Colonizing foreign terrain: Insights into bacterial enteropathogens

In this present issue of the Biomedical Journal insights into pediatric campylobacteriosis are granted, and a potential path to developing a parenteral vaccine against enterotoxigenic E. coli is demonstrated. Additionally, a study shows how the use of extracorporeal shockwave therapy contributes to countering osteonecrosis of the femoral head. Furthermore, the relation between intimate partner violence and a saliva biomarker is explored. Finally, findings concerning the risk of dementia in patients with autonomic nervous system dysregulation are elucidated; and patterns of non-Alzheimer disease pathophysiology in individuals with depressive disorder are revealed.


Spotlight on reviews
Motecuhzoma II Xocoyotzin, the ninth Aztec ruler of the Mexican Empire, wielded a formidable reign that expanded the empire's borders into modern-day Honduras and Nicaragua at the dawn of the 16th century.However, discontent among subjected tribes grew as Motecuhzoma II imposed escalating demands for tribute and religious sacrifices.
During Motecuhzoma's rule, the initial encounter occurred with "visitors of the Old World," the Spanish conquistadores.The 500 Spanish colonizers arrived in the Aztec capital, Tenochtitlan, weary and ragged from previous battles and marches across challenging terrain.They were incredulously amazed at the opulence of the city, describing it as beyond anything they had ever heard, seen, or dreamed of before.In a gesture of hospitality, emperor Motecuhzoma offered lavish gifts to the invaders.Historical accounts of subsequent events have come under scrutiny, as contemporary perspectives suggest potential misunderstandings and misrepresentations of the Aztec civilization.Nevertheless, it seems that Motecuhzoma's diplomatic efforts were futile.He was eventually taken hostage by the leader of the Spanish conquistadores, Hernan Cortes.In the ensuing tumult between Aztec tribes and the Spanish, Motecuhzoma met a tragic end., 1 , 23  Cortes, though regarded as a skilled leader, faced a two-year struggle to conquer the Aztec capital.The key to his eventual success lay in a smallpox epidemic unleashed by the Spanish, decimating the native population by 40% within a single year.Smallpox, back then present in ancient Egyptian, Indian, and Chinese cultures, had traveled with the European crusaders to different parts of the world.The native people of the Americas were especially vulnerable to the virus as they had previously not been exposed to it. 4 Traveler's diarrhea (TD) is a common health concern for individuals exploring developing regions across Africa, Asia, and Latin America, such as backpackers, NGO volunteers, and deployed military personnel.The onset of TD typically occurs within the initial days of exposure to pathogens upon arrival, with bacterial infections accounting for 80-90% of cases and viral pathogens contributing to 2-15%.[1].Moreover, diarrheal ailments pose a significant public health challenge as a leading cause of morbidity and mortality among infants in affected areas.This unfortunate reality often stems from poor living conditions characterized by insufficient water supplies, inadequate environmental hygiene and sanitation, and a lack of access to educational resources.[2].Additionally, a connection exists between TD and post-infectious irritable bowel syndrome.[3].
Colloquially referred to as Moctezuma's or Montezuma's revenge, TD carries historical connotations linked to the belief that emperors possessed supernatural powers, capable of influencing the world even after their death.Some interpret the persistent prevalence of acute TD among visitors to Aztec lands as a symbolic message from Motecuhzoma, cautioning against the colonization of foreign lands.[4].
Peer review under responsibility of Chang Gung University.Bacterial enteropathogens tap into a variety of mechanisms that elicit diarrheal disease.Key culprits are among others Campylobacter spp.and various strains of E. coli.[5].
In this issue of the Biomedical Journal, Guo et al. explore potential risk factors and clinical manifestations of Campylobacteriosis in Taiwanese children under the age of five.[6].Campylobacteriosis encompasses various infectious diseases, with some strains posing a significant health threat.Campylobacter often stems from contaminated food or water.C. jejuni infection is identified as most prevalent in such cases.The pathogen is also notably linked to Guillain-Barré Syndrome.Moreover, HIV/AIDS patients worldwide face a heightened risk of clinical manifestations of campylobacter-associated diarrhea and bacteremia, leading to substantial mortality and morbidity compared to their HIV-negative counterparts.[7,8].
In a retrospective case-control study Guo et al. establish manifestations indicative of campylobacteriosis such as a shorter duration of vomiting, the presence of bloody and mucoid stools, and less elevated AST levels.Identified risk factors include low parental education, and consumption of takeout food and seafood.Conversely, potential protective factors consist in the intake of municipal water, milk, and soft beverages.[6].
The gut microbiota, a dynamic and diverse ecosystem, possesses the capability to impede the colonization and expansion of enteric pathogens -a property known as colonization resistance.However, the underlying mechanisms remain poorly understood.Regardless, pathogens seek to adapt to the inhospitable environment of the gastrointestinal system to access nutrients and express virulence factors.Consequently, they have evolved distinct strategies to ensure successful colonization.[3,11].
Each E. coli pathotype exhibits unique pathogenicity mechanisms characterized by a specific profile of virulence factors encoded in distinct gene clusters.These genes may be associated with activities such as adhesion f. i. to mucus and cell surface receptors, invasion, iron acquisition, motility such as the expression of flagella to navigate the mucus layer, or the production of proteases and toxins(Fig.1).Additionally, nutrient sensing systems significantly contribute to infection.In the past, ETEC was considered the most widespread pathogenic E. coli strain.However, the contemporary landscape reveals a shift with EPEC and EAEC now emerging as the prevailing forces.Understanding underlying molecular virulence factors enables the implementation of preventive strategies against specific pathotypes.[1,12,13].
EPEC's causes attaching and effacing (A/E) lesions in the intestinal epithelium, thus destroying microvilli.Intimin is an outer membrane protein facilitating A/E lesions in EHEC and EPEC in conjunction with the translocated intimin receptor (Tir).To infect adults, a substantial

R. Yong
bacterial load of 10 8 -10 10 is required.In liquid culture, EPEC forms tight bacterial aggregates.Upon small intestine infection, it adheres diffusely, creating a cup-like pedestal structure on the enterocyte membrane.Dense plaques of actin and cytoskeletal filaments form beneath the bacteria.EPEC employs a sophisticated quorum sensing mechanism, particularly involving flagellar motility to regulate virulence and facilitate host colonization.[14][15][16][17].
ETEC uses flagella for initial attachment to the host cell, and produces major virulence factors such as colonization factors (CFs), and heat-labile (LT) or heat-stable (ST) enterotoxins.These toxins bind to specific epithelial receptors, and the interplay of motility, host cell contact, and adhesion are essential for effective toxin delivery.LT facilitates intestinal colonization through exerting an impact on the cell membrane surface charge, on antimicrobial peptide as well as adhesin expression.Enterotoxin activity induces water and electrolyte secretion, leading to rapid dehydration and prostration.ETEC strains exhibit high genetic diversity, with the maintenance of virulence traits heavily driven by selective pressure.[3,12,16,17].
EIEC is an obligate intracellular pathogen with neither adherence nor flagella factors.The bacteria gain access to the enterocytes after escaping from macrophages and dendritic cells from the basolateral side, and then replicating in the cytoplasm.Diarrhea is caused by the invasion and destruction of enterocytes.The complex colonization process and EIEC survival depends on presence of a large plasmid, which led to the assumption that EIEC shares a common ancestor with Shigella.However EIEC requires a higher infectious dose than Shigella.The pathogen captures iron to facilitate development of infectious processes, and suppresses host immune response by using protein effectors.[12,16].
EHEC/STEC produces the Shiga toxin (Stx), and also induces A/E lesions.It targets the large intestine, manifesting symptoms ranging from mild to severe, including hemorrhagic colitis and potentially lifethreatening hemolytic uremic syndromes.Stx damages eukaryotic ribosomes, and binds to the Gb3 cellular receptor primarily present in endothelial cells.The toxin is able to assail endothelial, kidney, and brain cells.EHEC's low infectious dose leads to the pathogen highly relying on sensing multiple signals to coordinate virulence gene expression.EHEC appears to engage in cross-communication with the host's epinephrine signaling system.It furthermore senses a gluconeogenic versus glycolytic environment, and employs fucose sensing to finetunes its colonization strategy.[13,15,16,[18][19][20][21].
The very heterogeneous EAEC strains share three traits: abundant adherence to intestinal mucosa, secretion of enterotoxins and cytotoxins, and the induction of mucosal inflammation.In culture, EAEC displays an aggregative adherence (AA) pattern, forming a biofilm with a thick mucus layer, that possibly facilitates persistent colonization.The stacked-brick lattice structure intervenes cell growth surface.EAEC is able to attach to jejunal, ileal, and colonic epithelium.Autotransporter proteins are important contributors to EAEC's virulence.EAEC may incite asymptomatic colonization, entailing chronic intestinal inflammation, malnutrition, and impaired growth in children.It often manifests as watery diarrhea with mucus, showing acute self-limiting characteristics, and with potential genetic susceptibility in specific traveler groups.[16,22].

A colonization factor derived vaccine
In the current journal issue, Zhou and colleagues investigate the prevalent colonization factor antigen I (CFA/I) of ETEC.The use of antibodies targeting CFA/I demonstrated efficacy in inhibiting ETEC adherence and preventing diarrhea.The team opted for soluble, recombinant antigens derived from CFA/I, incorporating a vaccine adjuvant.Their study in mice revealed that cobalt-porphyrin phospholipid (CoPoP)/synthetic monophosphoryl lipid A (PHAD) liposomes offered a promising route for the development of parenterally-delivered subunitbased ETEC vaccines.Utilizing CF-derived antigens in immunogenic particle-based formulations proved thus successful in eliciting immunogenicity.[23].

Original articles 2.1.1. Wave of change: countering osteonecrosis
Avascular necrosis, also known as osteonecrosis, of the femoral head (ONFH) arises from compromised blood supply, leading to the demise of osteocytes and bone marrow.Non-surgical interventions encompass protective weight-bearing, and the application of biophysical modalities, such as extracorporeal shock waves and pulsed electromagnetic fields, albeit with limited success.[24].
In their study, Hsu et al. made use of extracorporeal shockwave therapy (ESWT), adipose-derived mesenchymal stem cells (ADSCs), and combination therapy to modulate pro-inflammatory cytokines in earlystage rat ONFH.The innovative approach not only showcased significant preservation of articular cartilage and subchondral bone but also demonstrated a notable regulation of IL33 and its receptor ST2.This was achieved by decrease of hypertrophic chondrocytes and enhancement of structural integrity.[25].Unlike most cytokines, IL33 emerges as an alarmin, and passively released during cell necrosis or tissue damage.This suggests its role as a sentinel, alerting the immune system to endothelial or epithelial cell damage during instances of infection, physical stress, or trauma.[26].

Health implications of a rising shadow pandemic
In the wake of the COVID-19 pandemic, the world witnessed a profound impact on numerous layers of society.The implementation of stringent measures, such as lockdowns, stay-at-home orders, and social distancing gave rise to an insidious phenomenon known as the shadow pandemic.This term encapsulates the alarming escalation of violence against women and girls, particularly in the realm of domestic abuse perpetrated by intimate partners.The confluence of gender-based violence and preventive confinement measures created a perilous environment, facilitating perpetrators in controlling and isolating their victims.Simultaneously, women and girls found themselves with diminished access to essential life-saving services, including counseling, legal guidance, sexual health resources, crucial medical assistance as well as the provision of refuge., 56 In comparison to the past two decades, the number of femicides reached peak-levels in 2022, even as overall homicide numbers decline. 7 Exploring the intricate relation between intimate partner violence (IPV) and coping mechanisms, Ramesh et al. shed light on a potentially overlooked aspect.The research posits that some women that experience IPV turn to smoking as a means of coping.Utilizing saliva as a biomarker, the study unveils the detection of benzo(a)pyrene [B(a)P] metabolites in IPV-affected female patients.This discovery marks the first instance where IPV is implicated in the accumulation of B(a)P in the oral cavity, subsequently triggering inflammatory cascades that potentially exacerbate adverse health outcomes within this vulnerable patient population.[27]. 5https://www.unwomen.org/en/news/in-focus/in-focus-gender-equality-incovid-19-response/violence-against-women-during-covid-19,last access 11/ 24/2023. 6 As pivotal player in a number of cardiovascular diseases, dysregulation of the autonomic nervous system prompts an exploration of various neuromodulatory techniques.This pursuit seeks to enhance the management of cardiovascular disorders by strategically countering the remodeling processes inherent in disease states.[28].The far-reaching implications of autonomic nervous system dysregulation extend beyond cardiovascular domains, serving as a noteworthy predictor for diabetes, and demonstrating an association with the metabolic syndrome.[29].Perceived stress, a ubiquitous force in modern life, impacts the neuroendocrine system in a multifaceted way.Through experience-dependent plasticity, stress may induce nervous system dysregulation, finally contributing to the complex web of physiological imbalances.[30].
Delving into the depths of aging and cognitive health, Chou et al. conducted a retrospective study spanning a follow-up period of 17 years.They put a focus on unraveling the connection between altered autonomic modulation, as measured by heart rate variability (HRV), and the risk of dementia in the elderly.The study suggests that a lower parasympathetic activity, coupled with a higher sympathetic vagal imbalance, correlates with an elevated risk of dementia.These findings not only elucidate the connection between autonomic modulation and cognitive health, but furthermore offer a potential avenue for early prevention and intervention strategies.[31].

The black dog barking from breakfast to dinner
Major depressive disorder, a common mental disorder impacting approximately 5% of adults globally, manifests in episodes that profoundly disrupt various facets of life.During these episodes, individuals may experience loss of pleasure, or interest in once-enjoyed activities.Depression may entail self-harm. 8The weight of major depression is further compounded by societal stigmatization.[32].Historically, the English writer Samuel Johnson coined the term "black dog" to encapsulate his experience of clinical depression. 9In a poignant letter, Winston Churchill bemoaned his inability to banish this metaphorical black dog from his companionship. 10 Examining late-life major depressive disorder (MDD), Wu et al. propose the concept of suspected non-Alzheimer disease pathophysiology (SNAP) for a considerable subset of individuals.Their research reveals discernible patterns of atrophy extending beyond the hippocampus, coupled with hypometabolism affecting significant portions of the lateral and medial prefrontal cortex in patients with late-life MDD with SNAP.[33].

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Declaration of competing interest
The author declares no conflict of interests.