The Gut Microbiota
The human gut microbiota (hGM), also known as the “forgotten organ” is
a highly diverse composition of microbial agents that increase in
density and diversity from proximal to the distal
gut1,18,19. The GI tract is colonized by trillions of
bacteria, with more than 1000 different bacterial
species20. These commensal bacteria play a crucial
role in maintaining the homeostatic environment in the
gut21.
Newborns have a functionally and structurally immature GI
system22. During birth, the GI tract is inoculated
with microorganisms, and the mode of delivery affects the microbial
composition23-25. The gut microbiota takes its
rudimentary shape during the first year of life and begins to resemble
that of an adult by age one26. The mature, healthy gut
microbiota is primarily composed of phyla such as Bacteroidetes,
Firmicutes, Acinetobacteres, Proteobacteria, and Actinobacteria;
Bacteroidetes and Firmicutes being the most dominant
phyla27-29. These symbiotic bacteria have various
roles in metabolism, such as producing essential vitamins, helping
digest the polysaccharides that are otherwise indigestible, maintaining
tissue homeostasis, and protecting the host against opportunistic
pathogens30,31. The effects of microbiota greatly
depend on its composition which varies due to factors such as age, diet,
and antibiotic usage32-37.
Dysbiosis is associated with diseases, such as IBDs, CRCs, and metabolic
syndrome, and is a main causative factor in the course of these
diseases38-40. The microbiota’s composition also
changes with the host’s physiological state. For example, obese
individuals harbor less diverse microbiota compared to lean
individuals41,42. Improved overall hygiene due to
urbanization may lead to a decrease in the diversity of bacterial genera
in the gut, especially Bacteroides, Prevotella, and Lactobacilli, as
reviewed by Fan and Pedersen1. This decreased
bacterial diversity and bacterial gene complexity can be linked to
insulin resistance, inflammation, and eventually
dyslipidemia40. Antibiotics, while essential in
medical practice, can cause GI side-effects, such as hypersensitivity
and antibiotic-associated diarrhea43. According to a
study, a short course of broad-spectrum antibiotic treatment can lead to
dysbiosis and a decrease in some commensal bacteria in
adults44.
Patients with IBDs, such as Crohn’s disease, ulcerative colitis (UC),
and indeterminate colitis, typically have low microbial diversity in
their gut microbiota (Table 1)45. Irritable bowel
syndrome (IBS), Clostridium difficile (C.
difficile )-associated colitis, and acute diarrhea are also associated
with an alteration in fecal microbiota
composition46-48. Dysbiosis is a well-established
phenomenon in CRCs, the second leading cause of cancer-related deaths in
the U.S., as demonstrated by large-scale human
studies49,50. Increased numbers of resident bacteria
such as Bacteroides fragilis (B. fragilis ),Escherichia coli (E. coli ), and Streptococcus
gallolyticus (S. gallolyticus ) were observed in CRC
patients39,51-53. In addition, specific pathogenic
bacterial populations are found to be enriched in CRC patients, most
notably Fusobacterium nucleatum (F. nucleatum ),Solobacterium moorei (S. moorei ), Peptostreptococcus
anaerobius (P. anaerobius ), and Parvimonas micra(P. micra ) (Table 1)39. Interestingly,
dysbiosis is present even in patients with colorectal adenomas ,
resulting in increased numbers of pathogens like F. nucleatum andS. moorei 54.
The epithelial and the immune cells of the GI tract act as a physical
barrier between the host and microbes and mediate mucosal immune
responses to regulate its microbiota55. The immune
responses include mucus composition, IgA, and antimicrobial secretion
such as RegIIIγ (an antibacterial lectin produced by enterocytes and
Paneth cells) and defensins56-60. Another mechanism of
bacterial selection in the gut is positive growth selection, whereby the
beneficial species outgrow their less beneficial
counterparts61. This positive growth can be achieved
by bacteria feeding on molecules from the host epithelia, such as fucose
and bacteria attaching to the gut epithelia (Fig.
1G)62,63.