A thorough review of relevant research showed that the current study is the first nationwide population-based study to investigate the risk of CFS in patients with IBD. We observed that the risk of CFS was significantly higher in patients with IBD than in the general population. In addition, we identified male sex, advanced age, absence of comorbidities, and CD as the predictors of increased CFS risk. The average age of the sample of newly diagnosed IBD patients was 47.5 years, which is higher than epidemiological studies suggesting peak onset is in the 20s and 30s. This average age may reflect geographic differences . CFS has a multifactorial etiology and several models have been proposed to explain mechanisms underlying CFS, including immunoinflammatory pathways , oxidative and nitrosative stress (O&NS) pathways , and bacterial translocation .
Although the definite pathogenesis of IBD remains unclear, unusual intestinal immune reaction triggered by intestinal flora could lead to inflammation  or deficit in the intestinal barrier and bacterial translocation . Noticeably, bacterial translocation has been also proposed as one of the mechanism underlying CFS . This hypothesis could be evidenced by the fact that serum IgA levels against the Lipopolysaccharide (LPS) of enterobacteria were significantly higher in patients with CFS. A study demonstrated the peripheral inflammation is induced by the LPS via binding to the toll-like receptor-4 complex . If there is a mutation of Nucleotide binding oligomerization domain 2 (NOD2), a protein that binds to the peptidoglycan of bacteria resulting in NF-κB activation and inflammatory response, it could lead to CD development . NF-κB is associated with a subjective feeling of fatigue  and activation of this pathway is common in both IBD  and CFS populations. Moreover, pro-inflammatory cytokines signals could also be relayed to brain by the autonomic nervous system and activated microglia could result in neuroinflammation and increased cytokine levels in brain . There is an association between increased brain Interferon-γ (IFNγ), levels and certain somatic traits such as fatigue and hyperalgesia . The hypothesis of bacterial translocation from the gastrointestinal tract is illustrated as Fig. 3. However, the above hypothesis is one of the possible explanations. Dysbiosis of the gut microbiota and an increased incidence of microbial translocation were suggested to play a principal role in inflammatory symptoms in CFS . Thus, microbiota-gut-brain interactions were indicated essentially in the clinical presentations of a subgroup of patients with CFS [31, 32]. More basic research is warranted before we justify the role of gut-brain inflammation in CFS pathogenesis .
We observed that the risk of CFS was higher in patients with CD than in patients without IBD; however, the risk was not higher in patients with UC. Although it may be caused by the underpowered of the data of UC (26.3% power), there are some possible implications from a clinical point of view. The extent of the intestinal barrier integrity may have a crucial role. Firstly, the extent of the inflammation of UC is restricted in colorectal region, and it invades mainly within the mucosa, whereas CD invades different areas of the digestive tract with transmural involvement. On the other hand, a curative operation can be conducted in UC patients, while there is no known cure for Crohn’s disease. To be speculative, the impairment of the intestinal barrier and bacterial translocation may be more severe in CD, and the immune responses exhibited in UC may be less because of the relatively complete integrity of the gut barrier.
It is noteworthy that certain probiotics, such as Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus bulgaricus, and a specific formula diet showed protective effects on the intestinal barrier and decreased rate of bacterial translocation among patients with biliary disease . Future studies can aim to access the response of these therapies in IBD patient with CFS.
The strength of the study obviously is the large number of patients included in both groups (cases and controls). The NHI database of Taiwan provides complete and valid information regarding the demographic characteristics of patients in both the case and control groups. Since we have considered variables, such as sex, age, comorbilities and medical treatment and adjust them individually as well.
Our study has some limitations. First, because of the availability of limited information related to claims data in the NHIRD, we could not further evaluate the effect of biochemical laboratory data and disease severity of patients with IBD. However, this can be investigated by conducting a hospital-based study in which the biochemical laboratory data can be obtained, following which the patients can be stratified into groups according to the severity of their clinical diagnoses. In addition, prescription details are not included in this study. Fatigue has been reported as a side effect to certain medications used in IBD, but we believe that the impact on the incidence rate of CFS is minimal, because the diagnosis of CFS requires not only the long lasting complaints of fatigue but should be “unexplainable” in nature . Theoretically, the diagnoses of IBD and CFS were reliable because this study only included hospitalized patients whose diagnoses were strictly audited for the purpose of reimbursement. Reasonably, specialists should address the issue of adverse events from the use of biologic agents and steroid during the diagnosis. Moreover, the high prevalence of fatigue in IBD is not related to the tapering of steroid .
Furthermore, genetic and territorial discrepancies among the different populations should be investigated by conducting additional multinational further studies.
Based on our findings, it’s essential to pay attention not only to the medications applied on the patients with IBD and susceptible CFS, but also to variability in the type and cost of care delivered to patients. Thus, several gastroenterology societies are developing measures to assess quality of care, which should be integrated to quality measures of care in practice .