change in thymidine dosage and the production of IL-10.<ref name=":0" /> Due to LL-Thy12’s dependence on thymidine, they will die upon exiting the body through [[defecation]].<ref name=":2" />

=== ''B. ovatus'' mechanism ===
''B. ovatus'' has been used in animal studies as a mode of microbial drug delivery due to its [[xylanase]] [[operon]].<ref name=":0" /> Operons exist in bacteria to control [[gene expression]] and are composed of a DNA sequence containing an [[Operator (biology)|operator]] followed by the genes of interest. The operator in the xylanase operon prevents [[Transcription (genetics)|transcription]] of genes when bound to a [[Repressor|repressor protein]]. The ''B. ovatus'' xylanase operon only functions in the presence of the starch, [[xylan]], which removes the repressor and enables production of whichever proteins correlate with the genes located after the operator.<ref name=":0" /> For microbial drug delivery, the genes after the operator include those inserted as part of the genetic modification.  Xylan is non-[[Digestion|digestible]] to human [[gastric acid]] or [[digestive enzyme]]s, so a predictable quantity of dietary xylan will reach the recombinant ''B. ovatus'' in the gut, hypothetically allowing for a precise quantity of drug to be produced by the recombinant ''B. ovatus''.<ref name=":0" /> In [[Mouse|mice]], recombinant ''B. ovatus'' strains containing genes for [[growth factor]]s TGF-β and KGF-2 within the xylanase operon have successfully treated [[ulcerative colitis]] (UC).<ref name=":0" /> The secreted drugs from ''B. ovatus'' are applied topically to the epithelial lining, affecting local tissues rather than acting systemically. Systemic administration of these growth factors could otherwise cause [[Neoplasm|tumors]] and increased [[vascularization]] of tissues.<ref name=":0" /> When administered microbially, TGF-β and KGF-2 facilitate tissue repair only in the colon where they are released.<ref name=":0" />

== Safety of microbial drug delivery ==
Safety is a major factor in the efficacy of microbial drug delivery. Depending on the type of drug being administered, a certain level of control is required for effective and safe treatment of colonic diseases.<ref name=":0" /> The ''L. lactis'' system has a 72-hour delay between ingesting thymidine and activating IL-10 production, while the ''B. ovatus'' system allows the drug to be produced once xylan reaches the bacteria.<ref name=":0" /> Regarding IL-10 secretions in ''L. lactis'', the delay is acceptable for treatment of IBD,<ref name=":0" /><ref name=":1" /><ref name=":2" /> however any drug that requires a precise dosage and timing may necessitate ''B. ovatus'' for controlling drug output.<ref name=":0" />

The safety of microbial drug delivery is tied to the microbes’ commensal capability and instance of [[pathogenesis]]. A highly pathogenic microbe would not be suitable for medical treatment due to an inherent [[infection]] risk. ''L. lactis'' is considered by the [[Food and Drug Administration]] (FDA) to be [[generally recognized as safe]] (GRAS),<ref>{{Cite journal|last1=Wessels|first1=Stephen|last2=Axelsson|first2=Lars|last3=Bech Hansen|first3=Egon|last4=De Vuyst|first4=Luc|last5=Laulund|first5=Svend|last6=Lähteenmäki|first6=Liisa|last7=Lindgren|first7=Sven|last8=Mollet|first8=Beat|last9=Salminen|first9=Seppo|date=2004-10-01|title=The lactic acid bacteria, the food chain, and their regulation|journal=Trends in Food Science & Technology|volume=15|issue=10|pages=498–505|doi=10.1016/j.tifs.2004.03.003}}</ref> as it is commonly found in widely consumed [[dairy]] products, suggesting its safety in medical treatment.<ref name=":1" /><ref name=":2" /> ''B. ovatus'' is naturally found in 10% of healthy human [[Large intestine|colons]],<ref name=":3">{{Cite journal|last=Wexler|first=Hannah M.|date=2007-10-01|title=Bacteroides: the Good, the Bad, and the Nitty-Gritty|journal=Clinical Microbiology Reviews|language=en|volume=20|issue=4|pages=593–621|doi=10.1128/CMR.00008-07|issn=0893-8512|pmc=2176045|pmid=17934076}}</ref> demonstrating safety in its compatibility with the human gut microbiota;<ref name=":0" /> however, ''[[Bacteroides]]'' species are known in some cases to cause infections, typically resulting from [[Gastrointestinal surgery|surgery in the GI tract]].<ref name=":3" />

Concerns regarding the containment of recombinant microbes in the gut have been addressed through safety mechanisms in both ''L. lactis'' and ''B. ovatus''.<ref name=":0" /><ref name=":1" /><ref name=":2" /> Containment refers to the inability of microbes to colonize the external environment, where they may have unknown consequences. LL-Thy12 will die upon removal from the body, as they depend on dietary thymidine for survival.<ref name=":1" /><ref name=":2" /> ''B. ovatus'' is naturally an [[obligate anaerobe]], so any recombinant strain is expected to die in the presence of oxygen once removed from the body.<ref name=":0" /><ref name=":3" />

== See also ==
* [[Gut flora]]
* [[Oral administration]]
* [[Mucous membrane]]
* [[Absorption (pharmacokinetics)]]
* [[List of human flora]]
* [[List of microorganisms used in food and beverage preparation]]

== References ==
{{Reflist}}

[[Category:Drug delivery devices]]