Study of eu- and dysbiosis in the intestinal microbiome of very preterm infants in the PRIMAL study cohort
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Abstract
Dysbiosis, generally defined as a reduction of diversity and beneficial bacteria and a bloom of
pathobionts in a given microbiome, has been proposed as a concept to explain why changes
in the (gut) microbiome composition can lead to negative health outcomes, especially in the
vulnerable population of preterm infants. This microbiome state is in contrast to an implicit state
of balanced eubiosis.
The main aims of this thesis were to analyze and comprehensively describe the gut microbiome
composition of preterm neonates and mothers enrolled in the PRIMAL study cohort and to
evaluate the overall utility of the dysbiosis concept in the context of the preterm infant gut
microbiome and the use of probiotics.
For 1353 infant fecal samples comprised of three visits (day 0, day 28 and day 365 of life)
and 290 associated mother samples, taxonomic profiles were compiled through 16S rRNA gene
sequencing to establish a baseline characterization of their microbiome composition. Right after
birth, infant gut microbiomes were dominated by the genera Staphylococcus and Bifidobacterium.
During the further development over the course of the first month of life, Bifidobacterium gained
dominance in the microbiomes. Bifidobacterium remained the most abundant genus after one
year of life during which the infant microbiome slowly matured to more closely resemble the
adult mother microbiome which was primarily dominated by the genera Bacterioides, Blautia and
Faecalibacterium.
To evaluate the usefulness and validity of the dysbiosis concept, results from conventional, culture
based microbiological analyses and next-generation sequencing were compared with a focus
on taxonomic classifications and antibiotic resistance capacity. Further, possible interactions in
the microbiomes from the PRIMAL study cohort were analyzed through co-occurrence network
analyses and the PRIMAL microbiomes were set into the context of publicly available preterm and
full term reference microbiome datasets. Conceptual challenges with the generic term dysbiosis
were resolved by proposing that dysbiosis should be used as a description of a dysfunctional
state with defined genetic deficits within the microbiome. A distinction can be made between
dysbiosis as an umbrella term for a general deviation from the genetic capabilities of a normal
reference microbiome on the one hand and a two-part actionable concept on the other hand that
can drive hypothesis driven research. This two-part concept differentiates between a short-term
(acute) dysbiosis characterized by the presence of a concrete pathogen and a long-term (chronic)
dysbiosis characterized by complex microecological interactions with the host that cause chronic
diseases. Overall, this study demonstrates the complexity within the human gut microbiome even
at the earliest stages of life and stresses the importance of a deep mechanistic understanding of
host-microbe interactions to develop rationally designed therapeutic interventions.