Gnotobiotic
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Gnotobiosis (from
Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...
roots ''gnostos'' "known" and ''bios'' "life") refers to an engineered state of an
organism An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...
in which all forms of life (i.e.,
microorganisms A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...
) in or on it, including its
microbiota Microbiota are the range of microorganisms that may be commensal, mutualistic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found ...
, have been identified. The term gnotobiotic organism, or gnotobiote, can refer to a
model organism A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mo ...
that is colonized with a specific community of known microorganisms (isobiotic or defined flora animal) or that contains no microorganisms ( germ-free) often for
experimental An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs whe ...
purposes. The study of gnotobiosis and the generation of various types of gnotobiotic model organisms as tools for studying interactions between
host A host is a person responsible for guests at an event or for providing hospitality during it. Host may also refer to: Places * Host, Pennsylvania, a village in Berks County * Host Island, in the Wilhelm Archipelago, Antarctica People * ...
organisms and microorganisms is referred to as gnotobiology.


History

The concept and field of gnotobiology was born of a debate between
Louis Pasteur Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist, pharmacist, and microbiologist renowned for his discoveries of the principles of vaccination, Fermentation, microbial fermentation, and pasteurization, the la ...
and Marceli Nencki in the late 19th century, in which Pasteur argued that animal life needed bacteria to succeed while Nencki argued that animals would be healthier without bacteria, but it wasn't until 1960 that the Association for Gnotobiotics was formed. Early attempts in gnotobiology were limited by inadequate equipment and nutritional knowledge, however, advancements in nutritional sciences, animal
anatomy Anatomy () is the branch of morphology concerned with the study of the internal structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old scien ...
and
physiology Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...
, and
immunology Immunology is a branch of biology and medicine that covers the study of Immune system, immune systems in all Organism, organisms. Immunology charts, measures, and contextualizes the Physiology, physiological functioning of the immune system in ...
have allowed for the improvement of gnotobiotic technologies.


Methods

Guinea pigs were the first germ-free animal model described in 1896 by George Nuttall and Hans Thierfelder, establishing techniques still used today in gnotobiology. Early methods for maintaining
sterile Sterile or sterility may refer to: *Asepsis, a state of being free from biological contaminants * Sterile (archaeology), a sediment deposit which contains no evidence of human activity *Sterilization (microbiology), any process that eliminates or ...
environments involved sterile glass jars and gloveboxes, which developed into a conversation surrounding uniformity of the methods in the field at the 1939 symposium on Micrurgical and Germ-free Methods at the University of Notre Dame. Many early (1930-1950s) accomplishments in gnotobiology came from Notre Dame University, The
University of Lund Lund University () is a public research university in Sweden and one of Northern Europe's oldest universities. The university is located in the city of Lund in the Swedish province of Scania. The university was officially founded in 1666 on the ...
, and
Nagoya University , abbreviated to or NU, is a Japanese national research university located in Chikusa-ku, Nagoya. It was established in 1939 as the last of the nine Imperial Universities in the then Empire of Japan, and is now a Designated National Universit ...
. The Laboratories of Bacteriology at the
University of Notre Dame The University of Notre Dame du Lac (known simply as Notre Dame; ; ND) is a Private university, private Catholic research university in Notre Dame, Indiana, United States. Founded in 1842 by members of the Congregation of Holy Cross, a Cathol ...
(known as LOBUND) was founded by John J. Cavanaugh and is cited for making some of the most notable achievements in the field of gnotobiotic research. Under the direction of James A. Reyniers, early work at LOBUND focused on obtaining gnotobiotes by sterilizing animals and maintaining the animals using high-pressure steam sterilized steel isolators; however, later work at the institute shifted the focus of the field towards establishing
colonies A colony is a territory subject to a form of foreign rule, which rules the territory and its indigenous peoples separated from the foreign rulers, the colonizer, and their '' metropole'' (or "mother country"). This separated rule was often or ...
of animals born germ-free. The first germ-free rat colony was generated and maintained using a steam sterilized isolator in 1946 by Swedish scientist Bengt Gustafsson. Flexible film isolators using
peracetic acid Peracetic acid (also known as peroxyacetic acid, or Percidine) is an organic compound with the formula CH3CO3H. This peroxy acid is a colorless liquid with a characteristic acrid odor reminiscent of acetic acid. It can be highly corrosive. Perac ...
vapor for sterilization began being developed in the 1950s. Refined sterilization techniques and manufacturing changes from LOBUND significantly reduced the size and cost of isolators, making gnotobiotic research more universally accessible. After numerous advances in gnotobiotic research and technologies, the main challenges facing gnotobiotic research today are cost, space, efficiency, and operational procedure requirements. In 2015, the costs of maintaining gnotobiotic mice cages was greater than 4 times the cost of maintaining those of non-gnotobiotic mice, creating a challenge for establishing and maintaining facilities using typical funding sources, such as federal grants from institutions like the NIH.


Applications

The early focus of the field of gnotobiology was on proving that an organism could live in the absence of microorganisms, which ultimately resulted in the development of gnotobiotic organisms as a tool for research. Between the 1950s and 1970s, germ-free models were used to study the effects of the absence of bacteria on host organism metabolism and physiology, which later evolved into intentionally infecting germ-free organisms with specific microorganisms to investigate their functions and other questions relating to the
biomedical Biomedicine (also referred to as Western medicine, mainstream medicine or conventional medicine)
field. In the early 1970s, gnotobiotes were used to study the role of microorganisms in host nutrition acquisition and immune response; however, this was limited because animals reared in a gnotobiotic colony often have poorly developed immune systems, lower
cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: tha ...
, and thin intestinal walls, which make them highly susceptible to infectious pathogens. After the early 1970s, gnotobiotic research decreased until the mid-1980s. Within the 21st century, gnotobiotic model systems have become an important tool for investigating interactions between host organisms and their
commensal Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit f ...
microbiota, as they allow for researchers to investigate specific microbes in a highly controlled host system. Historically, mouse models have been used to investigate the impacts of the microbiota composition (which microorganisms are present) on host
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
,
nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
, metabolism, and physiology; however, an increasing interest in this field has led to the incorporation of other model organisms to address a larger variety of questions relating to these topics.


Animals

A gnotobiotic animal (gnotobiote) is an animal in which all microorganisms interacting with it are known and controlled. Gnotobiotic animals are typically born under aseptic conditions, which may include removal from the mother by
Caesarean section Caesarean section, also known as C-section, cesarean, or caesarean delivery, is the Surgery, surgical procedure by which one or more babies are Childbirth, delivered through an incision in the mother's abdomen. It is often performed because va ...
followed by immediate transfer of the newborn to an isolator where all incoming air, food and water is sterilized. Gnotobiotes are usually raised in a sterile laboratory environment, and are only intentionally exposed to microorganisms of interest to researchers.
Mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
and
rats Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' (pack rats), '' Bandicota'' (bandicoot ...
are common gnotobiotic animals used in research, but other examples of important gnotobiotes include ''Caenorhabditis elegans'' (''C. elegans''), ''Drosophila melanogaster'' (''D. melanogaster''),
zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
, and piglets. Gnotobiotes are used as a controlled environment in which to study host anatomy and physiology, the specific
symbiotic Symbiosis (Ancient Greek : living with, companionship < : together; and ''bíōsis'': living) is any type of a close and long-term biolo ...
interactions between a host and specific microorganisms, and the impacts of chemicals on the host and its microbiota.


Mammals

Rodents Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are n ...
(primarily mice and rats) are the most common
mammalian A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
model systems used for studying gnotobiosis and are widely used to study human health relating to the gut and interactions between microorganisms and their host; however, recently there has been a rise in using gnotobiotic mice to study interactions between different microorganisms (microbe-microbe interactions) in the gut. Humanized gnotobiotic mice, or gnotobiotic mice introduced to human intestinal microorganisms by
fecal microbiota transplant Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for Clostridioides diffic ...
with human feces, are used in the context of studying
gut microbiota Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the g ...
and their relationship with host
cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
, immune system, and nutrition. Some advantages of gnotobiotic mice and rat systems include the uniformity of the organism, historical prevalence, and established system-specific methods, as well as the ability to obtain reliable gnotobiotic mice and rats commercially.


Fish

Gnotobiotic
fish A fish (: fish or fishes) is an aquatic animal, aquatic, Anamniotes, anamniotic, gill-bearing vertebrate animal with swimming fish fin, fins and craniate, a hard skull, but lacking limb (anatomy), limbs with digit (anatomy), digits. Fish can ...
have been used as a model organism for human health; however, an increased interest in
aquaculture Aquaculture (less commonly spelled aquiculture), also known as aquafarming, is the controlled cultivation ("farming") of aquatic organisms such as fish, crustaceans, mollusks, algae and other organisms of value such as aquatic plants (e.g. Nelu ...
for sustainable food production has led to increasing prevalence of gnotobiotic studies focused on maximizing production and maintaining healthy captive populations. The majority of research is still only conducted on a few species of fish, such as the zebra fish. Some of the advantages of gnotobiotic fish systems include high numbers of offspring per reproduction event coupled with fast generation times and eggs that can be sanitized.


Plants

Gnotobiotic plants are plants that are either grown without microorganisms present (aseptic, axenic, or sterile) or grown in the presence of one (monoxenic) or more than one (polyxenic) known microorganism. To obtain gnotobiotic plants, researchers sterilize seeds using chemical agents (e.g.,
ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
,
sodium hypochlorite Sodium hypochlorite is an alkaline inorganic chemical compound with the formula (also written as NaClO). It is commonly known in a dilute aqueous solution as bleach or chlorine bleach. It is the sodium salt of hypochlorous acid, consisting of ...
(bleach),
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
) on the surface of the seed. A wide variety of plants have been used to generate gnotobiotic systems such as ''
Arabidopsis thaliana ''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small plant from the mustard family (Brassicaceae), native to Eurasia and Africa. Commonly found along the shoulders of roads and in disturbed land, it is generally ...
'',
peanuts ''Peanuts'' (briefly subtitled ''featuring Good ol' Charlie Brown'') is a print syndication, syndicated daily strip, daily and Sunday strip, Sunday American comic strip written and illustrated by Charles M. Schulz. The strip's original run ext ...
,
oats The oat (''Avena sativa''), sometimes called the common oat, is a species of cereal grain grown for its seed, which is known by the same name (usually in the plural). Oats appear to have been domesticated as a secondary crop, as their seed ...
,
corn Maize (; ''Zea mays''), also known as corn in North American English, is a tall stout Poaceae, grass that produces cereal grain. It was domesticated by indigenous peoples of Mexico, indigenous peoples in southern Mexico about 9,000 years ago ...
, and many others. Similar to animals, gnotobiotic plant systems have been used to study integral components of host physiology (e.g.,
nitrogen fixation Nitrogen fixation is a chemical process by which molecular dinitrogen () is converted into ammonia (). It occurs both biologically and abiological nitrogen fixation, abiologically in chemical industry, chemical industries. Biological nitrogen ...
), as well as pathogenic and symbiotic interactions between plants and microorganisms.


See also

*
Specific-pathogen-free Specific-pathogen-free (SPF) is a term used for laboratory animals that are guaranteed free of particular pathogens. Use of SPF animals ensures that specified diseases do not interfere with an experiment. For example, absence of respiratory path ...
(SPF) * Axenic culture


References

{{Reflist Ecology terminology Model organisms