A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Neonatal sepsis remains a global burden. A preclinical model to screen effective prophylactic or therapeutic interventions is needed. Neonatal mouse ...

Probiotic Studies in Neonatal Mice Using Gavage

Adult mouse models have been widely used to understand the mechanism behind disease progression in humans. The applicability of studies done in adult ...

University of British Columbia

Human existence can be viewed as an "." A healthy interaction of the human host with the microbes in and around us heavily relies on a well-functioning immune system. As development of both the microbiota and the host immune system undergo rapid changes in early life, it is not surprising that even minor alterations during this co-development can have profound consequences. Scrutiny of existing data regarding pre-, peri-, as well as early postnatal modulators of newborn microbiota indeed suggest strong associations with several immune-mediated diseases with onset far beyond the newborn period. We here summarize these data and extract overarching themes. This same effort in turn sets the stage to guide effective countermeasures, such as probiotic administration. The objective of our review is to highlight the interaction of host immune ontogeny with the developing microbiome in early life as a critical window of susceptibility for lifelong disease, as well as to identify the enormous potential to protect and promote lifelong health by specifically targeting this window of opportunity.

Early-Life Host-Microbiome Interphase: The Key Frontier for Immune Development.

The burden of newborn infectious disease has long been recognized as the highest across the entire human life span. The precise underlying cause is unfortunately still far from clear. A substantial body of data derived mostly from in vitro experimentation indicates "lower" host immune responses in early vs. adult life and is briefly summarized within this review. However, emerging data derived mostly from in vivo experimentation reveal that the newborn host also exhibits an exuberant immune and inflammatory response following infection when compared to the adult. In this context, it is important to emphasize that "infection" does not equate "infectious disease," as for many infections it is the host response to the infection that causes disease. This simple insight readily arranges existing evidence into cause-effect relationships that explain much of the increase in clinical suffering from infection in early life. We here briefly summarize the evidence in support of this paradigm and highlight the important implications it has for efforts to ameliorate the suffering and dying from infection in early life.

Newborn susceptibility to infection vs. disease depends on complex in vivo interactions of host and pathogen.

Newborns suffer high rates of mortality due to infectious disease-this has been generally regarded to be the result of an "immature" immune system with a diminished disease-fighting capacity. However, the immaturity dogma fails to explain (i) greater pro-inflammatory responses than adults  and (ii) the ability of neonates to survive a significantly higher blood pathogen burden than of adults. To reconcile the apparent contradiction of clinical susceptibility to disease and the host immune response findings when contrasting newborn to adult, it will be essential to capture the entirety of available host-defense strategies at the newborn's disposal. Adults focus heavily on the disease resistance approach: pathogen reduction and elimination. Newborn hyperactive innate immunity, sensitivity to immunopathology, and the energetic requirements of growth and development (immune and energy costs), however, preclude them from having an adult-like resistance response. Instead, newborns also may avail themselves of disease tolerance (minimizing immunopathology without reducing pathogen load), as a disease tolerance approach provides a counterbalance to the dangers of a heightened innate immunity and has lower-associated immune costs. Further, disease tolerance allows for the establishment of a commensal bacterial community without mounting an unnecessarily dangerous immune resistance response. Since disease tolerance has its own associated costs (immune suppression leading to unchecked pathogen proliferation), it is the maintenance of homeostasis between disease tolerance and disease resistance that is critical to safe and effective defense against infections in early life. This paradigm is consistent with nearly all of the existing evidence.

Rym Ben-Othman

Department of Pediatrics,
Division of Infectious Diseases,
Department of Pediatrics, Division of Infectious Diseases

University of British Columbia

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Probiotic Studies in Neonatal Mice Using Gavage

Rym Ben-Othman

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pediatrics,Division of Infectious Diseases,Department of Pediatrics, Division of Infectious Diseases

University of British Columbia

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Probiotic Studies in Neonatal Mice Using Gavage

Department of Pediatrics,
Division of Infectious Diseases,
Department of Pediatrics, Division of Infectious Diseases