Helecobacter. suis vs Helecobacter pylori: The Brain-Gut axis and neurological disorders : A systemic review

The human microbiota is composed of trillions of symbiotic microbial cells that reside both in and on our bodies, with the majority located in the gastrointestinal tract (1-4). These commensal microorganisms play crucial roles in maintaining our health and well-being. They are responsible for various essential functions, including the digestion of food (5-6), the activation of specific pharmaceuticals (4), and the prevention of infections by outcompeting pathogenic microorganisms (7-9). Additionally, there is evidence to suggest that these microbes may contribute to the maturation and regulation of the immune system, thereby influencing our overall immune responses (10-11). Their diverse functions underscore the importance of a balanced microbiota for human health.

For decades, the intricate relationship between changes in the gastrointestinal microbiota and a diverse array of health challenges has captured our attention, revealing connections to rheumatoid arthritis, inflammatory bowel diseases, asthma, and cancer (12–17). Furthermore, the impact of gastrointestinal transformations on neurological disorders—such as depression, anxiety, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS)—has unveiled new realms of understanding (18–29). The recent discovery of the microbiome–gut–brain axis highlights the profound ways in which the gut microbiome influences our brains, inspiring new possibilities for health and wellness (30–34).

The complex interplay between the microbiota and the brain can be categorized into four distinct pathways:

1. Neuronal Route, This pathway involves the enteric nervous system and the vagus nerve, both of which serve as direct communication channels between the gut and the brain. The enteric nervous system functions as a second brain, capable of operating independently while also transmitting signals to the central nervous system via the vagus nerve (35).
2. Endocrine Route, This pathway primarily involves hormonal signals, such as cortisol, which is released in response to stress and influences both gut health and brain function. Hormones produced in the gut can also affect mood and cognitive processes through their interaction with the brain (35.36).
3. Metabolic Route, This route highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs) and tryptophan, in modulating brain function. SCFAs, produced through the fermentation of dietary fibers by gut bacteria, have been shown to impact inflammation and neuronal health, while tryptophan is a precursor to serotonin, a key neurotransmitter involved in mood regulation (35.36).
4. Immunological Route, In this pathway, cytokines and immune cells play a crucial role in mediating the communication between the gut and the brain. The immune response triggered by gut microbiota can influence neuroinflammation and thus affect cognitive and emotional processes. Furthermore, the composition of gut microbiota itself is not static; it can be altered by various factors, including diet and antibiotic use. These changes in microbial diversity and abundance can indirectly influence gut-brain signaling, impacting overall mental health and cognitive function (35).

This intricate relationship underscores the critical role of the microbiota in not only digestive health but also in psychological well-being and neurological disorders.

H.Pylori and neurological disorders correlation

Helicobacter pylori, a Gram-negative, spiral-shaped microorganism, colonizes the stomach of over half of the global human population, albeit with significant geographical variations. Apart from being a well-established cause of gastritis and peptic ulcer disease, H. pylori infection has also been linked to mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma, as well as various neurological disorders. Despite the activation of both innate and adaptive immune responses in individuals infected with H. pylori, the host is typically unable to eradicate the bacterium, resulting in a chronic and lifelong infection (37,38).

To evade the host’s immune defenses and survive in the harsh gastric environment, H. pylori has developed multiple strategies, including manipulation of innate immune receptors and inhibition of effector T-cell responses (39,40). The efficacy of these immune evasion mechanisms is contingent upon the presence or absence of specific bacterial virulence factors (39). The immune response elicited by the host can lead to localized secretion of various inflammatory mediators, such as interleukin (IL)-8, IL-6, IL-1β, IL-10, IL-12, tumor necrosis factor (TNF), and interferon (IFN)-γ, which may subsequently enter systemic circulation and induce further systemic effects (41,42). The persistence of significant local and systemic levels of these pro-inflammatory factors may contribute to neuroinflammation and neurotoxicity (41).

Moreover, H. pylori infection is associated with the release of several neurotransmitters, including acetylcholine, adrenaline, noradrenaline, serotonin, and dopamine (43,44). This infection may also lead to axonal and neuronal damage, the production of free radicals, and alterations in neuropeptide expression, such as vasoactive intestinal peptide (VIP) and c-fos (43) Additionally, H. pylori infection is correlated with changes in the composition of the gastrointestinal microbiome, which could potentially affect the progression and outcomes of neurological disorders, as illustrated in the accompanying figure (43,45):

Seropositivity for Helicobacter pylori has been associated with significant adverse health outcomes, including poor cognitive performance (46), neurologic impairment (47), and cerebrovascular disease (48), positioning it as a substantial risk factor for the development of dementia (21,49). The relationship between H. pylori and Parkinson's disease underscores the necessity of addressing this infection (41,51,52); it not only increases the likelihood of developing the disorder but also demonstrates potential for improvement in motor symptoms following eradication (53,54). Furthermore, the influence of H. pylori on the bioavailability of L3,4-dihydroxyphenylalanine (L-DOPA) emphasizes the critical link between gastrointestinal health and effective management of Parkinson’s disease (52,55).

Additionally, the association of H. pylori with Alzheimer’s disease (56,57,58,59), reveals further implications, as infection is linked to mild cognitive impairment and cognitive decline (60,61). Notably, the eradication of H. pylori has been reported to enhance cognitive and functional abilities (62,63).

In the domain of multiple sclerosis (MS), it is noteworthy that H. pylori is found less frequently in affected individuals compared to healthy controls, suggesting a potentially beneficial role in this context (64,65). Evidence indicates that infected mice exhibit reduced clinical signs compared to non-infected counterparts (66), which calls for further exploration into the intricate interactions between this bacterium and various neurological disorders, with the aim of fostering innovative approaches to treatment and a deeper understanding of these complex relationships.

The human stomach houses a complex ecosystem that includes not only Helicobacter pylori but also a diverse array of microorganisms, digestive enzymes, and other factors that contribute to overall gastrointestinal health and function

Following the identification of H. pylori, numerous other gastric species within the genus Helicobacter have been documented. These non-H. pylori Helicobacter (NHPH) species have been identified in the stomachs of various hosts, such as pigs, dogs, cats, and non-human primates, with some exhibiting zoonotic potential (67,68). The most common gastric NHPH species found in humans is Helicobacter suis, which naturally inhabits the stomachs of pigs and non-human primates (67.68). This bacterium is of zoonotic significance, affecting approximately

0.2–6% of the human population and is linked to conditions such as gastritis, peptic ulcers, and MALT lymphoma (67). However, as some infections with this microorganism remain asymptomatic, the actual prevalence in humans is likely underestimated (67).

Additionally, these spiral-shaped bacteria may not always be detected in the human stomach following the examination of small biopsy samples due to their focal and patchy colonization pattern (67, 69-71). Similar to H. pylori, H. suis can result in a chronic infection associated with a tolerogenic immune response (24,72).

There is a notable lack of literature regarding the relationship between NHPH infections and neurological disorders. In fact, no studies have been published that explore the connection between NHPH and neurodegenerative or immunological disorders such as amyotrophic lateral sclerosis, spinocerebellar degeneration, acute disseminated encephalomyelitis, and GuillainBarre syndrome. One study indicated that mice infected with Helicobacter felis exhibited both gastric and neuroinflammation (73). Another investigation revealed a significantly higher presence of H. suis DNA (27%) in gastric biopsies from patients with idiopathic Parkinson’s disease compared to a control group without clinical symptoms of Parkinson’s disease (2%)(74).

Unlike other zoonotically significant gastric NHPH species, H. suis DNA was detected in a blood sample from a patient suffering from both Parkinson’s and Alzheimer’s diseases. Following the successful treatment of the H. suis infection, there was a significant improvement in the patient's gastric and neurological symptoms (74). Furthermore, recent studies have associated H. suis infection in Parkinson’s patients with increased mortality rates (75). To date, there are no other publications that explore the involvement of H. suis in neurological conditions.

In this discussion, we will explore various potential mechanisms through which H. suis may impact brain function, as illustrated in Figure 1B. The first section will address the inflammatory changes occurring in the stomach and their potential effects on the brain through systemic circulation, while the second section will focus on the alterations caused by H. suis virulence factors and their implications for the microbiome.

Immune responses and GIT Barrier reactions to H.Suis infection 

According  to (72, 76–78), an evident gastritis has been noticed and closely linked to H. Suis infection in mice and pigs. Such infection is set apart by the higher expression of IL-8,-10,-1b, and-4,keratinocytechemoattractant (KC), lipopolysaccharide-induced CXC chemokine (LIX), and macrophage inflammatory protein (MIP2) depending on the host.  This process result in a consequent Th2 response secondary to infiltration of B-and T-cells and macrophages in pigs and mice.

Gastritis is complicated  by mucosal edema (67) and gastric epithelial cell death (79), all of which lead to bad impacts of  the integrity of the gastrointestinal (GIT) barrier.

The GIT barrier compose of two layers: First is the epithelial cell sheet, connected by firm junctions, and second is the mucus layer.

In pigs, significant down regulation of claudin 18 (CLDN18) was found in the gut of H. suis infected animals (72). In a recent mouse study, we found increased permeability of the GIT barrier subsequent to H. suis infection, followed by increased expression of mucine 13 (Muc13) and abnormal localization of zonula occludens 1 (ZO1) (77). This further progressed to becteremia, characterized by the leakage of TLR4 ligands into the blood stream, affecting the brain homeostasis through the blood–cerebrospinal fluid barrier (77).

Consequently, TLR4 ligands, also IL1b was found in the serum of H. suis-infected mice, which is clinically manifested as sickness behavior due to inflammatory gene expression in the hippocampus and hypothalamus (80). As discussed below, and as a result of leaky gut, also other molecules that are observed in the stomach upon H. suis infection might affect the brain when reaching the systemic circulation.

In addition, a Th17 response has been linked with H. suis infection in the different hosts including mice, gerbils, pigs, and humans, characterized by the presence of Th17 cells and/or increased levels of IL-17 in the gut to the Th2 response (76, 78, 81, 82).

In humans, significantly, IL-17 is known to block adult hippocampus neurogenesis (83) and is associated to depression in MS (84). Moreover,  a specific increased levels of IFN-g were found in the stomach of H. suis infected gerbis (81). IFN-g is shown to be a regulator of the neural precursor pool in the healthy brain (85). However, in the inflamed brain with H.Suis, the IFN-g is associated reduced proliferation and viability of oligodendroglial cells with a consequent brain neuronal demyelination  (86, 87).

Further studies explored that increased levels of lymphotoxin (LT)-a and-b in the stomach of mice is linked to H. suis infection (88). These cytokines play a vital role in the generation of follicular dendritic cells and also regulate neuronal and glial lineage differentiation (89,90).

In addition, Lymphotoxins play a role in MS, causing demyelination due to oligodendrocyte toxicity (91). Blocking lymphotoxin in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, minimise disease symptoms linked with minor levels of the chemokine CXCL13 (92). This chemokine plays a role in the position of B-cells and its expressionis increased in the gut after H.suis infection in pigs, mice, and gerbils (72, 81), as are other chemokines such as C X-C motif chemokine receptor (CXCR) 7, 15 and 4, C-C motif chemokine ligand (CCL) 19 and 21, and C-X-C motif chemokine ligand12(CXCL12)(88).

Higher levels of CXCL13 have been observed in B-cell aggregates in the inflamed meninges in case of MS (92), and link with demyelination, neural cell loss, and rapid disease progression (93).

Metabolic changes due to H.suis virulence 

The GIT tissue can be damaged by H.suis virulence factor known as g-glutamyl transpeptidase (GGT) which harmfully affect the normal function of glutamine and glutathione which are precursors responsible foe healthy GIT (81,82,94). Besides, Glutamine and glutathione are  precursors for the neurotransmitters glutamate, aspartate, and g-amino butyric acid (GABA), which are important neurotransmitters in the brain (95). Thus, reduction of glutamine, caused by H. suis infection, might lead to changes in these neurotransmitters, and the gut–brain signaling.

It is crucial to address that infection with H.suis can convert urea to ammonia by urease activity (96,97). Therefore, a consequent abnormal and high level of ammonia result in encephalopathy and severe neuropsychological symptoms (98,99).  Also, H.suis can make alteration in the  H+/K+ ATPase and subsequent changes in pH, which is associated with more fluid gastric content (72), and subsequently influence the gastric normal flora.

Lastly, in infected pigs, reseracheres found that Fusobacterium was established in the gut of infected pig with H.suis (100). Another NHPH known to infect humans, for instance, H.felis is associated with a reduce in Lactobacillus and a raise in Clostridium, Bacteroidetes, Prevotella, Eubacterium, Ruminococcus, Streptococcus, and E. coli in the stomach (94, 101). Lactobacillus has been shown to secrete acetylcholine, which is significant in regulating memory, attention, and learning, and has beneficial effects in mental illnesses, reducing anxiety and depression (102). Thus, deplesion of Lactobacillus due to H. suis could affect mood. Also, Increased levels of Clostridium has been linked to autism (103), demonstrating that increased presence of Clostridium in H. suis-infected animals might  negatively affect brain homeostasis.