Concluding Remarks and Future Directions
The human gut is vast and complex, posing a challenge in comprehending
the yet-to-be-discovered physiological processes that regulate
homeostasis. Ongoing research provides a glimpse into its intricacies.
As we continue to understand the hGM, it will lead to new investigation
into dysbiosis-associated diseases. Dysbiosis is often found in diseases
such as IBDs and CRCs. This raises the question: which comes first, the
disease or the dysbiosis? As a way to approach this question, stool
samples from patients with CRC were transferred to germ-free or
conventional mice, and colonic inflammation
occurred248. Since most diseases associated with
dysbiosis are inflammation-related, in addition to the already
established pathophysiologic mechanisms, infestation with pathogenic
bacteria (or dysbiosis) may also play an inducing role in diseases like
CRCs and IBDs. Various models have been proposed to understand the
relationship between dysbiosis and CRCs. The alpha-bug model is based on
the Enterotoxigenic B. fragilis inducing activation of signal
transducer and activator of transcription-3 (STAT-3), which causes
colitis through Th17 responses51,249. The inflammation
caused by this process is postulated to promote colorectal cancer. This
alpha-bug can displace commensal bacteria that protect against
cancer249. The driver-passenger model suggests that
the ”driver” bacteria initiate the formation of CRC through their
products causing epithelial cell damage. This damage allows other
commensal ”passenger” bacteria to breach the epithelia, further
deteriorating the disease prognosis250. Although not
fully elucidated, these two models may potentially be applicable to
IBDs, too.
Aberrant mucin O-glycosylation and overexpression of T, Tn, and STn
antigens are observed in both CRC and IBD tissues (Fig.
3B)152,251. Although we don’t fully understand the
mechanisms behind the glycosylation changes seen in ulcerative colitis
and CRCs, it’s clear that these changes are involved in the development
of both diseases. For instance, F. nucleatum can be recruited to
the tumor tissue through the expression of T antigen, via fatty-acid
binding protein 2252. Additionally, these
glycosylation changes may potentially explain why we observe specific
changes in bacterial taxa in both diseases (Table 1).
There has been a growing interest in modulating the composition of hGM
to prevent diseases like IBDs, as it plays an important role in
regulating immune responses in the gut directly or through diet-derived
metabolites253. Current approaches to modulate the gut
microbiota include diet modifications and over-the-counter
pre-/pro-/syn-/post-biotics, as well as oral and fecal microbiota
transplantations. Diet is a major factor regulating the gut microbiota
by either fiber or fat content222. The hGM is
negatively influenced by diets with high saturated or monosaturated fat
contents254. Conversely, a diet with a high
polyunsaturated fat content does not have a negative influence on the
hGM254. Faecalibacterium prausnitzii ,
Firmicutes with fiber degrading abilities, and fecal SCFA levels were
shown to increase in individuals on a Mediterranean diet (high-fiber,
low animal protein, low in glycemic index carbohydrates) compared to the
individuals on a Western diet222. Sialic acid
consumption through HMOs or meat-based foods is beneficial for the
growth of commensal bacteria that possess sialic acid
metabolism255. Because HMOs are rich in sialic acid,
necrotizing enterocolitis (NEC) was more frequently (6-10 times)
observed in formula-fed infants, compared to the breast-fed
infants256. Thus, supplementing the diet of
formula-fed infants with sialic acids may prevent NEC. Probiotics, such
as Lactobacillus species, can increase the MUC2 production and mucin
secretion, enhancing the pathogenic resistance of the
intestine257. SCFAs, such as sodium butyrate and
propionate, can be used in colitis patients since they enhance the
production of MUC2258. While prebiotics and probiotics
may boost immune responses, their effects are often transient and not
significant259,260. In addition to these
over-the-counter supplements, fecal microbiota transplantation (FMT) is
a medical procedure to re-establish the homeostatic environment in the
gut. There are two prominent FMT methods: heterologous and autologous.
While heterologous FMT is the transfer of fecal material from a healthy
donor to a recipient with the purpose of re-establishing or replacing
the recipient’s gut microbiota, autologous FMT is the transplantation of
an individual’s own fecal content prior to disease or
dysbiosis261,262. FMT is considered an effective
therapy option for recurrent C. difficile infections, but it is
yet to be an established treatment method for IBDs, such as Crohn’s
disease and ulcerative colitis since the data suggests that the success
of FMT in IBDs is still uncertain (clinical remission 24% to
50%)148,263-267. Recent studies have demonstrated
that FMT could be an important tool in the treatment regimen of CRC
patients after observing FMT improve refractory immune checkpoint
inhibitor-induced colitis39. Although both the donors
and the donated fecal content are tested for transmissible pathogens,
FMT still carries the risk of infectious agent transmission. FMT is an
emerging procedure and there is still more progress to be made in
eligible patient selection, donor selection, preventing unwanted
infections and allergic reactions, and administration
methods268,269. As a major step forward from using
FMT, the FDA recently approved rectally and orally administered
microbiota therapeutics that are consortia of defined bacteria for the
prevention of recurrent C. difficile infections.
To summarize, glycans play crucial roles in regulating immune cells,
maintaining mucus structure and integrity, and promoting symbiosis among
gut microbes. As a result, it is becoming increasingly apparent that we
must uncover the specific mechanisms by which glycans contribute to
regulatory processes. By doing so, we can develop effective treatments
that modify the gut glycome to promote homeostasis and prevent diseases
in the future.