Table 1.

Germ-free animal model studies

Observations in Germ-Free AnimalsPossible MechanismPotential Implications for Science/MedicineArising Research Questions
Increased longevityNDThe use of pre/pro/synbiotics in geriatric populationsIs the increased longevity due to less inflammation-mediated damage in germ-free animals?
Extension of end points in basic geriatric researchIs the increased longevity due to absence of detrimental metabolites produced by the normal gut microbiota?
Increased radioresistanceNDFurther defining the pathophysiological mechanisms underlying radiation-induced tissue damageWhat is the contribution of microbial metabolites to radiation-induced tissue damage?
Improvements to tissue damage in radiotherapyWhat is the contribution of microbiota-stimulated intestinal epithelial renewal to radiation-induced tissue damage?
Increased adipose deposits in geriatric animalsNDFurther defining the role of microbiota in obesityDoes microbial-host signaling promote generation of adipose deposits?
Can pre/pro/synbiotics be used therapeutically in metabolic syndrome and insulin resistance?
Decreased intestinal surface areaReduced villous thicknessFurther defining the mechanisms of nutrient absorptionWhich microbial metabolites are involved in promoting anatomical maturation of the GI tract? What is the time frame of their activity?
Reduced crypt cell productionStudies of signaling in postnatal anatomical developmentCan pre/pro/synbiotics be used therapeutically in GI mucosa atrophy?
Reduced villous capillary network
Impaired bile acids and cholesterol metabolismLargely NDPotential for pro-/pre-/synbiotic therapeutic or prophylactic interventions in atherosclerotic disease and hypercholesterolemiaWhich bacterial species/products are involved in maintenance of bile acid metabolism?
Impaired cholesterol metabolism likely secondary to impaired bile acids metabolismWhich signaling pathways are targeted?
Impaired local and systemic lymphoid organ structureNDEnhanced understanding of prenatal lymphoid organogenesisWhat are the relative contributions of different bacterial species/products to lymphoid organogenesis?
Studies of signaling in postnatal lymphoid developmentDoes local and systemic lymphoid organ maturation happen simultaneously or sequentially?
Reduced levels of secretory immunoglobulinsMechanisms per se NDEnhanced understanding of signaling involved in isotype switchingWhich component(s) of segmented filamentous bacteria is involved in IgA induction?
Segmented filamentous bacteria stimulate IgA productionPotential improvements to vaccine responses
Impaired generation of oral toleranceReduced number of CD25+CD4+ Treg cellsEnhanced understanding of food allergy and toleranceWhich bacterial species/products induce CD25+CD4+ Treg cell expansion?
Reduced production of TGF-β by CD25+CD4+ Treg cellsPotential improvements to vaccine responsesCan CD25+CD4+ Treg cell expansion and activity be induced independently of each other?
Decreased cardiac outputNDPotential implications for treatment of disorders resulting in decreased cardiac output (e.g., dilated cardiomyopathies)Is decreased cardiac output due to a reduced stroke volume, reduced heart rate, or a combination of both factors?
Enhanced understanding of cardiac physiologyIs the abnormality largely anatomical or physiological? Is it reversible?
Is the presence of live bacteria/microbial components or the presence of microbial metabolites required to normalize cardiac output?
Hypotonic and hyporesponsive mesenteric vasculatureExact mechanisms NDPotential implications for treatment of hypertensionIs the abnormal lumen-to-wall ratio of germ-free arterioles the “default” state that can be corrected by conventionalization, or does it develop over time in the face of abnormal physiology of germ-free animals?
Proposed mechanisms:Enhanced understanding of determinants of vasculature developmentWould modifications in microbiota numbers/composition skew the host towards hypo- or hypertonic responses?
1) greater lumen:wall ratio of mesenteric arterioles
2) accumulation of compounds that antagonize vasoactive substances in the cecum
Exaggerated stress response of HPA axisPossible pathways:Uncovering the etiology of gastrointestinal disorders with a neurogenic component (e.g., irritable bowel syndrome)Which microbial species/products are involved in the brain-gut axis signaling?
Microbe-mediated release of cytokines (e.g., IL-1) that stimulate secretory activity of HPA axisFurther defining the mechanisms of neural developmentWhich neural pathways are affected, both centrally and peripherally?
Decreased sensitivity to inflammatory painSCFAs mediated release of 5-HT from enterochromaffin cells that stimulates 5-HT3 receptors on vagal afferent fibersPotential therapeutic implications for the treatment of neurogenic disordersWhat is the relative contribution of the brain-to-gut versus gut-to-brain signaling in the development of associated gastrointestinal and neuropsychiatric disorders?
Direct production of neuroactive substances by the microbiota
Increased production of IL-10
Reduced bioactivity of inflammatory mediators
  • HPA, hypothalamic-pituitary-adrenal; TGF, transforming growth factor; 5-HT, 5-hydroxytryptamine; IL, interleukin; ND, not defined.