Skip to main content
SpringerLink
Log in

Pivotal role of the gut microbiota in congenital insensitivity to pain with anhidrosis

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background

Increasing evidence has shown that the occurrence and development of various human diseases are closely related to the gut microbiota. We compared the gut microbial communities of human subjects with congenital insensitivity to pain with anhidrosis (CIPA) and healthy controls (HCs) to assess whether fecal microbiota transplantation (FMT) into germ-free mice and mice in acute pain influenced the behaviors of the host.

Methods

We utilized 16 s rRNA analysis to compare the gut microbial communities of CIPA subjects and HCs and assessed whether FMT into germ-free mice and mice in acute pain influenced the behaviors of the host.

Results

In a 16 s RNA analysis, the CIPA group had significant decreases in the relative abundance of 11 bacteria, whereas 7 bacteria were significantly increased. In further animal experiments, the transplantation of fecal samples from CIPA patients to healthy mice significantly increased their scores on both the mechanical withdrawal test and the tail flick test; in an acute plantar incision model, scores were also significantly increased on the mechanical withdrawal test at 4 and 5 days after the operation. Moreover, pseudo-germ-free mice receiving fecal bacteria from patients with CIPA took significantly longer to escape and had a significantly longer path length on training days 1, 2, and 5 and also had fewer platform crossings and spent less time in the target quadrant in the probe trial.

Conclusions

Our results suggest that the gut microbiota in CIPA subjects plays a key role in behaviors. Therapeutic strategies for improving the gut microbiota might alleviate CIPA symptoms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72

    Article  CAS  Google Scholar 

  • Brandwein M, Horev A, Bogen B, Fuks G, Israel A, Shalom G, Pinsk V, Steinberg D, Bentwich Z, Shental N, Meshner S (2020) The role of sweat in the composition of skin microbiome: lessons learned from patients with congenital insensitivity to pain with anhidrosis. J Eur Acad Dermatol Venereol 34:e183–e186

    Article  CAS  Google Scholar 

  • Brennan TJ, Vandermeulen EP, Gebhart GF (1996) Characterization of a rat model of incisional pain. Pain 64:493–502

    Article  Google Scholar 

  • Das V, Kroin JS, Moric M, McCarthy RJ, Buvanendran A (2019) Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain. Reg Anesth Pain Med

  • de Sousa MVP, Kawakubo M, Ferraresi C, Kaippert B, Yoshimura EM, Hamblin MR (2018) Pain management using photobiomodulation: Mechanisms, location, and repeatability quantified by pain threshold and neural biomarkers in mice. J Biophotonics 11:e201700370

    Article  CAS  Google Scholar 

  • Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108:3047–3052

    Article  Google Scholar 

  • Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20:145–155

    Article  CAS  Google Scholar 

  • Gao L, Guo H, Ye N, Bai Y, Liu X, Yu P, Xue Y, Ma S, Wei K, Jin Y, Wen L, Xuan K (2013) Oral and craniofacial manifestations and two novel missense mutations of the NTRK1 gene identified in the patient with congenital insensitivity to pain with anhidrosis. PLoS One 8:e66863

    Article  CAS  Google Scholar 

  • Geng X, Liu Y, Ren X, Guan Y, Wang Y, Mao B, Zhao X, Zhang X (2018) Novel NTRK1 mutations in Chinese patients with congenital insensitivity to pain with anhidrosis. Mol Pain 14:1744806918781140

    Article  CAS  Google Scholar 

  • Grimaldi R, Gibson GR, Vulevic J, Giallourou N, Castro-Mejía JL, Hansen LH, Leigh Gibson E, Nielsen DS, Costabile A (2018) A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome 6:133

    Article  Google Scholar 

  • Guo R, Chen LH, Xing C, Liu T (2019) Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth 123:637–654

    Article  CAS  Google Scholar 

  • Haga N, Kubota M, Miwa Z (2013) Epidemiology of hereditary sensory and autonomic neuropathy type IV and V in Japan. Am J Med Genet A 161a:871–4

    Article  Google Scholar 

  • Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fåk F, Jucker M, Lasser T, Bolmont T (2017) Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 7:41802

    Article  CAS  Google Scholar 

  • Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–1463

    Article  CAS  Google Scholar 

  • Indo Y (2018) NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis. Neurosci Biobehav Rev 87:1–16

    Article  CAS  Google Scholar 

  • Kim S, Jazwinski SM (2018) The Gut Microbiota and Healthy Aging: A Mini-Review. Gerontology 64:513–520

    Article  CAS  Google Scholar 

  • Kim YS, Unno T, Kim BY, Park MS (2020) Sex differences in gut microbiota. World J Mens Health 38:48–60

    Article  Google Scholar 

  • Kraetzer BB (2018) Editorial commentary: an alternative to opioids? adhesive drapes and chlorhexidine skin preparation may reduce propionibacterium acnes-related pain after shoulder surgery. Arthroscopy 34:1156–1157

    Article  Google Scholar 

  • Li R, Tun HM, Jahan M, Zhang Z, Kumar A, Dilantha Fernando WG, Farenhorst A, Khafipour E (2018) Author Correction: Comparison of DNA-, PMA-, and RNA-based 16S rRNA Illumina sequencing for detection of live bacteria in water. Sci Rep 8:17427

    Article  CAS  Google Scholar 

  • Li N, Guo S, Wang Q, Duan G, Sun J, Liu Y, Zhang J, Wang C, Zhu C, Liu J, Zhang X (2019) Heterogeneity of clinical features and mutation analysis of NTRK1 in Han Chinese patients with congenital insensitivity to pain with anhidrosis. J Pain Res 12:453–465

    Article  CAS  Google Scholar 

  • Lin YP, Su YN, Weng WC, Lee WT (2010) Novel neurotrophic tyrosine kinase receptor type 1 gene mutation associated with congenital insensitivity to pain with anhidrosis. J Child Neurol 25:1548–1551

    Article  Google Scholar 

  • Lv Y, Qin X, Jia H, Chen S, Sun W, Wang X (2019) The association between gut microbiota composition and BMI in Chinese male college students, as analysed by next-generation sequencing. Br J Nutr 122:986–995

    Article  CAS  Google Scholar 

  • Lynch SV, Pedersen O (2016) The Human Intestinal Microbiome in Health and Disease. N Engl J Med 375:2369–2379

    Article  CAS  Google Scholar 

  • Montiel-Castro AJ, González-Cervantes RM, Bravo-Ruiseco G, Pacheco-López G (2013) The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 7:70

    Article  CAS  Google Scholar 

  • Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O’Leary OF (2015) Adult Hippocampal Neurogenesis Is Regulated by the Microbiome. Biol Psychiatry 78:e7-9

    Article  Google Scholar 

  • Pogatzki EM, Raja SN (2003) A mouse model of incisional pain. Anesthesiology 99:1023–1027

    Article  Google Scholar 

  • Shatzky S, Moses S, Levy J, Pinsk V, Hershkovitz E, Herzog L, Shorer Z, Luder A, Parvari R (2000) Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet 92:353–360

    Article  CAS  Google Scholar 

  • Swanson AG (1963) Congenital insensitivity to pain with anhydrosis. A unique syndrome in two male siblings. Arch Neurol 8:299–306

    Article  CAS  Google Scholar 

  • Thompson AC, Feeney C, Kristal MB (2018) Amniotic-fluid ingestion enhances central δ-opioid-induced hypoalgesia in rats in the cold-water tail-flick assay in a repeated-measures design. Brain Res 1697:53–58

    Article  CAS  Google Scholar 

  • Udayashankar C, Oudeacoumar P, Nath AK (2012) Congenital insensitivity to pain and anhidrosis: a case report from South India. Indian J Dermatol 57:503

    Article  Google Scholar 

  • Vindigni SM, Surawicz CM (2017) Fecal Microbiota Transplantation. Gastroenterol Clin North Am 46:171–185

    Article  Google Scholar 

  • Wang J, Ye F, Cheng X, Zhang X, Liu F, Liu G, Ni M, Qiao S, Zhou W, Zhang Y (2016a) The Effects of LW-AFC on Intestinal Microbiome in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer’s Disease. J Alzheimers Dis 53:907–919

    Article  CAS  Google Scholar 

  • Wang QL, Guo S, Duan G, Ying Y, Huang P, Liu JY, Zhang X (2016b) Phenotypes and Genotypes in Five Children with Congenital Insensitivity to Pain with Anhidrosis. Pediatr Neurol 61:63–69

    Article  Google Scholar 

  • Wang T, Li H, Xiang J, Wei B, Zhang Q, Zhu Q, Liu M, Sun M, Li H (2017) Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis. J Int Med Res 45:549–555

    Article  CAS  Google Scholar 

  • Yang C, Fang X, Zhan G, Huang N, Li S, Bi J, Jiang R, Yang L, Miao L, Zhu B, Luo A, Hashimoto K (2019) Key role of gut microbiota in anhedonia-like phenotype in rodents with neuropathic pain. Transl Psychiatry 9:57

    Article  CAS  Google Scholar 

  • Yu F, Han W, Zhan G, Li S, Jiang X, Wang L, Xiang S, Zhu B, Yang L, Luo A, Hua F, Yang C (2019) Abnormal gut microbiota composition contributes to the development of type 2 diabetes mellitus in db/db mice. Aging (Albany NY) 11:10454–10467

    Article  CAS  Google Scholar 

  • Yuan M, Li D, Zhang Z, Sun H, An M, Wang G (2018) Endometriosis induces gut microbiota alterations in mice. Hum Reprod 33:607–616

    Article  CAS  Google Scholar 

  • Zhan G, Yang N, Li S, Huang N, Fang X, Zhang J, Zhu B, Yang L, Yang C, Luo A (2018) Abnormal gut microbiota composition contributes to cognitive dysfunction in SAMP8 mice. Aging (Albany NY) 10:1257–1267

    Article  CAS  Google Scholar 

  • Zhan G, Hua D, Huang N, Wang Y, Li S, Zhou Z, Yang N, Jiang R, Zhu B, Yang L, Yu F, Xu H, Yang C, Luo A (2019) Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota. Aging (Albany NY) 11:1778–1790

    Article  CAS  Google Scholar 

  • Zhu B, Shen J, Jiang R, Jin L, Zhan G, Liu J, Sha Q, Xu R, Miao L, Yang C (2020) Abnormalities in gut microbiota and serum metabolites in hemodialysis patients with mild cognitive decline: a single-center observational study. Psychopharmacology 237:2739–2752

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding for this study was supported by Mundipharma (China) Pharmaceutical Co., Ltd. (2017004), and the Natural Science Foundation Project of China (81974171). We thank Microeco Tech Co. Ltd. (Shenzhen, China), Myhalic Biotechnology Co., Ltd. (Wuhan, China), and Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) for technical help and support. The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Mi Zhang, Yishun Hong, Wenyao Wu, Ningbo Li, Baowen Liu, Jiaoli Sun, Xueqin Cao & Xianwei Zhang

  2. Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ting Ye

  3. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Ling Zhou, Cunming Liu & Chun Yang

Authors
  1. Mi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yishun Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenyao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ningbo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Baowen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiaoli Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueqin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ting Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ling Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cunming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xianwei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chun Yang or Xianwei Zhang.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 708 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, M., Hong, Y., Wu, W. et al. Pivotal role of the gut microbiota in congenital insensitivity to pain with anhidrosis. Psychopharmacology 238, 3131–3142 (2021). https://doi.org/10.1007/s00213-021-05930-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-021-05930-8

Keywords

Search

Navigation