The new insights of hyperbaric oxygen therapy: focus on inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBD), with an increasing incidence, pose a significant health burden. Although there have been significant advances in the treatment of IBD, more progress is still needed. Hyperbaric oxygen therapy (HBOT) has been shown to treat a host of conditions such as carbon monoxide poisoning, decompression sickness, and gas gangrene. In the last few years, there has been an increase in research into the use of HBOT as an adjunct to conventional treatment for IBD. Related research has shown that HBOT may exert its therapeutic effects by decreasing oxidative stress, inhibiting mucosal inflammation, promoting ulcer healing, influencing gut microbes, and reducing the incidence of IBD complications. This paper aims to provide a comprehensive review of experimental and clinical trials exploring HBOT as a supplement to IBD treatment strategies.

Introduction

Inflammatory bowel diseases (IBD) encompass chronic inflammatory conditions, including ulcerative colitis (UC) and Crohn's disease (CD). UC occurs primarily in the colonic mucosa, whereas CD can involve the entire gastrointestinal tract. Abdominal pain, diarrhea, and weight loss are the most common clinical symptoms of IBD. In UC, bloody stools may occur. In addition, extra-intestinal manifestations may occur in the eyes, joints, and other areas before the onset of intestinal disease [1].

Moreover, a comprehensive study investigating the global implications of IBD from 1990 to 2017 revealed a rise in the age-specific prevalence of IBD between 1990 and 2017. This trend was particularly pronounced within developed nations [2]. Between 1990 and 2019, the incidence of IBD in China consistently increased. The number of cases for females increased from 6.81 thousand to 22.6 thousand, while for males it increased from 10.4 thousand to 28.9 thousand [3]. The development of IBD may be related to genetic susceptibility, immune abnormalities, altered intestinal flora, and environmental factors [4]. A cohort study found that the incidence of IBD in immigrants to Canada from 1994 to 2010 was lower than that of native Canadians. However, the risk of developing IBD increases with the younger age at which immigrants arrive in Canada. This indicates that both environmental and genetic factors play important roles in the development of IBD [5]. Inflammation of the intestinal mucosa leads to rapid depletion of nutrients and oxygen, causing hypoxia. IBD also reduces intestinal blood supply and oxygen delivery through microvascular defects, resulting in mucosal hypoxia. Hypoxia-inducible factors (HIF) can enhance mucin production and promote integrin subunits to protect the intestinal epithelial barrier [6]. Currently, common treatments include 5-aminosalicylic acid, corticosteroids, thiopurines, biological drugs, immunosuppressive drugs, and surgery ^[7,8].

Due to the incurable nature of IBD and the potential side effects of many treatment methods, finding some complementary therapies is significant. Hyperbaric oxygen therapy (HBOT) is the inhalation of 100% oxygen at a pressure higher than 1 atm, which increases the level of oxygen dissolved in the blood plasma and tissues. HBOT reduces hypoxia and edema, allowing the host to adapt to infection and ischemia. Several studies have shown improvement of ischemia–reperfusion injury in the rat brain by constructing a rat model of ischemia–reperfusion after hyperbaric oxygen preconditioning ^[9,10]. HBOT has found application in various medical contexts including arterial gas embolism, carbon monoxide poisoning, gas gangrene, crush injuries, osteofascial compartment syndrome, and decompression sickness [11]. As early as 1991, it has been pointed out that HBOT inhibits both humoral and cellular immunity in mice and is related to the exposure time to hyperbaric oxygen. In addition, long-term administration of HBOT to autoimmune mice can reduce their autoimmune symptoms [12]. As early as 30 years ago, hyperbaric oxygen was used as an adjunct in the treatment of severe perineal and cutaneous CD. In a 48-year-old African–American woman with severe cutaneous CD, which extends from the perineum to the pelvic, gluteal, and abdominal wall areas and has been persistent without healing, a range of other treatment methods have been ineffective due to side effects. After undergoing HBOT, the patient is essentially asymptomatic, with a noticeable reduction in the severity of the skin condition compared to before treatment [13]. There has been increased interest in using HBOT in IBD in the past few years. This review aims to summarize prior studies, elucidate the role of HBOT in IBD, discuss potential adverse effects, present future prospects, and propose innovative clinical approaches for IBD therapy.

HBOT reduces oxidative stress

IBD is characterized by intestinal barrier disruption, immune dysregulation, and microbial dysbiosis. The typical intestinal epithelium exists in a state of “physiological hypoxia”, and under inflammatory conditions this can potentially result in exacerbated hypoxic conditions [14]. Hypoxia in the intestinal mucosa leads to the development of oxidative stress (OS), which inhibits mitochondrial function and exacerbates the inflammatory response, creating a vicious cycle (Fig. 1) [15]. OS is intricately associated with initiating and advancing intestinal inflammation, playing a pivotal role in the pathophysiological processes underlying and driving the progression of IBD ^[16,17]. Increased production of reactive oxygen species (ROS) and decreased antioxidant activity are the major reasons for the pathogenesis and progression of IBD. Increased ROS production and impaired antioxidant activity can cause OS and tissue damage ^[18,19]. Among individuals afflicted by IBD, discernible hallmarks encompass heightened levels of ROS, elevated instances of DNA damage, increased lipid peroxidation, and diminished antioxidant capacity [20]. Not only that, one study showed that plasma free thiols were decreased in CD patients in clinical remission in comparison to healthy controls, suggesting that CD patients are marked by systemic OS during clinical remission [21]. Antioxidant therapy has emerged as a promising approach for potentially intervening in the management of IBD, considering the significant role of OS in its development [22].

Figure 1.

Effect of hyperbaric oxygen therapy on oxidative stress in the intestine. In the inflammatory state, hypoxia in the intestinal mucosa leads to increased production of ROS and mitochondrial and DNA damage, further exacerbating the inflammatory response. HBOT increases superoxide dismutase and glutathione peroxidase levels, thereby reducing levels of oxidative stress. GSH-Px, Glutathione peroxidase; GSSG-R, glutathione reductase; ROS, reactive oxygen species; SOD, superoxide dismutase. (This figure was created with biorender.com.).

Superoxide dismutase (SOD) exhibits an important antioxidant function when the organism is under OS [23]. Several studies have indicated that levels of mucosal SOD are diminished in individuals afflicted with colitis [24]. SOD can break down superoxide into hydrogen peroxide. The hydrogen peroxide can then either be reduced to form hydroxyl radicals or be converted into water by catalase through enzymatic reactions. SOD or peroxidase-mimetic drugs have demonstrated efficacy in alleviating symptoms associated with colitis or CD [25].

Glutathione (GSH) has been used as a biomarker for inflammation and OS. Glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-R) work together to maintain low GSH levels and protect cells from peroxidative damage [17]. In addition, malondialdehyde (MDA) serves as an indicator for OS and lipid peroxidation [26]. A study evaluated the effect of HBOT on experimental acute distal colitis induced by acetic acid in rats. A total of 36 Sprague–Dawley rats were randomly divided into the sham control group, colitis group, colitis and HBOT group. The HBOT group was treated under 2.5-fold absolute atmospheric pressure for 5 days, twice a day, for 90 min each time. The authors found that compared with the colitis group, the HBOT group had reduced colonic infiltration, increased SOD and GSH-Px levels in intestinal tissue and erythrocyte lysate, and decreased MDA levels. This suggests that HBOT can treat colitis by reducing OS and alleviating tissue damage [27].

HBOT is employed comparably across various other medical conditions. Existing evidence demonstrates that HBOT holds the potential to exert a neuroprotective function against anterior ischemic optic neuropathy. This is achieved through its capacity to downregulate the expression of genes associated with OS [28]. Radiotherapy increases OS markers and causes many side effects. HBOT can mitigate deleterious outcomes through augmentation of SOD activity, thereby modulating radiation-induced OS and curbing inflammatory cascade reactions [29]. HBOT has been shown to enhance the activity of antioxidants, reduce levels of OS, and reduce tissue damage. This treatment can be used for various conditions, including neurodegenerative diseases, diabetes, and difficult-to-heal skin wounds [30–34].

Similarly, due to its ability to exacerbate inflammation, OS plays an essential role in the occurrence and development of IBD, while HBOT can reduce OS and enhance the body's antioxidant activity. Therefore, with this characteristic, HBOT holds great potential as a treatment for IBD.

HBOT reduces inflammatory responses

Effects of HBOT on inflammatory cytokines

HBOT inhibits pro-inflammatory cytokines

Several clinical trials have demonstrated that HBOT can be used as an adjunct to conventional drugs to achieve better results in the treatment of IBD. Patients with IBD therefore have this valuable treatment option available to them ^[35,36]. In a systematic review of 19 studies on the therapeutic effects of hyperbaric oxygen on IBD, 78% of patients with CD showed improvement in clinical symptoms, and 39 patients with UC showed improvement in symptoms after HBOT. Furthermore, the investigation demonstrated that HBOT exerted a dual effect by mitigating the activity of interleukin 1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), neopterin, and myeloperoxidase (MPO) among patients, alongside a concurrent decrease of OS markers, specifically MDA and plasma carbonyl levels. This implies that HBOT has the potential to benefit IBD, manifested through attenuation of the inflammatory response and mitigation of OS [37].

Investigation into the therapeutic potential of HBOT in experimental acute distal colitis revealed reduced levels of MPO, IL-1β, TNF-α, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 activities, while the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was downregulated after HBOT intervention. This shows that HBOT inhibits the inflammatory response and reduces the severity of colitis [38]. A survey conducted in 2016 further demonstrated that hyperbaric oxygen effectively diminished both the symptoms and severity of dextran sulfate sodium-induced colitis. Additionally, it led to a reversal in the expression of genes linked to IL-1β, IL-2, and IL-6, indicating significant anti-inflammatory properties. Furthermore, the mitigating effects of hyperbaric oxygen were found to be partially contingent on the expression of HIF-1α and antioxidant genes [39].

HBOT promotes anti-inflammatory cytokines

In addition to the inhibition of pro-inflammatory cytokines, HBOT also enhances anti-inflammatory cytokines. A systematic review including 780 patients showed that HBOT significantly improved IL-10 and reduced TNF-α and IL-6 and has become a promising therapeutic approach for the treatment of UC [40]. The proposition has been made that HBOT possesses the capability to substantially elevate the levels of IL-10 while concurrently serving as an anti-inflammatory agent when combined with N-acetylcysteine. This synergistic intervention produces a neuroprotective outcome against traumatic spinal cord injury in rats ^[41,42]. A study suggests that HBOT can potentially elevate the expression of IL-4 and IL-10, mitigate neuroinflammation, and ameliorate the pathological alterations associated with Alzheimer's disease [43]. Emerging evidence proposes that subjecting mice to inflammatory stimuli precipitated a reduction in pro-inflammatory cytokine synthesis, concomitant with a notable surge in the anti-inflammatory cytokine IL-10, as observed within the splenocytes of the HBOT group [44]. Radiotherapy can induce many side effects, and some studies have demonstrated that HBOT could raise IL-10 and reduce TNF-α and IL-1, which in turn counteract the inflammatory effects of radiotherapy in the blood and tissues ^[29,45]. Moreover, HBOT ameliorated inflammation and oxidative damage in rat brain tissue afflicted by focal cerebral ischemia. Furthermore, it exerted a neuroprotective effect in mouse models of traumatic brain injury, with both outcomes intricately linked to the upregulation of IL-10 [46–48].

Effects of HBOT on inflammatory immune cells

HBOT and neutrophils

When tissues are hypoxic, neutrophil degranulation is increased, especially for azurophilic granules, and this enhanced degranulation is often also cited as the cause of local tissue damage. Hypoxic microenvironments enhance neutrophil degranulation, which is considered partially HIF-dependent; HIF-independent pathways include ROS, mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 3 (STAT3) signaling [49]. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes are connected directly to azurophilic granules, and the upregulation of inflammasomes induces abnormal activation of azurophilic granule cytosol and exacerbates the inflammatory response [50]. It has been proved that NLRP3 protein expression and IL-1β release can be inhibited by inhibiting STAT3 [51]. Many studies show that HBOT reduces ROS, MAPK, STAT3, and NLRP3 [52–54]. A recent investigation into the host–microbiome interaction following HBOT in patients with UC has revealed that HBOT mitigates neutrophil degranulation and notably attenuates STAT3 activity within neutrophils [55].

Hypoxia extends the lifespan of neutrophils while inhibiting apoptosis [56]. Interestingly, exposure to hyperbaric oxygen has been observed to facilitate neutrophil apoptosis, augmenting their phagocytosis by macrophages. This, in turn, contributes to the attenuation of inflammation. The clearance effect of macrophages may be related to their induction of IL-10 expression ^[57,58]. Research in 2022 showed that HBOT can also enhance the levels of Bim and Bcl-XL while reducing the activity of MAPK [55]. As early as 2005, animal experiments found that HBOT can increase Bcl-XL [59]. Bim and Bcl-XL are members of the Bcl-2 family, and Bim restricts cytokine-mediated long-term survival of neutrophils and encourages their apoptosis [60]. Bcl-XL has the potential to inhibit the assembly of NLRP3 inflammasomes and the triggering of IL-1β activation [61]. These mechanisms render HBOT a more effective therapeutic intervention for individuals with moderate to severe UC.

HBOT and macrophages

Microglia, a category of brain-resident macrophages, demonstrated altered biomarker expression in response to HBOT in a rat model of traumatic brain injury. HBOT reduces iNOS and TNF-α expression while increasing arginase 1 and transforming growth factor-β1 expression, promoting the transition of microglial cells from M1 to the anti-inflammatory M2 phenotype [62]. Similarly, HBOT can alter the inflammatory environment through the induction of macrophage phenotypic transformation from M1 to M2, the facilitation of muscle regenerative processes, and the stimulation of axonal elongation, culminating in the enhancement of functional recovery ^[63,64].

HBOT promotes the clearance of apoptotic cells by monocyte-derived macrophages and phagocytosis of neutrophils, resulting in the regression of inflammation, an effect that may be associated with elevated IL-10 levels ^[58,65]. In addition, HBOT increases the production of superoxide anions by macrophages during Pseudomonas aeruginosa infection, and oxygen radicals may play an essential part in the bactericidal effect of HBOT-promoted macrophages [66]. All of the above studies may provide pieces of evidence for further studies in the future.

HBOT and T cells

One study validated the effect of HBOT on keloids, and the authors observed a reduction in inflammatory infiltration and a notable increase in CD4⁺ T cells in the HBOT group, indicating that CD4 lymphocyte T cells may be the critical regulatory immune cells [67]. HBOT suppresses T helper cell 17 (Th17) responses, reduces the expression of CD4 T helper cells that produce granulocyte-macrophage colony-stimulating factor or TNF-α, and augments CD4 T cells expressing IL-4 or IL-10. Early modulation of T cell responses by HBOT can lead to a reduction in autoimmune encephalomyelitis [68]. Elevated TNF-α and interferon-γ (IFN-γ) expression is observed in fibromyalgia patients, while HBOT exhibits the potential to mitigate the production of pro-inflammatory cytokines originating from CD4 T cells, thereby ameliorating the pro-inflammatory state [69].

HBOT has the capacity to modulate the immune equilibrium by influencing the interplay between pro-inflammatory Th17 cells and anti-inflammatory regulatory T cells (Tregs), thereby impeding the progression of arthritis [70]. HBOT decreases HIF-1α activity and Th17 differentiation toward the Treg phenotype. Diminished Th17 cell population results in a decrease in the synthesis of pro-inflammatory cytokines, thereby mitigating the clinical manifestations of arthritis [71]. The impact of HBOT on T cells predominantly manifests within the context of tumor treatment. Apart from facilitating the infiltration of T cells into the tumor parenchyma, HBOT can further induce the activation of programmed cell death-1 antibodies, stimulating cytotoxic T lymphocytes and fostering enduring immune memory to counteract tumor recurrence effectively [72].

It has been shown in a review that there is a close relationship between inflammatory cytokines and immune cells involved in inflammation. For example, IL-6 is mainly produced by macrophages and CD4 T cells in the inflamed colon, and it can exert pro-inflammatory functions by activating antigen-presenting cells and T cells. Macrophages can release anti-inflammatory IL-10 when the colon is damaged, but they can also produce IL-1β or TNF-α, thereby worsening intestinal inflammation [73]. As mentioned above, HBOT can inhibit the production of pro-inflammatory cytokines and promote the release of anti-inflammatory cytokines, thereby complementing the inflammatory cells and playing a role in reducing inflammation. Therefore, HBOT is a method with potential for IBD treatment.

HBOT protects and repairs the intestinal epithelial barrier

HBOT reduces intestinal epithelial barrier damage

MUC2 is a key structural mucosal protein whose reduction is closely associated with the development of UC [74]. The investigators clearly stated that the increase in MUC2 was more remarkable with more prolonged HBOT exposure, indicating that HBOT can protect the intestinal barrier by upregulating MUC2 levels [55]. The intestinal epithelial barrier is severely disrupted after spinal cord injury. HBOT can suppress intestinal OS via the upregulation of nuclear factor E2-related factor 2, mitigation of mucosal permeability, and interception of bacterial translocation. This multifaceted mechanism consequently curtails the extent of intestinal injury [75].

Moreover, tight junction proteins are an essential structural foundation of the intestinal mechanical barrier. A study on improving spinal cord injury in rats by HBOT suggests that HBOT can promote the expression of tight junction proteins by inhibiting the Ras homolog/Rho-associated coiled-coil forming protein kinase signaling pathway, thus protecting the intestinal epithelial barrier [76]. Furthermore, HBOT hampers the activation of nuclear factor kappa-B (NF-κB), reduces nitric oxide (NO) and MPO activity, and mitigates the impairment of the intestinal epithelial barrier [77].

HBOT promotes stem cell differentiation and recruits repair cells

Influence of HBOT on stem cells in IBD

Presently, stem cell therapy has emerged as a prominent subject in the realm of IBD treatment, demonstrating a degree of efficacy. Applying stem cell therapy and organoid culture can induce the formation of new intestinal tissues, subsequently fostering the restoration of the compromised barrier function inherent in individuals with IBD [78]. HBOT has been shown to increase the rate of stem cell proliferation, increase angiogenesis, improve tissue repair, and promote wound healing in the small intestinal crypts of mice [79]. A prospective case series study investigating HBOT in the context of refractory UC delved into the underlying mechanism of HBOT's effects. Notably, all enrolled patients exhibited ameliorated clinical symptoms subsequent to the administration of HBOT. In this study, CD44 served as an indicator of stem cell activity across various organs. The researchers noted a substantial elevation in CD44 levels post-treatment, indicating that HBOT could stimulate colonic stem cell proliferation and differentiation, subsequently fostering mucosal healing [80].

Influence of HBOT on stem cells in other diseases

The impact of hyperbaric oxygen has been validated in various other medical conditions. A case study employing HBOT for patients afflicted with traumatic brain injury demonstrated that this approach facilitated the mobilization of stem cells, restoration of impaired neuronal tissue, and enhancement of cognitive function [81]. According to reports, diabetic patients with recalcitrant neuropathic ulcers in their lower extremities who received HBOT showed increased activity of nitric oxide synthase (NOS) in their platelets. This led to the activation of bone marrow-derived stem cells and an augmentation of more than 2-fold in the population of circulating stem cells among the patients. Consequently, this phenomenon promoted the recruitment of a greater number of cells for involvement in wound repair processes, thereby fostering the advancement of ulcer healing [82]. In animal experiments exploring treatment approaches for myocardial infarction, the synergistic efficacy of HBOT in association with stem cells surpassed that of solitary mesenchymal stem cell transplantation. It is suggested that this outcome can be attributed to the capability of HBOT to induce NOS3 expression while fostering both the proliferation and differentiation of stem cells [83]. The application of HBOT in other diseases also provides reliable evidence that HBOT can promote colonic stem cell differentiation and recruit cells to repair the intestine.

HBOT enhances blood supply to wounds

HBOT promotes angiogenesis

HBOT can promote wound healing by increasing tissue oxygen supply, influencing signaling pathways, and regulating inflammatory mediators and growth factors [84]. Chronic hypoxia delays diabetic wound healing, so continuous oxygenation can reduce hypoxia and promote wound healing. It has been found that a sustained oxygenation system that scavenges ROS promotes the survival of keratinocytes and dermal fibroblasts, stabilizes wound angiogenesis, and reduces the inflammatory response, which in turn promotes wound healing [85]. According to a case report, the utilization of rituximab in conjunction with HBOT holds the potential to induce enduring clinical enhancement in individuals afflicted by systemic lupus erythematosus and concomitant recalcitrant vasculitic ulcers [86].

HBOT has been demonstrated to improve the healing of ischemic colorectal anastomoses. In one study in which all rats underwent colonic resection with ischemic anastomosis, after follow-up it was observed that the rats in the HBOT group had no anastomotic dehiscence and had significantly better burst pressure on postoperative day 3 and renal function on postoperative day 7 than the control group. The authors postulate a potential correlation, suggesting that this phenomenon could be attributed to the impact of HBOT on the vascular perfusion of the anastomosed tissue, consequently amplifying the upregulation of genes associated with anti-inflammatory responses [87].

HBOT increases the level of vascular endothelial growth factor

In the year 2000, it was observed that HBOT led to an augmentation in levels of vascular endothelial growth factor (VEGF) within wounds and prompted the process of angiogenesis [88]. An experimental model of diabetic foot in mice was established, followed by treatment with HBOT. Subsequently, the researchers conducted an analysis of wound healing, revealing that HBOT significantly facilitated ulcer healing. HBOT triggers the activation of HIF-1α and NF-κB signaling pathways, influencing fibroblast behavior. Moreover, it incites the production of stromal cell-derived growth factor-1 and VEGF, ultimately prompting both endothelial cell proliferation and migration. This orchestrated process fosters angiogenesis and accelerates the healing of ulcers [89]. A study found that rats with traumatic brain injury showed reduced inflammation and increased populations of VEGF-positive cells and glial cell-derived neurotrophic factor-positive cells in vivo after HBOT, indicating that HBOT promotes both angiogenesis and neurogenesis [48]. After partial hepatectomy in rats, HBOT significantly increased VEGF protein expression within regenerating liver tissues, concurrently mitigating hepatic injury [90].

One review pointed out that intestinal inflammation is an important indicator of IBD. When chronic inflammation occurs in the intestines, ulcers, mucosal damage, and impaired intestinal epithelial barrier function occur [91]. A study showed that when cultivated G protein-coupled receptor 5-positive colon stem cells were transplanted into damaged mouse colon, after 4 weeks, the donor-derived cells formed a single layer of epithelium and developed functioning and histologically normal crypts. Acute colitis in mice was significantly improved [92]. The generation of new blood vessels is also a crucial step in the healing of ulcer wounds [93]. As mentioned above, HBOT can mobilize stem cells and promote their differentiation, as well as improve oxygenation at the site of the wound and stimulate wound healing. All of this can contribute to the repair of the intestinal epithelial barrier and also demonstrates the therapeutic potential of HBOT in IBD.

HBOT affects gut microbes

Upon analyzing the intestinal microbiota of 231 subjects, comprising both individuals with IBD and those in a healthy state, discernible alterations in the Firmicutes and Proteobacteria phyla were evident among the IBD patients [94]. The family Verrucomicrobiaceae, along with the genera Akkermansia and Dorea, have also been implicated as causal factors in IBD [95]. Microorganism distribution shows a correlation with tissue-provided oxygen and mucus distribution. Furthermore, researchers have identified that HBOT influences the composition of the intestinal flora [96].

MUC2 is the core structural protein of the mucus layer, and in the early stages of UC there is often a decrease in MUC2, a reduction in Firmicutes, and an increase in Muribaculaceae and Akkermansiaceae families [97]. The study conducted by Gonzalez et al. [55] demonstrated the potential of HBOT to diminish the abundance of Muribaculaceae and Akkermansiaceae. This reduction was concomitant with an elevation in Firmicutes levels and secondary bile acids. The Muribaculaceae and Akkermansiaceae are both mucin-degrading bacteria. Researchers have observed a decrease in Akkermansiaceae associated with higher levels of MUC proteins. Additionally, the authors have shown that the increase in Firmicutes is a result of significantly reduced Shannon diversity in HBOT responders, although there is still limited research on this and further investigation is needed. On the other hand, Akkermansia muciniphila exhibits enduring oxygen tolerance in individuals who do not respond to HBOT, implying that A. muciniphila's acclimatization to oxygen might contribute to the ineffectiveness of HBOT in these individuals. It is through these mechanisms that HBOT alleviates moderate-to-severe UC.

In addition, employing a mouse model of chronic unpredictable mild stress, the researchers demonstrated that HBOT has the capacity to reshape metabolites linked to Campylobacterota and ameliorate depression-like behaviors exhibited by mice [98]. However, HBOT does not exclusively confer advantages. Evidence suggests that mice subjected to hyperoxia exhibit modifications in both pulmonary and intestinal microbiota compositions, consequently contributing to the ensuing pulmonary damage [99].

HBOT improves IBD-related complications

HBOT serves as a reliable adjunctive approach for IBD. This assertion has been substantiated by numerous clinical studies (Table 1). The literature has documented the efficacy of HBOT in 40 IBD patients, addressing an array of complications: 33 patients had complications that completely healed, and 7 patients had complications that partially healed. Among them, the most notable recuperation rate was observed in pyoderma gangrenosum (PG) (100%), followed by enterocutaneous fistulas (ECF) (84.6%) and perianal fistulizing Crohn's disease (pCD) (80%) [100]. A retrospective case series encompassed 46 patients diagnosed with IBD who subsequently developed pouchitis following ileal pouch–anal anastomosis. The study included only patients who had clinical and endoscopic evidence before and after HBOT treatment, and all patients received HBOT treatment from January 2015 to October 2019. The clinical symptoms and endoscopic findings of patients improved after HBOT, and the modified Pouch Disease Activity Index score decreased from an average of 9.77 to an average of 5.44 [101].

Table 1.

Summary of HBOT in IBD-related complications.

			HBOT parameters
Indication	Study design	Complications	ATM	Treatment time (min)	Number of HBOT sessions	Effective rate	Side effects	Ref.
CD	Observational study	pCD	2.4	120	10–86	80%	None	[100]
		ECF	2.4	120	10–86	84.6%	None
		PG	2.4	120	10–86	100%	None
IPAA	Retrospective case series	CARP	2.4–3.0	90–120	10–60	100%	Ear barotrauma, hyperbaric myopic vision changes	[101]
UC	Case report	PG	2.6	120	60	100%	None	[102]
UC	Case report	PG	2.4	120	29	100%	Pain in the left ear	[103]
CD	Prospective interventional cohort study	pCD	2.4–2.5	80	40	100%	Ear barotrauma, vomiting, diarrhea, fatigue, visual changes	[104,105]
CD	Case series	pCD	2.0–2.4	90	18–30	100%	Not reported	[106]
Proctectomy for IBD	Clinical trial	PPS	2.2–2.4	90	Preoperative 25–30 Postoperative 10	100%	Ear barotrauma	[107]
CD	Case series	Metastatic CD	2.4	80	40	100%	Fatigue	[108]

ATM: Atmosphere; CARP: chronic antibiotic-refractory pouchitis; CD: Crohn's disease; ECF: enterocutaneous fistula; HBOT: hyperbaric oxygen therapy; IBD: inflammatory bowel disease; IPAA: ileal pouch–anal anastomosis; pCD: perineal fistulizing Crohn's disease; PG: pyoderma gangrenosum; PPS: persistent perineal sinus; UC: ulcerative colitis.

Refractory PG currently lacks a well-defined therapeutic approach as an extraintestinal manifestation of UC. Nonetheless, certain case reports have stated that HBOT has an essential value in the treatment of refractory PG. A 42-year-old female patient was diagnosed with PG and underwent treatment involving adalimumab followed by HBOT. Subsequently, after undergoing 60 HBOT sessions, the patient attained a state of full remission [102]. A 65-year-old male patient had a history of UC that had been present for 17 years. He also received a diagnosis of PG and presented with a painful skin defect located on the pretibial area. After 3 months of HBOT and local debridement treatment, the lesion has completely healed, and UC continues to improve [103].

Perianal fistula is one of the complications of CD. HBOT was administered to a cohort of 20 CD patients who resisted conventional treatment. Following a 16-week intervention, the investigator observed a reduction in the patients' perianal disease activity index. Noteworthy, HBOT conferred marked enhancements across clinical symptoms, imaging, and biochemical indices among patients contending with therapy-refractory perianal fistulas. This suggests that HBOT improves perianal fistulas in CD ^[104,105]. The investigators treated 9 patients with perianal fistulas who were unresponsive to conventional treatment using a new combination therapy. After a follow-up period of 6 to 28 weeks, all 9 patients' fistulas healed completely, with an average healing time of 18 months. The treatment was effective and consisted of infliximab, anti-Mycobacterium Avium ss. Paratuberculosis (MAP), and HBOT [106].

HBOT has also demonstrated efficacy in the treatment of persistent perineal sinus (PPS) that arises subsequent to proctectomy for IBD. A total of 4 PPS patients were treated with HBOT (2.2–2.4 atmospheres, 90 min each time, five times a week, for a total of 5–6 weeks) and underwent rectus abdominis myocutaneous flap repair surgery. Among them, 2 patients continued with HBOT. Observations on the 4 PPS patients revealed that all patients' perineal wounds healed [107]. In addition, a case report documented three cases of confirmed perineal metastatic CD patients undergoing HBOT (2.4 atmospheres, 80 min each time, a total of 40 times). After the treatment, one patient's perineal wound completely healed, another patient showed initial improvement during a 3-month follow-up, and the third patient indicated improvement in a questionnaire survey. This indicates that HBOT is also an effective means of treatment for metastatic CD [108].

Conclusions

There have been many clinical trials proving the effectiveness of HBOT as an adjunct in the treatment of IBD [109–112]. A systematic review also confirmed that HBOT is a relatively safe treatment option for patients with IBD [113]. In summary, the mechanisms of HBOT for IBD may include the following (Fig. 2): (1) HBOT can reduce oxidative stress; (2) HBOT can suppress inflammation by affecting inflammatory cytokines and inflammatory immune cells; (3) HBOT protects the intestinal epithelial barrier by reducing intestinal damage and promoting stem cell differentiation and enhances blood supply; (4) HBOT can affect intestinal microorganisms to achieve therapeutic effects.

Figure 2.

Changes in the pathological profile of IBD before and after HBOT. HBOT modulates intestinal microbial changes, upregulates MUC2 levels, reduces damage to the intestinal epithelial barrier by promoting stem cell differentiation and angiogenesis, and reduces inflammatory responses by reducing neutrophil degranulation, promoting neutrophil apoptosis, Th17 to Treg conversion, and macrophage differentiation from M1 to M2. (This figure was created with biorender.com.).

Nevertheless, the review found limited experimental research on HBOT treatment for IBD, and the specific mechanisms are still unclear. The mechanism of HBOT on immune cells and the intestinal epithelial barrier in IBD is still in the research stage and remains uncertain. Most clinical trials included a small number of patients, and the safety and effectiveness of HBOT in treating IBD still need further investigation. The specific treatment conditions for HBOT also need to be determined, and due to the lack of related experimental research, patients' acceptance of HBOT is not high. However, these shortcomings provide us with great opportunities to delve into the actual effects of HBOT therapy for IBD. The importance of experimental research is self-evident. It can provide more convincing evidence for the medical community, promote further development and progress in this field, and guide clinical practice. Through carefully designed clinical trials, we can better evaluate the long-term effects of HBOT on patients and their quality of life to better understand its potential clinical application value.

In conclusion, further investigation into the therapeutic efficacy of HBOT is needed. On the one hand, further experimental studies are necessary to validate the effectiveness of HBOT as a treatment method. On the other hand, there is a need for additional randomized, blinded, controlled clinical trials to assess the dependability and efficacy of HBOT while establishing refined treatment protocols. These efforts will yield expanded therapeutic prospects for the prospective management of IBD.

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

L.C. wrote the manuscript and designed the figures. Y.W., H.Z., Y.L., and F.Z. revised the manuscript. G.Z. conceived the idea and designed the manuscript. All authors gave final approval for the submission and agree to be accountable for all aspects of the work.We have obtained the relevant permissions for BioRender (www.biorender.com) and have used the correct permission text as required by the copyright holders.