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.