Cross talk between the gut microbiome and host immune response in ulcerative colitis: nonpharmacological strategies to improve homeostasis

Abstract

Ulcerative colitis (UC) is a chronic disease that is characterized by diffuse inflammation of the colonic and rectal mucosa. The burden of UC is rising globally with significant disparities in levels and trends of disease in different countries. The pathogenesis of UC involves the presence of pathogenic factors including genetic, environmental, autoimmune, and immune-mediated components. Evidence suggests that disturbed interactions between the host immune system and gut microbiome contribute to the origin and development of UC. Current medications for UC include antibiotics, corticosteroids, and biological drugs, which can have deleterious off-target effects on the gut microbiome, contributing to increased susceptibility to severe infections and chronic immunosuppression. Alternative, nonpharmacological, and behavioral interventions have been proposed as safe and effective treatments to alleviate UC, while also holding the potential to improve overall life quality. This mini-review will discuss the interactions between the immune system and the gut microbiome in the case of UC. In addition, we suggest nonpharmacological and behavioral strategies aimed at restoring a proper microbial-immune relationship.

INTRODUCTION

Ulcerative colitis (UC), an inflammatory bowel disease (IBD) of the large intestine, impacts millions worldwide. Although the pathogenesis of UC is vague, genetic, environmental, autoimmune, and immune-mediated components have been implicated as contributing factors (1). Evidence suggests that disrupted interactions between the host immune system and gut microbiome contribute to UC pathogenesis (2, 3). While effectively improving symptomology, current UC medications (i.e., antibiotics, corticosteroids, cytokine inhibitors) may disturb the microbial-immune relationship, further contributing to disease. In addition, these drugs can have off-target effects, increasing susceptibility to infection and inducing chronic immunosuppression, leading to decreased life quality. This has led to an emergence of nonpharmacological approaches that offer safe and effective alternatives to treat UC symptoms. This mini-review will 1) address the interactions between the immune system and the gut microbiome in UC and 2) suggest strategies to improve the microbial-immune relationship, including dietary manipulations, pre/probiotic supplementation, behavioral, psychological, and other lifestyle changes.

INTERACTIONS BETWEEN THE GUT MICROBIOME AND HOST IMMUNE SYSTEM IN HEALTHY INDIVIDUALS

The gut microbiome is a vastly diverse and complex ecosystem residing within the lumen of the gastrointestinal tract (GIT). The GIT houses over 100 trillion microorganisms, which live either in symbiosis or dysbiosis within the host (4). It is near impossible to universally define a healthy microbiome; however, it is typically characterized by microbial diversity and abundance (4). Bacteroidetes and Firmicutes are the two main phyla that compose the gut microbiota; the three most prevalent genera residing within healthy individuals include Bacteroides and Prevotella (4).

Microbiota serves many roles within the gut, including the synthesis of vitamins (e.g., vitamin K, B12, B9) (2, 3) and the breakdown of dietary fiber into usable short-chain fatty acids (SCFAs); SCFAs promote intestinal epithelial cell (IEC) health, provide energy to colonic cells, and increase gut barrier function (5). Arguably more importantly, however, these microbial species represent an important player in host immunity; microbes act as the first line of defense against pathogens and communicate with, educate, and modulate host immune responses (2, 3). Through factors like diet, the environment, stress, probiotics, and antibiotics, microbiota can be altered and directly impact intestinal homeostasis (3).

A proper microbial-immune relationship depends on several factors. Since the GIT is continuously exposed to microbial antigens, protective mechanisms have evolved to prevent unnecessary activation of the immune system. One such mechanism is tolerance to gut flora, which begins as early as birth (2, 3). Another mechanism includes tight junctions (TJs), which function to keep bacterial and other foreign antigens confined to the lumen (2, 3). Assuming these protective mechanisms are intact, the immune system can operate appropriately. Dendritic cells (DC) and other antigen-presenting cells (APC) sample antigen from within the lumen and present to naive CD4⁺ T cells within the lamina propria (LP) (2, 3). If a T-cell receptor (TCR) recognizes the specific antigen, it becomes activated to perform two main roles: 1) activated T cells activate B cells to mature into antibody-secreting plasma cells; 2) activated T cells differentiate into specific T-cell subtypes (i.e., Th1, Th2, Th17, or Treg) based on the cytokine profile within the local environment (2, 3). These immune-mediated effects represent normal physiological inflammation that is quickly resolved (see Fig. 1).

Figure 1.

Healthy versus diseased interactions between the gut microbiome and immune system in ulcerative colitis. Adapted from “Immune Response in IBD” by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.

INTERACTIONS BETWEEN THE GUT MICROBIOME AND HOST IMMUNE SYSTEM IN UC

Dysbiosis within the gut microbiome plays a role in the pathogenesis of UC. Whether dysbiosis is a cause or consequence of UC, changes occur within the microbial ecosystem, ultimately disrupting immune and intestinal homeostasis (2, 3). In UC, the microbiome composition loses its diversity and becomes imbalanced, typically demonstrating enriched levels of proinflammatory species and depleted levels of beneficial, anti-inflammatory species (6, 7). Indeed, a 10-fold reduction in total gut bacteria, with a particular loss of Bacteroidetes and Lachnospiraceae, and an enrichment of Proteobacteria and Bacillus has been reported (7). Furthermore, patients with UC suffer severe Escherichia coli and Clostridioides difficile infections, which are known to promote inflammation and worsen disease symptoms (5, 6). In addition, patients with UC demonstrate increases in mucosa-associated bacteria (i.e., γ-proteobacteria, actinobacteria, and bifidobacteria) and a disproportionate increase in colon-associated mucolytic bacteria (i.e., Ruminococcus gnavus and torques) (8). Thus, microbes breach the mucosal lining and enter closer proximity to the LP (where the immune cells reside). This increase in mucosal microbes is correlated with disease severity and is most likely due to impaired TJs and inflammatory signaling.

Although UC pathogenesis remains unclear, dysregulation occurs within both the innate immune system (i.e., neutrophils and monocytes) and adaptive immune system (i.e., T cells) (2, 3). Some have characterized UC as hyperactivation of Th1 and Th17 cells, resulting in increased intestinal permeability, and hypoactivation of regulatory T cells (Tregs), leading to decreased suppression of the immune response (9). Another study characterized UC as an atypical Th2 response in human colonic LP mononuclear cells (10). Although the exact immune mechanism is not well defined in the case of UC, there seems to be a clear imbalance between effector/helper T cells and regulatory T cells (see Fig. 1). Additional research in this area is required to better understand the immune mechanism driving UC.

As previously reviewed, many factors contribute to a dysfunctional microbiome-immune relationship in UC (2, 3). For instance, reduced microbial diversity decreases the strength of the first defenders. Enriched inflammatory species contribute to tissue damage and systemic inflammation. Depleted anti-inflammatory species contribute to decreased TJs and gut integrity, which ultimately impairs IEC function and worsens symptoms. A weakened intestinal barrier allows pathogenic antigens to enter closer proximity to the LP and persistently activate DCs (2, 3). A loss of tolerance to intestinal microbiota or an overly reactive response to bacterial antigen also can contribute to disease (9). As unresolved physiological inflammation becomes chronic inflammation, the cyclic damage continues. Further research is clearly needed to determine strategies to improve this important microbiome-immune relationship.

STRATEGIES TO IMPROVE THE INTERACTIONS BETWEEN THE GUT MICROBIOME AND HOST IMMUNE SYSTEM IN UC

Dietary Patterns, Dietary Supplementation

Diet greatly impacts the microbiome, which modulates the immune response and therefore can impact UC (see Fig. 2; Table 1). We will address the impact of dietary patterns and supplements on UC.

Figure 2.

Overview of discussed strategies to improve microbiome-immune interactions in ulcerative colitis. Adapted from “Healthy vs. Diseased Gut Microbiota” by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.

Table 1.

Nonpharmacological strategies with beneficial effects on the microbiome-immune interactions in ulcerative colitis

Nonpharmacological Strategy	Effect on Immune-Gut Relationship	References
Dietary patterns
AID	Promotes IEC growth and immune surveillance; modulates microbiome	(11–13)
Dietary supplementation
Vitamin D	Prevents VDR loss, which protects against colitis through TJ and IEC preservation	(14)
Vitamin A	Enhances IgA secretion, which contributes to IEC maintenance, improves mucosal immunity, and activates adaptive immune response	(15)
Vitamin E	Prevents macrophage- and neutrophil-induced oxidative damage	(16)
Selenium	Prevents macrophage-induced and neutrophil-induced oxidative damage, increases TJs, and decreases inflammation	(16, 17)
Bacterial supplementation
Probiotics, synbiotics	Promote remission and better patient outcomes; improves microbial composition through promotion and strengthens IEC barrier	(18,19)
FMT	Replenishes specific bacterial species that may be depleted in the colon itself due to UC	(20)
Alternative medicine
Ginseng	Promotes microbial diversity, gut barrier function, anticolitis, and anti-inflammatory benefits	(21–25)
Quercetin	Reduces oxidative stress, inflammation, and colitis symptoms; increases TJ; improves microbial diversity	(26, 27)
Rhein	Promotes microbial diversity; reduces proinflammatory cytokines	(28)
Emodin	Improves gut barrier dysfunction	(29)
Lifestyle changes
PA, exercise	Promotes microbial diversity by increasing health-promoting species and reducing pathogenic species; enhances SCFA production	(30–33)
Stress reduction, psychotherapy	Improves symptomology, overall quality of life, anxiety, and depression	(34–38)
Sleep	Improves mucosal integrity; reduces overall inflammation	(39–41)

IEC, intestinal epithelial cell; PA, physical activity; SCFA, short chain fatty acid; TJ, tight junction; UC, ulcerative colitis; VDR, vitamin D receptor.

Dietary patterns.

Two diets that have been commonly associated with worsened UC symptoms are the Western-style diet (WSD) and high-fat diets (HFDs). The WSD, high in sugar and simple carbohydrates, contributes to the growth of inflammatory bacteria and depletion of anti-inflammatory SCFA-producing bacteria (42). HFD increases intestinal permeability and negatively modulates cytokine production (42), both of which can exacerbate colitis. On the other hand, the anti-inflammatory diet (AID) has been associated with improved outcomes in UC. The AID, which is characterized by an increased intake of antioxidants, dietary fiber, probiotics, and a decreased/limited intake of common inflammatory foods (i.e., red meat, processed meat, added sugar, gluten, etc.), has been shown in clinical studies to modulate the gut microbiome by significantly increasing the abundance of 3 main bacterial families: Bifidobacteriaceae, Lachnospiraceae, and Ruminococcaceae (11). Since the AID is high in fiber, it helps promote proper bacterial growth and balance. Fiber-derived SCFAs are essential to differentiate colonic T cells into Tregs, which are critical modulators of the immune response (12). Leafy green vegetables (i.e., broccoli and lettuce) contain I3C, which binds to AhR ligands in IECs, promoting IEC growth and proliferation, as well as immune surveillance (13). In animal studies, AhR deficiencies have been linked to increased susceptibility to colitis, demonstrated by IEC apoptosis, poor immune surveillance, and an inflammatory phenotype (13, 43). Diets like AID (and others high in fiber and low in sugar) can contribute to intestinal homeostasis through improving the mucosal barrier and regulating the adaptive immune system, serving beneficial to patients with UC.

Dietary supplementation.

Select vitamins and minerals may play a role in regulating the microbiome-immune relationship in UC. Vitamin D supplementation prevents Vitamin D receptor (VDR) loss in colitis (14). Considering that patients with IBD demonstrate reduced VDR expression, an animal study demonstrated that human VDR expression in IECs protects mice against colitis by preserving TJs, suppressing colonic inflammation, and reducing IEC apoptosis (14). Vitamin A enhances intestinal IgA secretion (which contributes to intestinal barrier maintenance and improves mucosal immunity), increases the percentage of B cells in mesenteric lymph nodes, promotes DCs in the mucosa, and expands the percentage of T-helper cells during early life/development in animal studies (15). Vitamin E and selenium supplementation prevent macrophage- and neutrophil-induced oxidative damage in inflamed colons (16). Another animal study demonstrated how selenium polysaccharides alleviated colitis by improving histological architecture of the colon, increasing TJ proteins, decreasing oxidative stress, decreasing proinflammatory cytokines, and reinstituting the microbiome postinjury (17). Although there is no universal diet for UC, supplementation with select vitamins and minerals can help improve the gut-immune relationship.

Bacterial Supplementation

Increasing bacterial diversity and abundance is another potential strategy to improve the microbiome-immune relationship, consequently easing disease burden for patients with UC (see Fig. 2; Table 1).

Childhood intervention.

The establishment of the gut microbiome is primarily determined in early life. The mode of delivery, feeding type, and antibiotic usage all impact the microbiome and can contribute to IBD risk (44). Compared with vaginal delivery, cesarean-delivered babies have decreased microbial diversity and increased risk of developing UC (44). Interestingly, Bacteroides microbes have been demonstrated to be reduced in cesarean-delivered infants, which is similar to what has been observed in patients with UC (4, 7, 45). Regardless of the birthing method, compared with formula-fed babies, breastmilk-fed infants experience increased protection from UC; this is believed to be due to 1) the anti-inflammatory, antiviral, and bactericidal effects of lactoferrin and lysozyme within the breastmilk and 2) the passive transfer of immunoglobulins (e.g., IgA), which bind to microbes and prevent them from reaching mucosal membranes (46). Antibiotic usage (i.e., clindamycin and vancomycin) depletes intestinal microbiota, shifts bacterial composition, weakens the intestinal barrier, and unnecessarily activates the immune system, which increases UC risk (4, 47). Specifically, an imbalance between Firmicutes and Bacteroidetes and reduced Bifidobacteriaceae and Lactobacillus (4), which are microbial imbalances commonly seen in patients with UC (7), has been documented with antibiotic usage (4). Vaginal delivery, breastmilk, and limited antibiotic usage help shape and educate the microbiome by increasing bacterial colonization, diversification, and abundance, ultimately strengthening the mucosal/gut barrier and decreasing UC risk (44).

Adult intervention.

Adult interventions to promote microbial diversity/abundance in the gut include decreased antibiotic usage, increased usage of synbiotics, and fecal microbiota transplants (FMT). Clinical data showed that recent antibiotic-usage increased risk of developing UC (48). For example, three or more antibiotic dispensations were associated with a 55% increased risk for UC (48). This is likely due to the resulting short- and long-term disturbances in the gut microbiome, mainly the loss of abundance and diversity of Bacteroides (49). Strategies such as probiotics, synbiotics, and FMTs can be utilized to improve UC disease. Probiotics are live microorganisms that maintain or improve beneficial bacteria, which can increase bacterial diversity, inhibit pathogen colonization and invasion of the mucosa, produce antimicrobial proteins, secrete protective immunoglobulins, and protect the IEC barrier (3, 18). Indeed, probiotics containing Lactobacillus and Bifidobacterium have shown beneficial and influenced UC remission (18). Synbiotics, which combine prebiotics (i.e., indigestible fiber that feeds probiotics) with probiotics, have also demonstrated positive outcomes in UC clinical studies (18). Short-term (<16 wk) synbiotic supplementation was more effective than prebiotics or probiotics alone in relieving UC, which is speculated to be due to the increase in Bifidobacteria (18). In another study, synbiotics were effective in improving the composition of the microbiota by modifying the ratio of Bacteroidetes/Firmicutes (19). When deemed medically necessary, FMTs may also be used to directly replenish specific bacterial species that may be depleted in the colon itself (3, 20). Because of their direct impact on the mucosal barrier, probiotics, synbiotics, and even FMTs can be utilized to improve the microbiome-immune relationship.

Alternative Medicine

The multifactorial nature of UC and its associated complex microbiome-immune interaction have led to an emergence of investigations into the efficacy of natural compounds as alternative medicines for UC (16). Natural compounds can modulate multiple inflammatory pathways, are inexpensive, and have low toxicity for chronic treatment. In addition, natural compounds have been documented to alter gut microbe composition and diversity, leading to improved UC symptoms. We will discuss select natural compounds known to improve UC progression preclinically (see Fig. 2; Table 1).

Ginseng.

Ginseng is a diverse plant family of Korean, South China, and American origin. Ginseng has been shown to impact microbial diversity lending to its therapeutic promise across numerous inflammatory diseases, which has recently been reviewed (21). Panax Ginseng has been shown to improve microbial diversity with colitis (22), and its most potent component (Panaxynol) has demonstrated anticolitis effects by targeting macrophages (23). Consistent mechanisms of action for ginseng are suppressed colonic inflammatory signaling, improved gut barrier function, and increased microbial diversity (24, 25). Additional work, however, is needed to extend these studies to the clinic.

Quercetin.

Quercetin is a flavonoid found in numerous plants, possessing anti-inflammatory and antioxidant properties. As such, quercetin has emerged as a potential therapeutic for colitis (16). Quercetin nanoparticles improved colitis by reducing oxidative stress, reducing inflammation, and increasing TJs (26). In addition, dihydroquercetin improved colitis symptoms, reduced colonic inflammatory signaling, and improved microbial diversity (27). Quercetin is thought to exert these benefits due to being an AhR ligand, whose receptor has been understood to be a key driver in inflammation-induced colitis (43). Again, clinical evidence of quercetin’s therapeutic efficacy with UC is limited, but strong mechanistic and preclinical data provide evidence for quercetin to be a potential alternative therapy for UC.

Rhein, emodin.

Anthraquinone components of rhubarb, including rhein and emodin, have demonstrated therapeutic efficacy in UC. Rhein dose dependently improved colitis, enhanced microbial diversity, and reduced colonic protein synthesis (28). In addition, in vitro macrophages treated with rhein demonstrated reduced production of key proinflammatory cytokines following an inflammatory stimulus (28). Emodin has demonstrated similar benefits with colitis, while additionally improving the gut microbial environment and gut barrier dysfunction (29). Although rhein and emodin are traditional Chinese medicines, additional mechanistic evidence may support adopting them as UC treatments in the United States.

Lifestyle Changes

Various lifestyle factors, including physical activity (PA), stress, and sleep, have been shown to impact the symptoms, treatment, and overall burden for patients with UC (see Fig. 2; Table 1).

Physical activity, exercise.

Both PA and exercise modulate the gut microbiome and inflammatory microenvironment in UC (30, 31). Both human and animal data support the ability of PA to promote microbial diversity and abundance in the gut. According to human data, the microbial composition of active individuals contained increased bacterial diversity, decreased levels of pathogenic bacteria, and increased levels of health-promoting species (i.e., Akkermansia muciniphila); in addition, active individuals expressed overall decreased levels of proinflammatory cytokines (i.e., TNF-α), demonstrating the immune-modulating effects of PA (32). It has been reported that exercise is independently associated with 24–32% lower risk of symptomatic relapse over 6 mo among patients with UC in remission (33). The mechanisms for the benefits of exercise on UC are pleiotropic and have been reviewed elsewhere (30). Briefly, they are likely to include cross talk between skeletal muscle and the gut, alteration of fasting-induced adipose factor pathways, reduced fecal bile acids, enhanced production of SCFAs, increased gut luminal IgA, reduced luminal transit time, and activation of the stress hypothalamic-pituitary-adrenal axis. Although not all studies have reported a correlation between exercise and microbial changes, the majority of data on UC support a protective role of PA/exercise that is likely driven, at least in part, by alterations to the gut microbial profile.

Stress reduction, psychotherapy.

Multiple investigations have demonstrated the impact of perceived and chronic stress on UC progression. In fact, a mouse model demonstrated how chronic stress worsened colitis symptoms, impaired intestinal barrier function, disturbed gut microbes, and induced immune dysfunction (34). Furthermore, preclinical data suggest that the stress-related mediator, prolactin, may restrain the suppressive action of intestinal Tregs, transforming their phenotype rather than their quantity, which further contributes to intestinal inflammation (35). To mediate the negative impacts of stress, human studies have demonstrated how stress management psychotherapy (i.e., breathing, movement, meditation) in active patients with UC improved disease symptoms and decreased median C-reactive protein levels (36, 37). Furthermore, cognitive behavioral therapy (CBT), mindfulness meditation, and medical hypnosis similarly have shown improvements in gastrointestinal symptoms of patients with IBD supporting the potential utility of nonpharmacological approaches to treat UC (37). For example, in a randomized clinical study, children with IBD given psychotherapy (such as CBT) showed improvements in overall quality of life, depression severity, and disease severity (38). Although more research is required in this area, stress reduction and cognitive and psychological interventions can significantly improve overall pain, depressive behaviors, and overall quality of life in patients with UC.

Sleep hygiene.

Poor sleep hygiene has previously been linked to UC (39). Indeed, patients with UC have poorer sleep quality, prolonged sleep latency, greater sleep fragmentation, and increased use of sleeping pills (40). Furthermore, slow-wave sleep (i.e., stages 3–4 of NREM sleep), which is considered the “rest period” for the colon and integral in supporting colonic health, is reduced in active patients with IBD (41). The chronic secretion of inflammatory cytokines and immune factors that are known to affect sleep have been implicated as causative agents for the poor sleep hygiene in patients with UC (41). Sleep disturbances have been shown to alter mucosal integrity, intestinal permeability and inflammation, and colon contractility (41). In addition, patients with UC in clinical remission with “abnormal” sleep were at an increased risk of relapse at 6 mo compared with those with “good”/normal sleep (40). Because of sleep’s established immune-modulating effects, increased and improved sleep may benefit patients with UC and should be further investigated.

CONCLUSIONS AND FUTURE PERSPECTIVES

In this mini-review, we highlight the current literature on the interactions between the host immune system and the gut microbiome as related to UC pathogenesis. Furthermore, we emphasize nonpharmacological approaches that may offer safe and effective alternatives to treat UC symptoms. Despite UC impacting millions worldwide, our appreciation and understanding of its pathogenesis remains incomplete. It is clear, however, that the host immune response and the gut microbiome play a critical role. Understanding this relationship and its contribution to UC is essential to developing new approaches to improve patient outcome and life quality. The emergence of -omics over the last several decades provides the technology to further our understanding of this relationship in the context of UC. Indeed, much work remains needed to fully appreciate this complex interaction. Finally, the current pipeline of potential nonpharmacological strategies to treat UC, including diet and supplementation, manipulation of gut bacteria, use of natural compounds, and lifestyle interventions, are promising and should be further explored for their potential in improving the immune-gut microbiome interaction and consequently reducing symptom burden of patients with UC.

GRANTS

This paper was supported by National Cancer Institute (NCI) Grant R01CA246809 (to E.A.M.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

B.M.B. prepared figures; B.M.B., B.N.V., S.J.M., T.D.C., and E.A.M. drafted manuscript; B.M.B., B.N.V., S.J.M., T.D.C., and E.A.M. edited and revised manuscript; B.M.B., B.N.V., S.J.M., T.D.C., and E.A.M. approved final version of manuscript.