**7. Conclusions**

In recent years, numerous studies have provided data on the role of the gut microbiome and its influence on other tissues. It is known that alteration in the microbiome could be one of the factors contributing to the development of cancer and neurological, gastrointestinal, cardiovascular, and metabolic diseases. Lately, many studies have also investigated the role of the human microbiome in the pathogenesis of different types of pain (Table 1). Proper assessment and control of pain are essential for improving quality of life in many patients. Despite the availability of various pain management methods, there is still a great need for research on factors contributing to pain pathogenesis and novel therapies. Recent studies suggest that the human microbiome may be an essential component of the pathogenesis of multiple types of pain. Neuropathic pain could result from the gut microbiome's influence on T-cell immune response, disrupting the regulation of pro- and anti-inflammatory cytokine production. Furthermore, alteration of the immune cell response and cytokine production by the gut microbiome could contribute to the development of inflammatory diseases, such as endometriosis. Chronic visceral pain remains a challenge to efficient treatment. The human microbiome contributes to the still unknown pathogenesis of FGIDs, providing a promising direction for further studies. Additionally, common symptoms such as headaches are influenced by the gut microbiome. An altered gut–brain axis could trigger a migraine. Moreover, the regulation of inflammatory mediators that contributes to migraine is disrupted by dysbiosis. The gut microbiome could also impact the efficacy of pain management, leading to opioid tolerance. The contribution of the human microbiome to the pathogenesis of multiple types of pain leads to its use

as a possible target for analgesic therapies. Pro- and prebiotics are already widely used in clinical practice. They are reported to be effective in reducing chronic visceral pain and migraine. However, there is still a great need for further evaluation of their efficacy and influence on patients' quality of life. Another approach assumes the modification of the gut microbiome with a specific diet, such as a low-FODMAP diet, which could be beneficial for patients with IBS, reducing symptoms and pain episodes. The usage of FMT is recommended in the treatment of *Clostridium difficile* infection.

**Table 1.** Summary of novel studies that investigated the role of the human microbiome in the pathogenesis of different types of pain.


Moreover, FMT is reported to efficiently reduce visceral pain among IBS patients. However, these studies have some limitations. There is a strong need for further evaluation of concepts and previous results. Additional long-term studies are required to assess the potential side effects of gut microbiota alteration. Moreover, the differences in the methodology of the studies impede the precise comparison of the results. Pittayanon et al., in their systematic review, reported concerns about deficiencies in studies' methodology and statistical analysis [95]. The shortcomings, such as lack of data on administrated antibiotics, and differences in the microbiome evaluation methods, are reasons for inconsistency in reviewed papers.

Despite the significant development in the understanding of the human microbiome in the pathogenesis of pain, there are still many areas to be investigated. A detailed evaluation of the influence of the altered microbiome on the gut–brain axis could be a critical factor in understanding the impact of dysbiosis on several tissues and pain development [18]. The detailed characterization of the gut microbiome in chronic, visceral, or headache states and their interaction with the gut–brain axis could deliver novel insight into the pathogenesis of a different type of pain. Further molecular studies could develop novel targets for analgetic treatment that could significantly improve numerous patients' quality of life.

**Author Contributions:** Conceptualization, K.U. and A.P.; methodology, Ł.U.; formal analysis, J.R.; investigation, B.S.; writing—original draft preparation, A.G. and J.S.; writing—review and editing, F.M. and A.P.; visualization, B.S.; supervision, J.R.; project administration, A.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors thank Piotr Michalski from the Academy of Art in Szczecin for his assistance in composing the figures.

**Conflicts of Interest:** The authors declare no conflict of interest.
