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.