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Systemic sclerosis gastrointestinal dysmotility: risk factors, pathophysiology, diagnosis and management

Nature Reviews Rheumatology volume 19, pages 166–181 (2023)Cite this article

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An Author Correction to this article was published on 15 February 2023

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Abstract

Nearly all patients with systemic sclerosis (SSc) are negatively affected by dysfunction in the gastrointestinal tract, and the severity of gastrointestinal disease in SSc correlates with high mortality. The clinical complications of this dysfunction are heterogeneous and include gastro-oesophageal reflux disease, gastroparesis, small intestinal bacterial overgrowth, intestinal pseudo-obstruction, malabsorption and the requirement for total parenteral nutrition. The abnormal gastrointestinal physiology that promotes the clinical manifestations of SSc gastrointestinal disease throughout the gastrointestinal tract are diverse and present a range of therapeutic targets. Furthermore, the armamentarium of medications and non-pharmacological interventions that can benefit affected patients has substantially expanded in the past 10 years, and research is increasingly focused in this area. Here, we review the details of the gastrointestinal complications in SSc, tie physiological abnormalities to clinical manifestations, detail the roles of standard and novel therapies and lay a foundation for future investigative work.

Key points

  • Gastrointestinal disease in systemic sclerosis (SSc) is complex in its clinical presentation, physiology and mechanisms.

  • Data suggest that the neuromuscular pathways that control gastrointestinal motility are dysfunctional in SSc and are a target of the autoimmune response in some patients.

  • Identifying the part or parts of the gut affected and the type of gastrointestinal abnormality that is present can help to guide therapy.

  • The microbiome is probably an important contributor to gastrointestinal symptoms in SSc, although the extent of its involvement and the role of dysbiosis in diagnosis and guiding therapy are unclear.

  • Research is underway to better understand the mechanisms of gastrointestinal disease in SSc, and to optimize the approach to management.

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Fig. 1: Involvement of gastrointestinal motility in systemic sclerosis.
Fig. 2: The small intestine in health and in systemic sclerosis.

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References

  1. Steen, V. D. & Medsger, T. A. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 43, 2437–2444 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Richard, N. et al. Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality. Rheumatology 58, 636–644 (2019).

    Article  PubMed  Google Scholar 

  3. Gyger, G. & Baron, M. Systemic sclerosis: gastrointestinal disease and its management. Rheum. Dis. Clin. North. Am. 41, 459–473 (2015).

    Article  PubMed  Google Scholar 

  4. Kaniecki, T., Abdi, T. & McMahan, Z. H. A practical approach to the evaluation and management of gastrointestinal symptoms in patients with systemic sclerosis. Best Pract. Res. Clin. Rheumatol. 35, 101666 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jaovisidha, K., Csuka, M. E., Almagro, U. A. & Soergel, K. H. Severe gastrointestinal involvement in systemic sclerosis: report of five cases and review of the literature. Semin. Arthritis Rheum. 34, 689–702 (2005).

    Article  PubMed  Google Scholar 

  6. McMahan, Z. H. et al. Relationship between gastrointestinal transit, Medsger gastrointestinal severity, and University of California-Los Angeles scleroderma clinical trial consortium gastrointestinal tract 2.0 symptoms in patients with systemic sclerosis. Arthritis Care Res. 74, 442–450 (2022).

    Article  Google Scholar 

  7. Kawaguchi, Y. et al. Muscarinic-3 acetylcholine receptor autoantibody in patients with systemic sclerosis: contribution to severe gastrointestinal tract dysmotility. Ann. Rheum. Dis. 68, 710–714 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Lock, G. et al. Association of autonomic nervous dysfunction and esophageal dysmotility in systemic sclerosis. J. Rheumatol. 25, 1330–1335 (1998).

    CAS  PubMed  Google Scholar 

  9. Adler, B. L., Russell, J. W., Hummers, L. K. & McMahan, Z. H. Symptoms of autonomic dysfunction in systemic sclerosis assessed by the COMPASS-31 questionnaire. J. Rheumatol. 45, 1145–1152 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Furness, J. B., Callaghan, B. P., Rivera, L. R. & Cho, H. J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv. Exp. Med. Biol. 817, 39–71 (2014).

    Article  PubMed  Google Scholar 

  11. Kulkarni, S. et al. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis. Proc. Natl Acad. Sci. USA 114, E3709–E3718 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kulkarni, S. et al. Advances in enteric neurobiology: the “brain” in the gut in health and disease. J. Neurosci. 38, 9346–9354 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kulkarni, S. & Pasricha, P. J. Decoding the enteric nervous system: the beginning of our understanding of enteric neuromuscular disorders. Gastroenterology 160, 651–652 (2021).

    Article  PubMed  Google Scholar 

  14. McMahan, Z. H. et al. Anti-RNPC-3 (U11/U12) antibodies in systemic sclerosis in patients with moderate-to-severe gastrointestinal dysmotility. Arthritis Care Res. 71, 1164–1170 (2019).

    Article  CAS  Google Scholar 

  15. McMahan, Z. H., Paik, J. J., Wigley, F. M. & Hummers, L. K. Determining the risk factors and clinical features associated with severe gastrointestinal dysmotility in systemic sclerosis. Arthritis Care Res. 70, 1385–1392 (2018).

    Article  Google Scholar 

  16. Dein, E. et al. Evaluation of risk factors for pseudo-obstruction in systemic sclerosis. Semin. Arthritis Rheum. 49, 405–410 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ziessman, H. A., Jeyasingam, M., Khan, A. U., McMahan, Z. & Pasricha, P. J. Experience with esophagogastrointestinal transit scintigraphy in the initial 229 patients: multiple regions of dysmotility are common. J. Nucl. Med. 62, 115–122 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vigone, B. et al. Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study. Arthritis Res. Ther. 19, 145 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Karamanolis, G. P. et al. The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial. Arthritis Res. Ther. 18, 195 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. McMahan, Z. H. & Khanna, D. Managing gastrointestinal complications in patients with systemic sclerosis. Curr. Treat. Options Gastroenterol. 18, 531–544 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rigamonti, C. et al. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut 55, 388–394 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Morrisroe, K. et al. Gastric antral vascular ectasia in systemic sclerosis: a study of its epidemiology, disease characteristics and impact on survival. Arthritis Res. Ther. 24, 103 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Drokhlyansky, E. et al. The human and mouse enteric nervous system at single-cell resolution. Cell 182, 1606–1622.e1623 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Morarach, K. et al. Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA sequencing. Nat. Neurosci. 24, 34–46 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Jarret, A. et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 180, 813–814 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nickerson, A. J., Rottgen, T. S. & Rajendran, V. M. Activation of KCNQ (KV7) K+ channels in enteric neurons inhibits epithelial Cl– secretion in mouse distal colon. Am. J. Physiol. Cell Physiol. 320, C1074–C1087 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moreno, S. et al. Epithelial propionyl- and butyrylcholine as novel regulators of colonic ion transport. Br. J. Pharmacol. 173, 2766–2779 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fung, C. & Vanden Berghe, P. Functional circuits and signal processing in the enteric nervous system. Cell Mol. Life Sci. 77, 4505–4522 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Phillips, R. J. & Powley, T. L. Innervation of the gastrointestinal tract: patterns of aging. Auton. Neurosci. 136, 1–19 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kang, Y. N., Fung, C. & Vanden Berghe, P. Gut innervation and enteric nervous system development: a spatial, temporal and molecular tour de force. Development 148, dev182543 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Duan, H. et al. Regulation of the autonomic nervous system on intestine. Front. Physiol. 12, 700129 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Powley, T. L. Brain-gut communication: vagovagal reflexes interconnect the two “brains”. Am. J. Physiol. Gastrointest. Liver Physiol. 321, G576–G587 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Masliukov, P. M., Emanuilov, A. I. & Budnik, A. F. Sympathetic innervation of the development, maturity, and aging of the gastrointestinal tract. Anat. Rec. https://doi.org/10.1002/ar.25015 (2022).

    Article  Google Scholar 

  35. Mercado-Perez, A. & Beyder, A. Gut feelings: mechanosensing in the gastrointestinal tract. Nat. Rev. Gastroenterol. Hepatol. 19, 283–296 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Spencer, N. J. & Hu, H. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat. Rev. Gastroenterol. Hepatol. 17, 338–351 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kulkarni, S., Kurapati, S. & Bogunovic, M. Neuro-innate immune interactions in gut mucosal immunity. Curr. Opin. Immunol. 68, 64–71 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Dowling, L. R., Strazzari, M. R., Keely, S. & Kaiko, G. E. Enteric nervous system and intestinal epithelial regulation of the gut-brain axis. J. Allergy Clin. Immunol. 150, 513–522 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Vaes, N., Idris, M., Boesmans, W., Alves, M. M. & Melotte, V. Nerves in gastrointestinal cancer: from mechanism to modulations. Nat. Rev. Gastroenterol. Hepatol. 19, 768–784 (2022).

    Article  PubMed  Google Scholar 

  40. Holland, A. M., Bon-Frauches, A. C., Keszthelyi, D., Melotte, V. & Boesmans, W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol. Life Sci. 78, 4713–4733 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Agirman, G., Yu, K. B. & Hsiao, E. Y. Signaling inflammation across the gut-brain axis. Science 374, 1087–1092 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Zhao, Q. et al. A multidimensional coding architecture of the vagal interoceptive system. Nature 603, 878–884 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lagomarsino, V. N., Kostic, A. D. & Chiu, I. M. Mechanisms of microbial-neuronal interactions in pain and nociception. Neurobiol. Pain. 9, 100056 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Lai, N. Y. et al. Gut-innervating nociceptor neurons regulate Peyer’s patch microfold cells and SFB levels to mediate Salmonella host defense. Cell 180, 33–49 e22 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Lai, N. Y., Mills, K. & Chiu, I. M. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J. Intern. Med. 282, 5–23 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chang, H. Y., Mashimo, H. & Goyal, R. K. IV Current concepts of vagal efferent projections to the gut. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G357–G366 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Matzel, K. E., Stadelmaier, U., Hohenfellner, M. & Gall, F. P. Electrical stimulation of sacral spinal nerves for treatment of faecal incontinence. Lancet 346, 1124–1127 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Willemze, R. A. et al. Loss of intestinal sympathetic innervation elicits an innate immune driven colitis. Mol. Med. 25, 1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Muller, P. A. et al. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nature 583, 441–446 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schirmer, M. et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167, 1125–1136.e1128 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sato, Y. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature 599, 458–464 (2021).

    Article  CAS  PubMed  Google Scholar 

  52. Sjogren, R. W. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 37, 1265–1282 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Roberts, C. G., Hummers, L. K., Ravich, W. J., Wigley, F. M. & Hutchins, G. M. A case-control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma). Gut 55, 1697–1703 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. D’Angelo, W. A., Fries, J. F., Masi, A. T. & Shulman, L. E. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am. J. Med. 46, 428–440 (1969).

    Article  PubMed  Google Scholar 

  55. Howe, S. et al. Antimyenteric neuronal antibodies in scleroderma. J. Clin. Invest. 94, 761–770 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Singh, J. et al. Effects of scleroderma antibodies and pooled human immunoglobulin on anal sphincter and colonic smooth muscle function. Gastroenterology 143, 1308–1318 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Singh, J. et al. Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G1206–G1213 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Amaral, T. N., Peres, F. A., Lapa, A. T., Marques-Neto, J. F. & Appenzeller, S. Neurologic involvement in scleroderma: a systematic review. Semin. Arthritis Rheum. 43, 335–347 (2013).

    Article  PubMed  Google Scholar 

  59. Thoua, N. M., Schizas, A., Forbes, A., Denton, C. P. & Emmanuel, A. V. Internal anal sphincter atrophy in patients with systemic sclerosis. Rheumatology 50, 1596–1602 (2011).

    Article  PubMed  Google Scholar 

  60. Thoua, N. M., Abdel-Halim, M., Forbes, A., Denton, C. P. & Emmanuel, A. V. Fecal incontinence in systemic sclerosis is secondary to neuropathy. Am. J. Gastroenterol. 107, 597–603 (2012).

    Article  PubMed  Google Scholar 

  61. Plichta, D. R. et al. Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis. Genome Med. 13, 35 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kröner, P. T., Tolaymat, O. A., Bowman, A. W., Abril, A. & Lacy, B. E. Gastrointestinal manifestations of rheumatological diseases. Am. J. Gastroenterol. 114, 1441–1454 (2019).

    Article  PubMed  Google Scholar 

  63. Kaniecki, T., Abdi, T. & McMahan, Z. H. Clinical assessment of gastrointestinal involvement in patients with systemic sclerosis. Med. Res. Arch. 8, 2252 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kumar, S. et al. Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis. Aliment. Pharmacol. Ther. 45, 883–898 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McFarlane, I. M. et al. Gastrointestinal manifestations of systemic sclerosis. Rheumatology (Sunnyvale) 8, 235 (2018).

    Article  PubMed  Google Scholar 

  66. Bajraktari, I. H. et al. Oral manifestations of systemic sclerosis and correlation with anti-topoisomerase I antibodies (SCL-70). Med. Arch. 69, 153–156 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Jung, S., Martin, T., Schmittbuhl, M. & Huck, O. The spectrum of orofacial manifestations in systemic sclerosis: a challenging management. Oral. Dis. 23, 424–439 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Crincoli, V. et al. Orofacial manifestations and temporomandibular disorders of systemic scleroderma: an observational study. Int. J. Mol. Sci. 17, 1189 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Chu, C. H., Yeung, C. M., Lai, I. A., Leung, W. K. & Mok, M. Y. Oral health of Chinese people with systemic sclerosis. Clin. Oral. Investig. 15, 931–939 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Dagenais, M. et al. The Canadian Systemic Sclerosis Oral Health Study IV: oral radiographic manifestations in systemic sclerosis compared with the general population. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. 120, 104–111 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Auluck, A., Pai, K. M., Shetty, C. & Shenoi, S. D. Mandibular resorption in progressive systemic sclerosis: a report of three cases. Dentomaxillofac Radiol. 34, 384–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Abdouh, I. et al. Measuring the impact of systemic sclerosis on oral health-related quality of life in a UK population. J. Oral. Pathol. Med. 50, 812–819 (2021).

    Article  PubMed  Google Scholar 

  73. Baron, M. et al. The Canadian systemic sclerosis oral health study: orofacial manifestations and oral health-related quality of life in systemic sclerosis compared with the general population. Rheumatology 53, 1386–1394 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Raja, J., Ng, C. T., Sujau, I., Chin, K. F. & Sockalingam, S. High-resolution oesophageal manometry and 24-hour impedance-pH study in systemic sclerosis patients: association with clinical features, symptoms and severity. Clin. Exp. Rheumatol. 34, 115–121 (2016).

    PubMed  Google Scholar 

  75. Lock, G., Holstege, A., Lang, B. & Scholmerich, J. Gastrointestinal manifestations of progressive systemic sclerosis. Am. J. Gastroenterol. 92, 763–771 (1997).

    CAS  PubMed  Google Scholar 

  76. Lock, G. et al. Association of esophageal dysfunction and pulmonary function impairment in systemic sclerosis. Am. J. Gastroenterol. 93, 341–345 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Weston, S., Thumshirn, M., Wiste, J. & Camilleri, M. Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am. J. Gastroenterol. 93, 1085–1089 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Henry, M. A., Harbermann, M. C. & Rocha, O. M. Esophageal motor disturbances in progressive systemic sclerosis. Dis. Esophagus 12, 51–53 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Arif, T., Masood, Q., Singh, J. & Hassan, I. Assessment of esophageal involvement in systemic sclerosis and morphea (localized scleroderma) by clinical, endoscopic, manometric and pH metric features: a prospective comparative hospital based study. BMC Gastroenterol. 15, 24 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kahrilas, P. J. et al. The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol. Motil. 27, 160–174 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Yadlapati, R. et al. Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0. Neurogastroenterol. Motil. 33, e14058 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Aggarwal, N. et al. Spectrum of esophageal dysmotility in systemic sclerosis on high-resolution esophageal manometry as defined by Chicago classification. Dis. Esophagus 30, 1–6 (2017).

    Article  CAS  PubMed  Google Scholar 

  83. Roman, S. et al. Esophageal dysmotility associated with systemic sclerosis: a high-resolution manometry study. Dis. Esophagus 24, 299–304 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Adler, B., Hummers, L. K., Pasricha, P. J. & McMahan, Z. H. Gastroparesis in systemic sclerosis: a detailed analysis using whole-gut scintigraphy. Rheumatology 61, 4503–4508 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wegener, M., Adamek, R. J., Wedmann, B., Jergas, M. & Altmeyer, P. Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis. Dig. Dis. Sci. 39, 2209–2215 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Vettori, S. et al. Esophageal high-resolution impedance manometry alterations in asymptomatic patients with systemic sclerosis: prevalence, associations with disease features, and prognostic value. Clin. Rheumatol. 37, 1239–1247 (2018).

    Article  PubMed  Google Scholar 

  87. Ahuja, N. K. & Clarke, J. O. Scleroderma and the esophagus. Gastroenterol. Clin. North. Am. 50, 905–918 (2021).

    Article  PubMed  Google Scholar 

  88. Christmann, R. B., Wells, A. U., Capelozzi, V. L. & Silver, R. M. Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. Semin. Arthritis Rheum. 40, 241–249 (2010).

    Article  PubMed  Google Scholar 

  89. Orringer, M. B., Dabich, L., Zarafonetis, C. J. & Sloan, H. Gastroesophageal reflux in esophageal scleroderma: diagnosis and implications. Ann. Thorac. Surg. 22, 120–130 (1976).

    Article  CAS  PubMed  Google Scholar 

  90. Katzka, D. A. et al. Barrett’s metaplasia and adenocarcinoma of the esophagus in scleroderma. Am. J. Med. 82, 46–52 (1987).

    Article  CAS  PubMed  Google Scholar 

  91. Anilkumar, M., Alkhayyat, M., Grewal, U. S., Sanaka, M. R. & Thota, P. N. Higher risk of neoplastic progression of Barrett’s esophagus in patients with systemic sclerosis. Gastroenterol. Rep. 9, 595–596 (2021).

    Article  Google Scholar 

  92. Snyder, D. L. et al. Prevalence of Barrett’s esophagus in female patients with scleroderma. Am. J. Gastroenterol. 116, 517–521 (2021).

    Article  PubMed  Google Scholar 

  93. Hunt, R. H. et al. The stomach in health and disease. Gut 64, 1650–1668 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Chen, J. D. & McCallum, R. W. Clinical applications of electrogastrography. Am. J. Gastroenterol. 88, 1324–1336 (1993).

    CAS  PubMed  Google Scholar 

  95. Savarino, E. et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology 52, 1095–1100 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Gemignani, L. et al. Lactulose breath test to assess oro-cecal transit delay and estimate esophageal dysmotility in scleroderma patients. Semin. Arthritis Rheum. 42, 522–529 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Marie, I. et al. Delayed gastric emptying determined using the 13C-octanoic acid breath test in patients with systemic sclerosis. Arthritis Rheum. 64, 2346–2355 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Franck-Larsson, K., Hedenström, H., Dahl, R. & Rönnblom, A. Delayed gastric emptying in patients with diffuse versus limited systemic sclerosis, unrelated to gastrointestinal symptoms and myoelectric gastric activity. Scand. J. Rheumatol. 32, 348–355 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Chen, J. D., Schirmer, B. D. & McCallum, R. W. Serosal and cutaneous recordings of gastric myoelectrical activity in patients with gastroparesis. Am. J. Physiol. 266, G90–G98 (1994).

    CAS  PubMed  Google Scholar 

  100. McNearney, T., Lin, X., Shrestha, J., Lisse, J. & Chen, J. D. Characterization of gastric myoelectrical rhythms in patients with systemic sclerosis using multichannel surface electrogastrography. Dig. Dis. Sci. 47, 690–698 (2002).

    Article  PubMed  Google Scholar 

  101. McNearney, T. A. et al. Gastric slow waves, gastrointestinal symptoms and peptides in systemic sclerosis patients. Neurogastroenterol. Motil. 21, 1269–e1120 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Tack, J. Functional dyspepsia: impaired fundic accommodation. Curr. Treat. Options Gastroenterol. 3, 287–294 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Sridhar, K. R., Lange, R. C., Magyar, L., Soykan, I. & McCallum, R. W. Prevalence of impaired gastric emptying of solids in systemic sclerosis: diagnostic and therapeutic implications. J. Lab. Clin. Med. 132, 541–546 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Ghrénassia, E. et al. Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: a EUSTAR case-control study. J. Rheumatol. 41, 99–105 (2014).

    Article  PubMed  Google Scholar 

  105. Harrison, E., Herrick, A. L., McLaughlin, J. T. & Lal, S. Malnutrition in systemic sclerosis. Rheumatology 51, 1747–1756 (2012).

    Article  PubMed  Google Scholar 

  106. Caserta, L. et al. Assessment of intestinal permeability and orocecal transit time in patients with systemic sclerosis: analysis of relationships with epidemiologic and clinical parameters. Rheumatol. Int. 23, 226–230 (2003).

    Article  PubMed  Google Scholar 

  107. Medsger, T. A. et al. A disease severity scale for systemic sclerosis: development and testing. J. Rheumatol. 26, 2159–2167 (1999).

    PubMed  Google Scholar 

  108. Savarino, E. et al. Possible connection between gastroesophageal reflux and interstitial pulmonary fibrosis in patients with systemic sclerosis. Recent. Prog. Med. 100, 512–516 (2009).

    Google Scholar 

  109. Parodi, A. et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am. J. Gastroenterol. 103, 1257–1262 (2008).

    Article  PubMed  Google Scholar 

  110. Simrén, M. & Stotzer, P. O. Use and abuse of hydrogen breath tests. Gut 55, 297–303 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Quigley, E. M. Small intestinal bacterial overgrowth: what it is and what it is not. Curr. Opin. Gastroenterol. 30, 141–146 (2014).

    Article  PubMed  Google Scholar 

  112. Sachdev, A. H. & Pimentel, M. Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance. Ther. Adv. Chronic Dis. 4, 223–231 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kaye, S. A. et al. Small bowel bacterial overgrowth in systemic sclerosis: detection using direct and indirect methods and treatment outcome. Br. J. Rheumatol. 34, 265–269 (1995).

    Article  CAS  PubMed  Google Scholar 

  114. Feng, X., Li, X. Q. & Jiang, Z. Prevalence and predictors of small intestinal bacterial overgrowth in systemic sclerosis: a systematic review and meta-analysis. Clin. Rheumatol. 40, 3039–3051 (2021).

    Article  PubMed  Google Scholar 

  115. Marie, I., Ducrotté, P., Denis, P., Menard, J. F. & Levesque, H. Small intestinal bacterial overgrowth in systemic sclerosis. Rheumatology 48, 1314–1319 (2009).

    Article  PubMed  Google Scholar 

  116. Harrison, E., Herrick, A. L., McLaughlin, J. T. & Lal, S. An assessment of the nutritional status of patients with systemic sclerosis. Clin. Nutr. ESPEN 10, e177–e178 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Valenzuela, A. et al. Intestinal pseudo-obstruction in patients with systemic sclerosis: an analysis of the Nationwide Inpatient Sample. Rheumatology 55, 654–658 (2016).

    Article  PubMed  Google Scholar 

  118. Mecoli, C., Purohit, S., Sandorfi, N. & Derk, C. T. Mortality, recurrence, and hospital course of patients with systemic sclerosis-related acute intestinal pseudo-obstruction. J. Rheumatol. 41, 2049–2054 (2014).

    Article  PubMed  Google Scholar 

  119. Cheah, J. X. et al. Slow colonic transit in systemic sclerosis: an objective assessment of risk factors and clinical phenotype. Arthritis Care Res. https://doi.org/10.1002/acr.24767 (2021).

    Article  Google Scholar 

  120. Nagasako, K., Ota, Y., Sasaki, H. & Hamano, K. Progressive systemic sclerosis: report of a case with colonic involvement. Dis. Colon. Rectum 21, 364–368 (1978).

    Article  CAS  PubMed  Google Scholar 

  121. Trezza, M., Krogh, K., Egekvist, H., Bjerring, P. & Laurberg, S. Bowel problems in patients with systemic sclerosis. Scand. J. Gastroenterol. 34, 409–413 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Umar, S. B. et al. The impact of pelvic floor and lower gastrointestinal symptoms on quality of life in women with systemic sclerosis. J. Clin. Gastroenterol. 50, e55–e59 (2016).

    Article  PubMed  Google Scholar 

  123. Engel, A. F., Kamm, M. A. & Talbot, I. C. Progressive systemic sclerosis of the internal anal sphincter leading to passive faecal incontinence. Gut 35, 857–859 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jaffin, B. W., Chang, P. & Spiera, H. Fecal incontinence in scleroderma. Clinical features, anorectal manometric findings, and their therapeutic implications. J. Clin. Gastroenterol. 25, 513–517 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Richard, N. et al. Clinical correlates of faecal incontinence in systemic sclerosis: identifying therapeutic avenues. Rheumatology 56, 581–588 (2017).

    CAS  PubMed  Google Scholar 

  126. Fynne, L., Worsøe, J., Laurberg, S. & Krogh, K. Faecal incontinence in patients with systemic sclerosis: is an impaired internal anal sphincter the only cause. Scand. J. Rheumatol. 40, 462–466 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Fynne, L. et al. Distensibility of the anal canal in patients with systemic sclerosis: a study with the functional lumen imaging probe. Colorectal Dis. 15, e40–e47 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Rao, S. S., Rattanakovit, K. & Patcharatrakul, T. Diagnosis and management of chronic constipation in adults. Nat. Rev. Gastroenterol. Hepatol. 13, 295–305 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Vollebregt, P. F., Burgell, R. E., Hooper, R. L., Knowles, C. H. & Scott, S. M. Clinical impact of rectal hyposensitivity: a cross-sectional study of 2,876 patients with refractory functional constipation. Am. J. Gastroenterol. 116, 758–768 (2021).

    Article  PubMed  Google Scholar 

  130. Kim, K. C. et al. Anorectal dysfunction in systemic sclerosis. J. Korean Med. Sci. 11, 244–249 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sallam, H. S., McNearney, T. A. & Chen, J. Z. Anorectal motility and sensation abnormalities and its correlation with anorectal symptoms in patients with systemic sclerosis: a preliminary study. ISRN Gastroenterol. 2011, 402583 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Antoniou, A. J. et al. Comprehensive radionuclide esophagogastrointestinal transit study: methodology, reference values, and initial clinical experience. J. Nucl. Med. 56, 721–727 (2015).

    Article  PubMed  Google Scholar 

  133. Ahuja, N. K., Mische, L., Clarke, J. O., Wigley, F. M. & McMahan, Z. H. Pyridostigmine for the treatment of gastrointestinal symptoms in systemic sclerosis. Semin. Arthritis Rheum. 48, 111–116 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. Johnson, D. A. et al. Metoclopramide response in patients with progressive systemic sclerosis. Effect on esophageal and gastric motility abnormalities. Arch. Intern. Med. 147, 1597–1601 (1987).

    Article  CAS  PubMed  Google Scholar 

  135. Sarosiek, I. et al. Effect of domperidone therapy on gastroparesis symptoms: results of a dynamic cohort study by NIDDK gastroparesis consortium. Clin. Gastroenterol. Hepatol. 20, e452–e464 (2022).

    Article  CAS  PubMed  Google Scholar 

  136. Ou, L. B., Moriello, C., Douros, A. & Filion, K. B. Domperidone and the risks of sudden cardiac death and ventricular arrhythmia: a systematic review and meta-analysis of observational studies. Br. J. Clin. Pharmacol. 87, 3649–3658 (2021).

    Article  CAS  PubMed  Google Scholar 

  137. Sanger, G. J. & Furness, J. B. Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 38–48 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Fiorucci, S., Distrutti, E., Gerli, R. & Morelli, A. Effect of erythromycin on gastric and gallbladder emptying and gastrointestinal symptoms in scleroderma patients is maintained medium term. Am. J. Gastroenterol. 89, 550–555 (1994).

    CAS  PubMed  Google Scholar 

  139. Soudah, H. C., Hasler, W. L. & Owyang, C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N. Engl. J. Med. 325, 1461–1467 (1991).

    Article  CAS  PubMed  Google Scholar 

  140. Camilleri, M. Effects of somatostatin analogues on human gastrointestinal motility. Digestion 57, 90–92 (1996).

    Article  CAS  PubMed  Google Scholar 

  141. Hansi, N. et al. Consensus best practice pathway of the UK scleroderma study group: gastrointestinal manifestations of systemic sclerosis. Clin. Exp. Rheumatol. 32, S-214–S-221 (2014).

    Google Scholar 

  142. Nagaraja, V., McMahan, Z. H., Getzug, T. & Khanna, D. Management of gastrointestinal involvement in scleroderma. Curr. Treatm. Opt. Rheumatol. 1, 82–105 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Hughes, M. et al. Proton pump inhibitors in systemic sclerosis: a reappraisal to optimise treatment of gastro-oesophageal reflux disease. Lancet Rheumatol. 4, e795–e803 (2022).

    Article  CAS  Google Scholar 

  144. Foocharoen, C. et al. Prevalence and predictors of proton pump inhibitor partial response in gastroesophageal reflux disease in systemic sclerosis: a prospective study. Sci. Rep. 10, 769 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lombardo, L., Foti, M., Ruggia, O. & Chiecchio, A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin. Gastroenterol. Hepatol. 8, 504–508 (2010).

    Article  PubMed  Google Scholar 

  146. Yadlapati, R., Gyawali, C. P., Pandolfino, J. E. et al. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: expert review. Clin. Gastroenterol. Hepatol. 20, 984–994.e981 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Gyawali, C. P. et al. Modern diagnosis of GERD: the Lyon Consensus. Gut 67, 1351–1362 (2018).

    Article  PubMed  Google Scholar 

  148. Shirai, Y., Kawami, N., Iwakiri, K. & Kuwana, M. Use of vonoprazan, a novel potassium-competitive acid blocker, for the treatment of proton pump inhibitor-refractory reflux esophagitis in patients with systemic sclerosis. J. Scleroderma Relat. Disord. 7, 57–61 (2022).

    Article  PubMed  Google Scholar 

  149. Shibli, F., Kitayama, Y. & Fass, R. Novel therapies for gastroesophageal reflux disease: beyond proton pump inhibitors. Curr. Gastroenterol. Rep. 22, 16 (2020).

    Article  PubMed  Google Scholar 

  150. Foocharoen, C. et al. Effectiveness of add-on therapy with domperidone vs alginic acid in proton pump inhibitor partial response gastro-oesophageal reflux disease in systemic sclerosis: randomized placebo-controlled trial. Rheumatology 56, 214–222 (2017).

    Article  CAS  PubMed  Google Scholar 

  151. Koek, G. H., Sifrim, D., Lerut, T., Janssens, J. & Tack, J. Effect of the GABAB agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 52, 1397–1402 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Leiman, D. A. et al. Alginate therapy is effective treatment for GERD symptoms: a systematic review and meta-analysis. Dis. Esophagus 30, 1–9 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Malamood, M., Roberts, A., Kataria, R., Parkman, H. P. & Schey, R. Mirtazapine for symptom control in refractory gastroparesis. Drug. Des. Devel. Ther. 11, 1035–1041 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jubran, B. B., Bolduc, J., Eng, A., Stapleton, M. & Wilson, B. J. Off-label use of aprepitant for scleroderma-associated nausea and vomiting: a case report. J. Clin. Pharm. Ther. 44, 805–808 (2019).

    Article  PubMed  Google Scholar 

  155. Jehangir, A. & Parkman, H. P. Cannabinoid use in patients with gastroparesis and related disorders: prevalence and benefit. Am. J. Gastroenterol. 114, 945–953 (2019).

    Article  PubMed  Google Scholar 

  156. Tack, J., Janssen, P., Masaoka, T., Farré, R. & Van Oudenhove, L. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin. Gastroenterol. Hepatol. 10, 1239–1245 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Pittman, N. et al. Treatment of small intestinal bacterial overgrowth in systemic sclerosis: a systematic review. Rheumatology 57, 1802–1811 (2018).

    Article  CAS  PubMed  Google Scholar 

  158. Pazzi, P., Putinati, S., Bagni, B., Govoni, M. & Trotta, F. Bile acid malabsorption in progressive systemic sclerosis. Gut 29, 552–553 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Vijayvargiya, P. & Camilleri, M. Update on bile acid malabsorption: finally ready for prime time? Curr. Gastroenterol. Rep. 20, 10 (2018).

    Article  PubMed  Google Scholar 

  160. Corsetti, M. & Tack, J. New pharmacological treatment options for chronic constipation. Expert Opin. Pharmacother. 15, 927–941 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. Rao, S. S. C. Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation. Ther. Adv. Gastroenterol. 11, 1756284818777945 (2018).

    Article  Google Scholar 

  162. Fukudo, S. et al. High-dose linaclotide is effective and safe in patients with chronic constipation: a phase III randomized, double-blind, placebo-controlled study with a long-term open-label extension study in Japan. Neurogastroenterol. Motil. 31, e13487 (2019).

    Article  PubMed  Google Scholar 

  163. Farmer, A. D., Ruffle, J. K. & Hobson, A. R. Linaclotide increases cecal pH, accelerates colonic transit, and increases colonic motility in irritable bowel syndrome with constipation. Neurogastroenterol. Motil. 31, e13492 (2019).

    Article  PubMed  Google Scholar 

  164. Andresen, V. et al. Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 133, 761–768 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Lembo, A. J. et al. Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig. Dis. Sci. 56, 2639–2645 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Drossman, D. A. et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome — results of two randomized, placebo-controlled studies. Aliment. Pharmacol. Ther. 29, 329–341 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Miner, P. B. et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am. J. Gastroenterol. 112, 613–621 (2017).

    Article  CAS  PubMed  Google Scholar 

  168. Bassotti, G., Usai Satta, P. & Bellini, M. Plecanatide for the treatment of chronic idiopathic constipation in adult patients. Expert. Rev. Clin. Pharmacol. 12, 1019–1026 (2019).

    Article  CAS  PubMed  Google Scholar 

  169. Dein, E. J., Wigley, F. M. & McMahan, Z. H. Linaclotide for the treatment of refractory lower bowel manifestations of systemic sclerosis. BMC Gastroenterol. 21, 174 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Rao, S. S. Biofeedback therapy for constipation in adults. Best. Pract. Res. Clin. Gastroenterol. 25, 159–166 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Butt, S. K. et al. Lack of effect of sacral nerve stimulation for incontinence in patients with systemic sclerosis. Colorectal Dis. 17, 903–907 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Yin, J., Abell, T. D., McCallum, R. W. & Chen, J. D. Gastric neuromodulation with Enterra system for nausea and vomiting in patients with gastroparesis. Neuromodulation 15, 224–231 (2012).

    Article  PubMed  Google Scholar 

  173. Zhu, Y. et al. Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity. Am. J. Physiol. Gastrointest. Liver Physiol. 320, G700–G711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Gottfried-Blackmore, A. et al. Open-label pilot study: Non-invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis. Neurogastroenterol. Motil. 32, e13769 (2020).

    Article  PubMed  Google Scholar 

  175. Chen, J. D. Z., Ni, M. & Yin, J. Electroacupuncture treatments for gut motility disorders. Neurogastroenterol. Motil. 30, e13393 (2018).

    Article  CAS  PubMed  Google Scholar 

  176. McNearney, T. A., Sallam, H. S., Hunnicutt, S. E., Doshi, D. & Chen, J. D. Prolonged treatment with transcutaneous electrical nerve stimulation (TENS) modulates neuro-gastric motility and plasma levels of vasoactive intestinal peptide (VIP), motilin and interleukin-6 (IL-6) in systemic sclerosis. Clin. Exp. Rheumatol. 31, 140–150 (2013).

    PubMed  Google Scholar 

  177. Zhang, B. et al. Integrative effects and vagal mechanisms of transcutaneous electrical acustimulation on gastroesophageal motility in patients with gastroesophageal reflux disease. Am. J. Gastroenterol. 116, 1495–1505 (2021).

    Article  PubMed  Google Scholar 

  178. Liu, Z. et al. Preventive effects of transcutaneous electrical acustimulation on ischemic stroke-induced constipation mediated via the autonomic pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G293–G301 (2018).

    Article  PubMed  Google Scholar 

  179. Parrado, R. H., Lemus, H. N., Coral-Alvarado, P. X. & Quintana López, G. Gastric antral vascular ectasia in systemic sclerosis: current concepts. Int. J. Rheumatol. 2015, 762546 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Hoffmann-Vold, A. M. et al. Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial. BMJ Open. 11, e048541 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Raja, J., Nihtyanova, S. I., Murray, C. D., Denton, C. P. & Ong, V. H. Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatology 55, 115–119 (2016).

    Article  PubMed  Google Scholar 

  182. Hoffmann-Vold, A. M. & Volkmann, E. R. Gastrointestinal involvement in systemic sclerosis: effects on morbidity and mortality and new therapeutic approaches. J. Scleroderma Relat. Disord. 6, 37–43 (2021).

    Article  PubMed  Google Scholar 

  183. Clark, K. E., Etomi, O., Denton, C. P., Ong, V. H. & Murray, C. D. Intravenous immunoglobulin therapy for severe gastrointestinal involvement in systemic sclerosis. Clin. Exp. Rheumatol. 33, S168–S170 (2015).

    PubMed  Google Scholar 

  184. Kumar, S. et al. Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G1052–G1060 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Volkmann, E. R. & Hoffmann-Vold, A. M. Gastrointestinal tract microbiota modifications in systemic sclerosis. Eur. J. Rheumatol. 7, S228–S236 (2020).

    Article  PubMed  Google Scholar 

  186. Fretheim, H. et al. Fecal microbiota transplantation in systemic sclerosis: a double-blind, placebo-controlled randomized pilot trial. PLoS One 15, e0232739 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. de Groot, P. et al. Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial. Gut 70, 92–105 (2021).

    Article  PubMed  Google Scholar 

  188. Smillie, C. S. et al. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation. Cell Host Microbe 23, 229–240.e225 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Kong, L. et al. Linking strain engraftment in fecal microbiota transplantation with maintenance of remission in Crohn’s disease. Gastroenterology 159, 2193–2202.e2195 (2020).

    Article  CAS  PubMed  Google Scholar 

  190. Henke, M. T. et al. Ruminococcus gnavus, a member of the human gut microbiome associated with Crohn’s disease, produces an inflammatory polysaccharide. Proc. Natl Acad. Sci. USA 116, 12672–12677 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Henke, M. T. et al. Capsular polysaccharide correlates with immune response to the human gut microbe. Proc. Natl Acad. Sci. USA 118, e2007595118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. May-Zhang, A. A. et al. Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ. Gastroenterology 160, 755–770.e26 (2021).

    Article  CAS  PubMed  Google Scholar 

  193. Jarret, A. et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 180, 50–63.e12 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Baker, C. V. & Bronner-Fraser, M. Establishing neuronal identity in vertebrate neurogenic placodes. Development 127, 3045–3056 (2000).

    Article  CAS  PubMed  Google Scholar 

  195. Barki, N. et al. Chemogenetics defines a short-chain fatty acid receptor gut–brain axis. Elife 11, e73777 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Abdullah, N., Defaye, M. & Altier, C. Neural control of gut homeostasis. Am. J. Physiol. Gastrointest. Liver Physiol. 319, G718–G732 (2020).

    Article  CAS  PubMed  Google Scholar 

  197. Brookes, S. J., Spencer, N. J., Costa, M. & Zagorodnyuk, V. P. Extrinsic primary afferent signalling in the gut. Nat. Rev. Gastroenterol. Hepatol. 10, 286–296 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Serlin, H. K. & Fox, E. A. Neurotrophin-4 is essential for survival of the majority of vagal afferents to the mucosa of the small intestine, but not the stomach. Auton. Neurosci. 233, 102811 (2021).

    Article  CAS  PubMed  Google Scholar 

  199. Powley, T. L. et al. Vagal innervation of the stomach reassessed: brain-gut connectome uses smart terminals. Ann. N. Y. Acad. Sci. 1454, 14–30 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Chen, B. N., Olsson, C., Sharrad, D. F. & Brookes, S. J. Sensory innervation of the guinea pig colon and rectum compared using retrograde tracing and immunohistochemistry. Neurogastroenterol. Motil. 28, 1306–1316 (2016).

    Article  CAS  PubMed  Google Scholar 

  201. Kamitakahara, A., Wu, H. H. & Levitt, P. Distinct projection targets define subpopulations of mouse brainstem vagal neurons that express the autism-associated MET receptor tyrosine kinase. J. Comp. Neurol. 525, 3787–3808 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Megat, S. et al. Differences between dorsal root and trigeminal ganglion nociceptors in mice revealed by translational profiling. J. Neurosci. 39, 6829–6847 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Niu, X. et al. Mapping of extrinsic innervation of the gastrointestinal tract in the mouse embryo. J. Neurosci. 40, 6691–6708 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Gabella, G. in The Rat Nervous System 3rd edn (ed. Paxinos, G.) 77–109 (Academic Press, 2004).

  205. Browning, K. N. & Travagli, R. A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339–1368 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Benarroch, E. E. in Encyclopedia of the Neurological Sciences 2nd edn (eds Aminoff, M. J. & Daroff, R. B.) 805–808 (Academic Press, 2014).

  207. Maddern, G. J., Kiroff, G. K., Leppard, P. I. & Jamieson, G. G. Domperidone, metoclopramide, and placebo. All give symptomatic improvement in gastroesophageal reflux. J. Clin. Gastroenterol. 8, 135–140 (1986).

    Article  CAS  PubMed  Google Scholar 

  208. Chrysos, E. et al. Erythromycin enhances oesophageal motility in patients with gastro-oesophageal reflux. Anz. J. Surg. 71, 98–102 (2001).

    Article  CAS  PubMed  Google Scholar 

  209. Arts, J., Caenepeel, P., Verbeke, K. & Tack, J. Influence of erythromycin on gastric emptying and meal related symptoms in functional dyspepsia with delayed gastric emptying. Gut 54, 455–460 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Kao, C. H., Wang, S. J. & Pang, D. Y. Effects of oral erythromycin on upper gastrointestinal motility in patients with non-insulin-dependent diabetes mellitus. Nucl. Med. Commun. 16, 790–793 (1995).

    Article  CAS  PubMed  Google Scholar 

  211. Di Stefano, M. et al. Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers. Dis. Esophagus 25, 470–476 (2012).

    Article  PubMed  Google Scholar 

  212. Van Oudenhove, L., Kindt, S., Vos, R., Coulie, B. & Tack, J. Influence of buspirone on gastric sensorimotor function in man. Aliment. Pharmacol. Ther. 28, 1326–1333 (2008).

    Article  PubMed  Google Scholar 

  213. Scheerens, C., Tack, J. & Rommel, N. Buspirone, a new drug for the management of patients with ineffective esophageal motility? United European Gastroenterol. J. 3, 261–265 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Kumar, N., Barai, S., Gambhir, S. & Rastogi, N. Effect of mirtazapine on gastric emptying in patients with cancer-associated anorexia. Indian. J. Palliat. Care 23, 335–337 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Gooden, J. Y. & Takahashi, P. Y. Mirtazapine treatment of diabetic gastroparesis as a novel method to reduce tube-feed residual: a case report. J. Med. Case Rep. 7, 38 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Carbone, F., Vanuytsel, T. & Tack, J. The effect of mirtazapine on gastric accommodation, gastric sensitivity to distention, and nutrient tolerance in healthy subjects. Neurogastroenterol. Motil 29, https://doi.org/10.1111/nmo.13146 (2017).

  217. Omari, T. I. et al. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trial. J. Pediatr. 149, 468–474 (2006).

    Article  CAS  PubMed  Google Scholar 

  218. Andrews, P. L. & Wood, K. L. Systemic baclofen stimulates gastric motility and secretion via a central action in the rat. Br. J. Pharmacol. 89, 461–467 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Blonski, W., Vela, M. F., Freeman, J., Sharma, N. & Castell, D. O. The effect of oral buspirone, pyridostigmine, and bethanechol on esophageal function evaluated with combined multichannel esophageal impedance-manometry in healthy volunteers. J. Clin. Gastroenterol. 43, 253–260 (2009).

    Article  CAS  PubMed  Google Scholar 

  220. Dhar, S. I. et al. Effects of pyridostigmine on esophageal and pharyngeal motility in dysphagic patients undergoing high-resolution manometry. Dysphagia 37, 4–10 (2022).

    Article  PubMed  Google Scholar 

  221. Pasha, S. F., Lunsford, T. N. & Lennon, V. A. Autoimmune gastrointestinal dysmotility treated successfully with pyridostigmine. Gastroenterology 131, 1592–1596 (2006).

    Article  PubMed  Google Scholar 

  222. O’Dea, C. J., Brookes, J. H. & Wattchow, D. A. The efficacy of treatment of patients with severe constipation or recurrent pseudo-obstruction with pyridostigmine. Colorectal Dis. 12, 540–548 (2010).

    Article  PubMed  Google Scholar 

  223. Manini, M. L., Camilleri, M., Grothe, R. & Di Lorenzo, C. Application of pyridostigmine in pediatric gastrointestinal motility disorders: a case series. Paediatr. Drugs 20, 173–180 (2018).

    Article  PubMed  Google Scholar 

  224. Bharucha, A. E. et al. Pilot study of pyridostigmine in constipated patients with autonomic neuropathy. Clin. Auton. Res. 18, 194–202 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Schey, R. et al. Domperidone to treat symptoms of gastroparesis: benefits and side effects from a large single-center cohort. Dig. Dis. Sci. 61, 3545–3551 (2016).

    Article  CAS  PubMed  Google Scholar 

  226. Reddymasu, S. C., Soykan, I. & McCallum, R. W. Domperidone: review of pharmacology and clinical applications in gastroenterology. Am. J. Gastroenterol. 102, 2036–2045 (2007).

    Article  CAS  PubMed  Google Scholar 

  227. Shin, A. Patient considerations in the management of chronic constipation: focus on prucalopride. Patient Prefer. Adherence 10, 1373–1384 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Smart, C. J. & Malik, K. I. Prucalopride for the treatment of ileus. Expert. Opin. Investig. Drugs 26, 489–493 (2017).

    Article  CAS  PubMed  Google Scholar 

  229. Oustamanolakis, P. & Tack, J. Prucalopride for chronic intestinal pseudo-obstruction. Aliment. Pharmacol. Ther. 35, 398–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  230. Langworthy, J., Parkman, H. P. & Schey, R. Emerging strategies for the treatment of gastroparesis. Expert Rev. Gastroenterol. Hepatol. 10, 817–825 (2016).

    Article  CAS  PubMed  Google Scholar 

  231. Khanna, D. et al. Reliability and validity of the University of California, Los Angeles scleroderma clinical trial consortium gastrointestinal tract instrument. Arthritis Rheum. 61, 1257–1263 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Spiegel, B. M. et al. Development of the NIH patient-reported outcomes measurement information system (PROMIS) gastrointestinal symptom scales. Am. J. Gastroenterol. 109, 1804–1814 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Z.H.M.’s work is supported by funding from NIH/NIAMS K23 AR071473. D.K.’s work is supported by funding from K24 ARAR063120.

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Authors and Affiliations

  1. Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA

    Zsuzsanna H. McMahan

  2. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Subhash Kulkarni

  3. Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA

    Joan Chen & Jiande Z. Chen

  4. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

    Ramnik J. Xavier

  5. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA

    Ramnik J. Xavier

  6. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ramnik J. Xavier

  7. Division of Gastroenterology, Johns Hopkins University, Baltimore, MD, USA

    P. Jay Pasricha

  8. Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA

    P. Jay Pasricha

  9. Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA

    Dinesh Khanna

  10. University of Michigan Scleroderma Program, Ann Arbor, MI, USA

    Dinesh Khanna

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  1. Zsuzsanna H. McMahan
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  2. Subhash Kulkarni
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Contributions

All authors researched data for the article, made a substantial contribution to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Dinesh Khanna.

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Competing interests

J.C. declares that she is a consultant for Phathom Pharmaceuticals. R.J.X. declares that he is co-founder of Jnana Therapeutics and Celsius Therapeutics, a board member for Moonlake Immunotherapeutics and on the Scientific Advisory Board for Nestle. P.J.P. declares that he is co-founder of, holds equity in and is a consultant for Neurogastrx. D.K. declares that he has received consulting fees from Acceleron, Actelion, Amgen, Bayer, Boehringer Ingelheim, Chemomab, CSL Behring, Genentech/Roche, Horizon, Paracrine Cell Therapy, Mitsubishi Tanabe Pharma, Prometheus and Theraly. Z.H.M., S.K. and J.Z.C. declare no competing interests.

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Nature Reviews Rheumatology thanks G. Gyger, R. Naik and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

HealthMeasures: https://www.healthmeasures.net/

UCLA SCTC GIT 2.0 Questionnaire: http://bit.ly/UCLASCTCGIT

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McMahan, Z.H., Kulkarni, S., Chen, J. et al. Systemic sclerosis gastrointestinal dysmotility: risk factors, pathophysiology, diagnosis and management. Nat Rev Rheumatol 19, 166–181 (2023). https://doi.org/10.1038/s41584-022-00900-6

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