Shigella and Guillain-Barré syndrome: Reconsidering an overlooked link

A recent outbreak of Guillain-Barré Syndrome (GBS) occurred in Pune, India, which renewed our attention to the significance of GBS for public health.¹ GBS is a clinical condition that involves impairment of peripheral nerves, leading to muscle weakness with symptoms typically lasting from hours to wks. GBS is rare and one of the most common causes of acute flaccid paralysis worldwide. GBS can be fatal in some cases, where respiratory muscle failure can cause difficulty in breathing and may lead to death.² Preceding bacterial or viral gastroenteritis or respiratory infections trigger GBS by a misdirected immune attack on peripheral nerves.³ Campylobacter jejuni has widely been reported as the commonest bacterial trigger of GBS.⁴ Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Mycoplasma pneumoniae, Hepatitis E virus (HEV), Zika virus, and even Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 have also been found to be associated with GBS cases.³ Enteric infections have been found to precede various GBS cases; however, the potential role of some enteric pathogens needs to be explored in-depth. The recent outbreak of GBS in India has raised many questions on public health measures, such as safe drinking water and continuous environmental surveillance of infectious pathogens. This outbreak resulted in over 200 reported cases and 23 deaths.¹ Outbreak investigation pointed to a contaminated water supply and preceding enteric infections such as acute gastroenteritis or diarrhoea as the cause of GBS. Two pathogens, mainly C. jejuni and Norovirus, were isolated from water and patient samples. An established clinical case history of progressive weakness with neurological symptoms pointed towards GBS and led to targeted testing of bacterial and viral pathogens linked to GBS by molecular methods. The hypothesis of recombinant Norovirus genotype with C. jejuni as the causative agent further led to viral RNA extraction, qRT-PCR, and whole genome sequencing to identify the Norovirus genotypes.⁵

We hypothesise that Shigella has the potential to cause GBS, and its role must be explored in detail. Shigella is endemic to India and has caused multiple outbreaks in the past. Moreover, Shigella can cause neurological complications, including peripheral neuropathy, and this has ignited our interest in the potential exploration of Shigella in GBS pathogenesis.^6-8 Shigella can induce febrile seizures, encephalopathy, and, in rare cases, Ekiri syndrome, a rapidly fatal encephalopathy which is associated with subgroup S. dysenteriae.⁹ Recent studies have reported neurological symptoms in 12-45% of paediatric shigellosis cases, suggesting that the neuroinvasive or neuroinflammatory potential of Shigella is higher than generally recognised.¹⁰ Moreover, reactive arthritis is also being reported as a post-infectious sequelae of dysentery, associated with S. dysenteriae type 1, some S. flexneri serotypes, and S. sonnei serogroup.¹¹

Historical and recent clinical evidence further support the neuro-immunological link of Shigella infection. In the year 1976, the GBS outbreak in Salt, Jordan, remains the most compelling evidence linking Shigella infection to the subsequent development of GBS. Khoury and colleagues¹² described an outbreak of gastroenteritis attributed to contamination of the municipal water supply. Nineteen cases developed GBS in this outbreak, and seventeen patients (89%) had clear gastrointestinal symptoms before the onset of neurologic symptoms. Among these, one patient had a stool culture positive for Shigella boydii, further confirming the Shigella-GBS link. The cerebrospinal fluid profile and clinical features were consistent with immune-mediated GBS. This case offers a critical clinical and microbiological linkage between Shigella infection leading to GBS.¹² Regaieg and colleagues¹³ also reported a case of GBS in a previously healthy adult who developed acute flaccid paralysis following a laboratory-confirmed Shigella flexneri infection. The patient presented with typical GBS features and required hospitalisation and supportive care.¹³

Leaver et al¹⁴ in a case report described peripheral neuropathy as a complication of Shigella flexneri infection with an increase in CSF proteins and globulin levels in patients, which are characteristically higher in GBS. Furthermore, decreased power in forearm muscles and areflexia in lower limbs were also reported further supporting the neurological link of infection by different Shigella species.¹⁴ Convulsions as an extraintestinal manifestation was reported in 10-45% of children suffering from acute Shigellosis.¹⁵ Similarly, in an outbreak of dysentery in Andaman and Nicobar Islands, India, convulsions was reported as one of the extraintestinal manifestations of Shigellosis.¹⁶ Another study from Southwestern Iran also showed a significant association between neurological manifestations and Shigellosis in children, with S. sonnei being the predominant species. Most of the children had tonic-clonic seizures and sudden loss of consciousness, however, the pathogenesis of these neurological manifestations after Shigella infection remains unclear.¹⁷

A retrospective cohort study from London, UK, focusing on severe shigellosis cases, also identified one patient who developed GBS following a confirmed Shigella infection. Although this study primarily addressed drug resistance and clinical outcomes in shigellosis, the documentation of GBS as a post-infectious complication highlighted that this association may not be limited to outbreak settings or specific geographic regions.¹⁸ Altogether, the above studies strengthen the Shigella-GBS association across diverse geographical regions and clinical cases.

These observations, though sporadic, are not incidental. They mirror the early trajectory of discovery that linked Campylobacter jejuni to GBS decades ago. Shigella’s repertoire of lipo-oligosaccharides (LOS) and outer membrane components warrants careful comparison to ganglioside-mimicking structures of Campylobacter. While the mechanisms of ganglioside mimicry are well-characterised in Campylobacter, analogous patterns in Shigella remain uncharacterised and need further investigation. This hypothesis of ganglioside mimicry warrants systematic in silico and immunological investigation.

Shigella is endemic to large populations living in low- and middle-income countries (LMICs) with low or no access to safe drinking water. The global burden of shigellosis is estimated at 80-165 million cases annually, with around 212,000 deaths, the majority of which occur in children below 5 yr.¹⁹ Without comprehensive microbial screening, the relative contribution of Shigella to GBS outbreaks remains invisible. Therefore, we advocate for a strategic re-orientation of GBS research and surveillance priorities. Firstly, Shigella testing should be integrated into GBS outbreak and case investigations in regions where it is endemic in nature. Secondly, systematic surveillance of pathogens in drinking water, especially in areas of poor hygiene, should be established. Moreover, molecular mimicry and serological studies comparing Shigella LOS epitopes with human gangliosides should be pursued to identify possible cross-reactive determinants. Finally, an interdisciplinary collaboration between neurologists, microbiologists, and public health researchers should be encouraged to get new insights into this translational gap. Recognising Shigella as a potential trigger of GBS is not merely academic but has clinical and policy implications as well. Shigella is endemic to India and has caused various epidemics in the past.^16,20 A large number of virulence factors, including invasion plasmid antigens secreted during Shigella infection, involving a complex mechanism of pathogenesis.²¹ Previous GBS outbreaks and case reports of Shigellosis have strengthened the Shigella-neuronal link. Various bioinformatics tools for better understanding cell surface structures and their receptors, should be carried out to explore the possible role of Shigella in GBS. The link between Shigella and GBS remains an underexplored frontier of neurological complications. Establishing the role of Shigella in GBS complications will aid in the early diagnosis and improved management of GBS outbreaks, particularly in LMICs. Metagenomic next-generation sequencing (mNGS) can be used to identify new potential threats causing such outbreaks in LMICs. Artificial intelligence-enabled machine learning platforms can be used for real-time monitoring of water sources which can provide information on potential threats and a quick response to such outbreaks in the future.