Title

Combining Large-scale Electronic Health Records with Longitudinal Microbiome Profiles in Size-limited Cohorts To Reduce Future-risk of Respiratory Dysbiosis via Operationalizing the Gut-lung Axis

Research Problem

Gut microbiota has been liked to respiratory diseases. Particularly changes in microbiota in early life has been linked to long term respiratory issues.

Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections~\cite{Schuijt575}. It has been shown in animal models that gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls~\cite{Schuijt575}.

Studies have investigated the riole of intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut–lung axis in bacterial infections.

The gastrointestinal tract (GIT) and respiratory tract, although separate organs, are part of a shared mucosal immune system termed the gut–lung axis.

The microbiota of the GIT and the respiratory tract are involved in the gut–lung axis, influencing immune responses both locally and at distant sites.

Current research has identified specific bacterial taxa, their components and metabolites that can influence host immunity.

Expansion of the gut microbiota begins immediately after birth and is heavily influenced by environmental factors, with species in the phylum Actinobacteria often dominating during infancy123,124. In this early period of life, changes in the microbiota may be linked to the development of chronic lung disorders in later life~\cite{budden2017emerging}.

\cite{dang2019microbes}

The microbiota plays an essential role in the education, development, and function of the immune system, both locally and systemically. Emerging experimental and epidemiological evidence highlights a crucial cross-talk between the intestinal microbiota and the lungs, termed the ‘gut–lung axis’. {\color{Red1} Changes in the constituents of the gut microbiome, through either diet, disease or medical interventions (such as antibiotics) is linked with altered immune responses and homeostasis in the airways. The importance of the gut–lung axis has become more evident following the identification of several gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), as key mediators for setting the tone of the immune system.}

This gut dysbiosis in humans has been linked to inflammatory conditions in the gastrointestinal tract itself, but also in the airways, such as in asthma and chronic obstructive pulmonary disease (COPD).8,9} Of note, human epidemiological studies indicate microbial dysbiosis can have long-term consequences, which is supported by data from mouse models, where mice have an increased predisposition to allergic inflammation following early life antibiotic usage.10,11,12,13,14 Accumulating evidence has highlighted the influence of the gut microbiota on lung immunity, referred to as the gut–lung axis, though the underlying pathways and mechanisms are still areas of intensive research.15 Metabolic by-products derived from bacterial fermentation of dietary fibers have been reported as key local and systemic signaling molecules in sustaining immune and tissue homeostasis.16 The impact of various diets on lung health and disease has recently been reviewed.17

Exact mechanism which operationalizes this gut-lung axis is unknown

Microbiota may be modifiable by diet and other environmental factors, and is mesiurable with relative ease

We aim to investigathe and identify patterns of mirobiota perturbations that modulate risk of future repisratory illnesses such as asthma and peumococcal infections

Challenges

the cohorts for which microbiome data is available is limited in size. Teh amount of data required to properly probe the underlying factors is too large. The patterns are subtle, so statsuitically signaificat patterns would reqyure hude data sets. This project aims to solve thsi issue by leveraging underutilized diagnostic dimensions and sophisticated pattern recognition algorithms.

Clinical Problem

Asthma and pneumomococcal pnenomnia in infants and toddlers, risk mitigation via microbiome pattern analysis, and clinical validation.