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Page 2 of 18 Fabbrini et al. Microbiome Res Rep 2023;2:25 https://dx.doi.org/10.20517/mrr.2023.25

NETWORK ANALYSIS
Immediately after the discovery of the microscopic world, it became clear that our world is dominated by,
and extremely dependent on, a variety of complex microbial communities (or microbiomes, including
bacteria, archaea, fungi, viruses, and protists). These communities play critical roles in several functions
within different ecosystems (e.g., nitrogen and carbon cycling), but are also extremely important in the
[1-3]
development and health maintenance of their associated hosts (e.g., plants and animal species) . Indeed,
these communities are not simply established by independent individuals, but all actors are strictly
interconnected with each other and with the host so that they can communicate, cross-feed, recombine and
coevolve . For example, during the last decades, it has been seen that the human body serves as a host for
[4]
several microbiomes, which also interact with human cells, among others playing a key role in the
development of homeostasis and immune tolerance that are pivotal factors for health . Referring to the
[5,6]
human gut microbiota, thanks to numerous international projects such as the Human Microbiome Project,
the American gut project, and MetaHIT, it has been widely recognized that it plays a critical role in human
[7,8]
health and disease . Indeed, an imbalance in the gut microbiota composition, generally referred to as
dysbiosis, has been associated with a wide range of non-communicable diseases, for example, obesity [9,10] ,
diabetes , inflammatory bowel disease [12,13] , and colorectal cancer . More recently, other world programs,
[11]
[14]
such as the Earth Microbiome Project, have extended the concept of human health to the entire planet, with
a unified approach to optimizing the health of people, animals and the environment . In the current
[15]
context of global change linked to biodiversity loss, the goal of such initiatives is to characterize and map the
planet microbiomes. This can help to understand their role, interactions, and importance in global change-
[16]
related processes, not only for animal species but also for microorganisms .
However, even though it is now clear that microbiomes play a central role in life and global health, we are
just beginning to explore the variety of microbial communities and understand how these microbes interact
with each other and with their hosts and environments . Thanks to the advent of Next-Generation
[4]
Sequencing (NGS) techniques, it has been possible to understand the high complexity of microbial
communities and their layout associated with different conditions or pathologies. NGS techniques are
extremely powerful for characterizing microbial communities through the sequencing of specific
taxonomical molecular targets, such as the 16S rRNA gene for bacteria and the internal transcribed spacer
of rRNA for fungi and specific bacterial species such as those belonging to Bifidobacterium or
Lactobacillu [17,18] , or shotgun metagenomics for the evaluation of the composition and function of the whole
community, including viruses. However, microbiome studies often encounter challenges related to isolation
and sequencing biases. These issues can arise due to variations in sample collection, DNA extraction
methods, amplification techniques, and sequencing platforms. It is critical to gain accurate insights from
microbiome data. This requires rigorous quality control measures, normalization techniques, and the use of
computational tools to correct for biases such as sequencing errors and taxonomic assignments.

Understanding the composition and functional potential of the microbiota and exploring the possible
pairwise associations between a single taxon and a specific variable, condition or disease is just the surface
of a deeper knowledge of how the structure and dynamics of a complex microbial community could shape
human and planetary health [16,19] . Indeed, the intricate interplays that take place among microbial taxa and
between them and their host emphasize the significance of the overall functions of the microbial
community, often outweighing the importance of any function related to single taxa [20,21] . For this reason, a
comprehensive understanding of the microbial community interactomes could enable researchers to better
understand how microorganisms interact with each other and with a host, and how they are shaped by
external perturbations . Such understanding could lead to the design of novel and precise strategies in the
[19]
clinical, agricultural, and bioremediation fields, just to mention a few, and, more widely, in the current