Unraveling the gut-brain axis: the impact of steroid hormones and nutrition on Parkinson’s disease

Paula Maria Neufeld ,Ralf A.Nettersheim ,Veronika Matschke ,Matthias Vorgerd ,Sarah Stahlke, ,Carsten Theiss,

Abstract This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson’s disease within the context of the gut-brain axis.The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson’s disease,encompassing diverse components such as the gut microbiota,immune system,metabolism,and neural pathways.The gut microbiome,profoundly influenced by dietary factors,emerges as a key player.Nutrition during the first 1000 days of life shapes the gut microbiota composition,influencing immune responses and impacting both child development and adult health.High-fat,high-sugar diets can disrupt this delicate balance,contributing to inflammation and immune dysfunction.Exploring nutritional strategies,the Mediterranean diet’s anti-inflammatory and antioxidant properties show promise in reducing Parkinson’s disease risk.Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders.Beyond nutrition,emerging research uncovers potential interactions between steroid hormones,nutrition,and Parkinson’s disease.Progesterone,with its anti-inflammatory properties and presence in the nervous system,offers a novel option for Parkinson’s disease therapy.Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects.The review addresses the hypothesis that α-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve.Gastrointestinal symptoms preceding motor symptoms support this hypothesis.Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances,emphasizing the potential of microbiota-based interventions.In summary,this review uncovers the complex web of interactions between nutrition,the gut microbiome,steroid hormones,and Parkinson’s disease within the gut-brain axis framework.Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson’s disease.

Key Words:diet;gut-brain axis;microbiome;neurodegenerative diseases;nutrition;Parkinson’s disease;progesterone;steroid hormones

Introduction

Background and significance of the gut-brain axis

The gut-brain axis has emerged as a central focus of contemporary biomedical research,carrying profound implications for our understanding of human physiology and pathophysiology (Bicknell et al.,2023).This intricate and bidirectional communication network coordinates interactions between the enteric nervous system (ENS) situated in the gastrointestinal tract and the central nervous system (CNS),representing a dynamic frontier in scientific inquiry (Chanpong et al.,2022).

Within the field of neurology,the gut-brain axis has garnered significant attention due to its far-reaching implications.Extensive investigation has not only yielded profound insights into the etiology and progression of a spectrum of neurological disorders,including but not limited to Parkinson’s disease (PD),Alzheimer’s disease,multiple sclerosis,and psychotic disorders,but has also given rise to a compelling hypothesis (Bhattacharyya and Bhunia,2021;Giovannini et al.,2021;González Cordero et al.,2022;Ayan et al.,2023;Ullah et al.,2023;Videlock et al.,2023).This hypothesis posits that disturbances within the gastrointestinal (GI)milieu may precede and actively contribute to the initiation and progression of these intricate neurological conditions(Cantarero-Prieto and Moreno-Mencia,2022;Ishida et al.,2022).

Central to this intricate relationship is the pivotal role played by the gut microbiome,a thriving ecosystem comprising trillions of microorganisms.This microbiome is both influenced by and exerts influence upon the host organism,impacting various facets of physiology,encompassing immune responses (Zheng et al.,2020;Swaminathan et al.,2021),gut function (Hajela et al.,2015),and permeability (Schoultz and Keita,2020;Huang et al.,2022;Koutoukidis et al.,2022).The concept of dysbiosis,reflecting an imbalance within the gut microbiota,has not only been linked to functional GI disorders but also to perturbed interactions between the gut and the brain (Kaur et al.,2021;Schächtle and Rosshart,2021;Chidambaram et al.,2022).Such microbial imbalances have the potential to induce a systemic,low-grade chronic inflammatory state commonly referred to as “inflammaging”(Franceschi and Campisi,2014;Di Giosia et al.,2022),which has demonstrated associations with age-related neurological disorders,notably PD (Mohapatra et al.,2023).

Moreover,the emerging field of therapeutics has been invigorated by the gut-brain axis.New interventions targeting the gut,including probiotics,prebiotics,and dietary modifications,show promise in alleviating symptoms associated with neurologic,psychiatric,and GI disorders(Schächtle and Rosshart,2021;Zapanta et al.,2022).These novel therapeutic strategies underscore the axis’s potential as a focal point for individualized and effective treatments.

Considering these developments,this comprehensive review explores the potential therapeutic role of neurosteroids,with a particular focus on progesterone (P4),in safeguarding the ENS and mitigating neurodegenerative processes.P4,known for its anti-inflammatory properties,has demonstrated neuroprotective effects within the peripheral nervous system(PNS) (Koenig et al.,2000),CNS (González-Orozco and Camacho-Arroyo,2019;Theis and Theiss,2019;Guennoun,2020),and ENS (Stegemann et al.,2023).Its ability to strengthen the integrity of the intestinal barrier and to protect myenteric neurons from damage represents a promising option for innovative preventive and therapeutic strategies targeting functional GI disorders and associated neurological conditions like PD.

Objective of the review

ThiMethods ensively examine the intricate relationships among the gut-brain axis,steroid hormones,and nutrition.Additionally,it intends to elucidate the pivotal roles played by the ENS and the gut microbiome in mediating communication between the gut and the brain.Furthermore,this review investigates how steroid hormones influence the gut-brain axis and subsequently impact neurodegenerative processes,with specific attention to PD.Lastly,it explores the ramifications of dietary choices on the gut-brain connection and the potential of dietary interventions to provide novel therapeutic and preventive strategies for neurodegenerative diseases.

Overview of the structure of the review

We have divided the review into several sections.First,we would like to address the fundamental understanding of the gut-brain axis by describing the anatomy and functions of the ENS,emphasizing the pivotal role of the gut microbiome,and elucidating the intricate communication pathways connecting the gut and the brain.In the next section,we investigate the influence of steroid hormones.First,steroid hormones are classified,then their interactions with the gut-brain axis are described,and the consequences of steroid hormones on neurodegenerative processes are reviewed.

This structured approach allows us to comprehensively explore the multifaceted connections between the gut,the brain,steroid hormones,and nutrition,with a specific focus on their relevance to neurodegenerative conditions,notably PD.

Search Strategy

The studies referenced in this review were searched on the PubMed database using the following keywords: ‘ENS,’‘Enteric Nervous System,’ ‘Parkinson’s Disease,’ ‘Gut-Brain Axis,’ ‘Progesterone,’ ‘Steroid Hormones,’ ‘neurosteroid,’‘neuroprotection,’ ‘inflammation,’ ‘neurodegeneration,’and ‘nutrition‘,or different combinations of these.Only original publications from 1990 to 2023 were included in the review,priority was given to papers published within the last five years.The search was conducted between April and September of 2023.

Understanding the Gut-Brain Axis

Anatomy and function of the enteric nervous system

In recent years,the ENS,often referred to as the “abdominal brain”,has garnered increasing attention in the context of understanding neurodegenerative diseases.The ENS constitutes a highly intricate neural network comprising both neuronal and non-neuronal cells organized into two primary plexuses within the intestinal wall: the submucosal plexus and the myenteric plexus (Figure 1).Remarkably,the human ENS comprises approximately 200 million neurons and up to five times as many enteric glial cells,rendering it the largest component of the PNS (Michel et al.,2022).

Figure 1 ｜Organization of the enteric nervous system.

The submucosal plexus resides in close proximity to the intestinal lumen within the tunica submucosa.Its primary functions encompass the regulation of transmucosal fluid movement and the meticulous control of enzyme and electrolyte concentrations within glandular secretions.In contrast,the myenteric plexus is situated between the longitudinal and circular smooth muscles of the tunica muscularis and governs the contractile activity and motility of the intestine.These two plexuses are extensively interconnected through synaptic connections,ensuring precise coordination of intestinal peristalsis (Furness,2008).Notably,the ENS receives efferent innervation directly through the 10thcranial nerve,the vagus nerve,and via other parasympathetic and sympathetic pathways,including the hypothalamic-pituitary-adrenal axis.Afferent signals originating from the intestinal lumen are conveyed to the CNS through spinal,vagal,and hormonal pathways (Carabotti et al.,2015).These bidirectional connections between the ENS and CNS collectively constitute the “gut-brain axis”.

Remarkably,the ENS possesses the unique ability to regulate digestive functions independently of CNS input due to its integration of sensory and motor properties into microcircuits(Rao and Gershon,2016).In this regard,the GI tract surpasses most other organ systems in the body in terms of complexity,encompassing a myriad of structures and signaling molecules involved.

The ENS is comprised of enteric neurons,immune cells,intestinal cells of Cajal,and enteroendocrine cells,working in concert to execute both digestive and defensive functions within the GI tract.Further elaboration on the diversity of ENS cell types can be found in more specialized literature (Sharkey and Mawe,2023).Notably,all known neurotransmitters,including acetylcholine,glutamate,gamma-aminobutyric acid(GABA),dopamine,serotonin,etc.,which play crucial roles in the CNS also hold significance within the ENS (Furness,2008).Given that the ENS evolved prior to the CNS in evolutionary terms,it is often regarded as the “first brain” (Furness and Stebbing,2018).

Importance of the gut microbiome in the gut-brain axis

The gut microbiota exerts a profound influence on the development,motility,and immunological functions of the GI tract,collectively forming the microbiome-gut-brain axis.This intricate relationship encompasses a network of interactions involving the ENS and intestinal macrophages,underpinned by neuroimmunological crosstalk (Dóra et al.,2020).

Through the gut-brain axis,the gut microbiota plays a pivotal role in the pathogenesis of neurodevelopmental and neurodegenerative diseases.Multiple communication pathways between the gut microbiota and neural tissues have been identified,including the vagus nerve,tryptophan production,extrinsic enteric-associated neurons,and short-chain fatty acids.Disturbances in the gut microbiota composition,termed dysbiosis,disrupt the delicate balance between beneficial and pathogenic bacteria,typically favoring the latter (Ojeda et al.,2021).

The intestinal mucus,secreted by the epithelial mucosa within the intestinal lumen,houses trillions of archaea,bacteria,viruses,and fungi,collectively forming the intestinal microbiome.This microbiome establishes a complex reciprocal relationship with the human organism (Bäckhed et al.,2005).Acting as a robust physical barrier,the mucus normally prevents uncontrolled penetration of the intestinal wall by microbiome components and ingested substances,thus safeguarding the neurons and blood vessels.

Significantly,the human microbiome exhibits unique variability that resembles a fingerprint,influenced by life events and habits,including birth processes,infant feeding methods,dietary composition,aging,and environmental stressors (Ding and Schloss,2014).The microbiome,in turn,determines the physiology of its host by modulating the immune system(Dominguez-Bello et al.,2019;Wiertsema et al.,2021),gut function (Bäckhed et al.,2005),and gut permeability(Thevaranjan et al.,2017).Key determinants of susceptibility to neurodegenerative diseases include age,dietary patterns,and perceived stress.

Communication pathways between the gut and brain

The gut sends signals to the brain via spinal and vagal visceral afferent pathways and receives sympathetic and parasympathetic inputs.The ENS within the bowel senses the enteric environment and controls the detailed patterns of intestinal motility and secretion (Gershon and Margolis,2021).The gut-brain axis is facilitated by the immune system,the ENS,the vagus nerve,and microbial compounds such as tryptophan metabolites and short-chain fatty acids.The gut microbiome is an important regulator of the gut-brain axis and plays a critical role in brain physiology.Engaging microbiomegenerated metabolites such as short-chain fatty acids,the immune system,the ENS,the endocrine system (including the hypothalamic-pituitary-adrenal axis),tryptophan metabolism,or the vagus nerve plays a crucial role in communication between the gut microbes and the brain (Singh et al.,2022).

Steroid Hormone Progesterone and Its Role

Protective mechanism of progesterone in the enteric nervous system

While the precise mechanism by which P4 safeguards the ENS remains incompletely elucidated,recent investigations have illuminated its protective effects.P4 and its neuroactive metabolites have pleiotropic protective effects in neurons and glial cells,including the reduction of inflammation and reactive oxygen species,and the promotion of neurogenesis and myelination (Guennoun,2020).Experimental evidence suggests that nerve cells exposed to P4 exhibit enhanced resilience under conditions simulating PD,hinting at the potential involvement of progesterone receptors within the ENS in neuroprotection (Stegemann et al.,2023).Moreover,P4 displays a spectrum of neuroprotective and neuroplastic effects across both the CNS and PNS (González-Orozco and Camacho-Arroyo,2019;Stegemann et al.,2023).In summary,the intricate mechanism by which P4 shields the ENS remains the subject of ongoing research.Recent research underscores progesterone’s protective role in the ENS,but comprehensive investigations are required to delineate the enduring ramifications of progesterone treatment on the ENS.

Interactions between progesterone and the gut-brain axis

Neurosteroids are a class of steroid hormones that are synthesized in the CNS and PNS (Baulieu,1997).They are known to modulate various physiological processes,including neuronal excitability,synaptic plasticity,and neuroprotection.The ENS as a part of the PNS contains a variety of neurotransmitters,including GABA,which is a target of neurosteroids.GABA is an inhibitory neurotransmitter that plays a key role in regulating gut motility and secretion(Krantis,2000).Studies have shown that neurosteroids can modulate GABAergic neurotransmission in the ENS,leading to changes in gut motility and secretion.For example,one study found that the neurosteroid allopregnanolone can enhance GABAergic neurotransmission in the ENS,leading to increased colonic motility in rats (Bianchi and Macdonald,2003).Neurosteroids have also been implicated in the pathogenesis of various GI disorders,including irritable bowel syndrome and inflammatory bowel disease.In line with this,a study found that patients with irritable bowel syndrome have altered levels of neurosteroids in their fecal samples,suggesting a potential role in the pathogenesis of the disorder (MacKenzie and Maguire,2013).

Effects of progesterone on neurodegenerative processes

P4 has exhibited potential neuroprotective effects across various neurodegenerative conditions,as evidenced by several studies.In the context of spinal cord injury,a study employing a rat model demonstrated that P4 treatment not only improved functional recovery but also reduced levels of inflammation and tissue damage (Roof et al.,1994).Similarly,regarding traumatic brain injury,research utilizing a mouse model found that P4 treatment led to a reduction in brain swelling and an improvement in cognitive function (Sayeed and Stein,2009).Regarding Alzheimer’s disease,a mouse model study revealed that P4 treatment was associated with a decrease in amyloid-beta accumulation,a hallmark of the disease,along with an improvement in cognitive function (Wang et al.,2015).In the case of multiple sclerosis,P4 treatment was effective in reducing inflammation and demyelination,ultimately leading to improved motor function in a mouse model (Gutzeit et al.,2021).

Remarkably,recent research has unveiled progesterone’s protective influence on the ENS,as nerve cells treated with P4 demonstrated enhanced resistance to conditions simulating PD (Stegemann et al.,2023).These collective findings suggest that P4 may possess neuroprotective properties that could be beneficial across a range of neurodegenerative conditions.However,it is important to note that further research is required to comprehensively understand the underlying mechanisms of these effects and to determine the optimal dosing and treatment regimens for these various conditions.

Nutrition and Gut-Brain Connection

Influence of diet on the gut microbiome

The interplay between nutrition and the microbiome is complex and multifaceted.The microbiome,especially the gut microbiome,is influenced by diet and nutrition,and in turn,it modulates various diseases and health status (Gou et al.,2023).Not only nutrition during the first 1000 days of life plays a key role in the proper development of a child,both directly through the intake of essential nutrients and indirectly by affecting the composition of the gut microbiota (Fragkou et al.,2021),diet can still influence the adult microbiome (Ball and Athanasiadou,2021).

An important function of the gut microbiome is the digestion and metabolism of food.Studies have shown that each individual digests and metabolizes identical food substances differently depending on their GI microbiome composition(Adalsteinsdottir et al.,2018).Nutrition can affect the composition of the gut microbiome,which in turn can affect the immune system.For example,a diet high in fat and sugar can lead to an imbalance in the gut microbiome,which can contribute to inflammation and immune dysfunction.The gut microbiome affects the immune system,both locally in the gut and systemically.The gut is home to 70–80% of immune cells,and the gut microbiome plays a crucial role in the susceptibility,persistence,and clearance of infections(Wiertsema et al.,2021).

Nutritional strategies to promote the health of the gut-brain axis

There is limited research on the interaction of nutrition or diet,the gut microbiota,and neurosteroids in the context of the ENS.However,some studies suggest that dietary interventions can affect the gut microbiota and subsequently impact the ENS and neurosteroids.Diet is a major factor involved in shaping the gut microbiota composition across the lifespan.Several mechanisms for gut-to-brain communication have been identified,including microbial metabolites,immune-,neuronal-,and metabolic-pathways,some of which could be prone to dietary modulation (Berding et al.,2021).The relationship between an individual’s diet,gut microbiota,and host metabolic phenotype is multidirectional and complex,yielding a challenge for the practical implementation of targeted dietary guidelines.However,insight into the role of the baseline gut microbial and metabolic phenotype in dietary intervention response may provide leads for precision-based nutritional strategies (Jardon et al.,2022).A Mediterranean diet has been associated with lower mortality,reductions in obesity,type 2 diabetes,low-grade inflammation,cancer,Alzheimer’s disease,depression,and more recently,the delayed onset of Crohn’s disease.The exact mechanisms of action are not yet fully understood,but a presumed link between the Mediterranean diet and the gut microbiota has been proposed (Cani and Hul,2020).A review article suggests that diet-induced microbiome states can impact brain health and behavior and that microbiome-targeted dietary approaches have the potential to improve brain disorders (Ribeiro et al.,2022).However,the integration of microbiome into clinical nutrition perspectives of brain health is sparse,and there are several methodological limitations and knowledge gaps.Another study found that Roux-en-Y gastric bypass surgery led to gut microbiota-related systemic alterations,including changes in fecal GABA and ENS signaling.The study suggests potential therapeutic targets in the gutbrain system to mimic the surgery mode of action (Zizmare et al.,2022).

Nutrition and steroid hormones: interactions and implications in Parkinson’s disease

While there is limited research on the interaction between the ENS,neurosteroids,nutrition,and PD,some studies suggest that dietary interventions and neurosteroid-based therapies may have the potential for the treatment of PD.PD is a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra of the brain.However,PD is also associated with GI dysfunction,including constipation and dysmotility,which may be related to ENS dysfunction (Braak et al.,2003;Kujawska and Jodynis-Liebert,2018).Neurosteroids may be implicated in the pathogenesis of PD,as they can modulate dopaminergic neurotransmission in the brain.For example,the neurosteroid allopregnanolone can enhance dopaminergic neurotransmission in the striatum of rats (Cabrera et al.,2002).

The gut microbiome has also been implicated in the pathogenesis of PD,as alterations in the gut microbiome have been observed in PD patients (Yang et al.,2019;Salim et al.,2023).The gut microbiome can affect the production and metabolism of neurosteroids,which may have implications for PD (Diviccaro et al.,2021).Dietary interventions,such as the Mediterranean diet,have been associated with a reduced risk of PD (Bisaglia,2022).The Mediterranean diet is rich in fruits,vegetables,whole grains,and healthy fats,and has been shown to have anti-inflammatory and antioxidant effects(Mischley et al.,2017).Additionally,a ketogenic diet,which is high in fat and low in carbohydrates,can improve motor function and reduce inflammation in a mouse model of PD(Jiang et al.,2023),implicating that the ketogenic diet may have therapeutic potential for the treatment of PD (Pietrzak et al.,2022).

All in all,the data are limited but research suggests potential interactions between the ENS,neurosteroids,nutrition,and PD,opening avenues for therapeutic exploration.Further research is essential for a comprehensive understanding and therapeutic applications of these interactions.

Parkinson’s Disease in the Gut–Therapeutic and Preventive Strategies

The gut-brain axis in neurodegenerative diseases

In recent years,the focus on ENS systemic integration has changed from just understanding the complex digestive processes to being involved in systemic neural states that also affect the entire PNS or CNS.Given the bidirectional connection between the brainstem area of the CNS and the ENS,it is clear that the gut-brain axis is now also being discussed in the context of neurodegenerative diseases such as sporadic PD.The progression of PD is not only associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta,but also with the formation of pathological α-synuclein aggregates,so-called Lewy bodies and Lewy neurites,in projection neurons of the CNS (Spillantini et al.,1997).This process is thought to begin in the brainstem,particularly in the dorsal nucleus of the vagus nerve,and progress to the cerebral cortex (Braak et al.,2003).α-Synuclein tends to misfold and aggregate.It is discussed that misfolded α-synuclein is able to trigger further misfolding in neighboring α-synuclein proteins,and these α-synuclein proteins then also spread prion-like from cell to cell (Desplats et al.,2009;Goedert,2015).

Braak and colleagues formulated the hypothesis that such α-synuclein aggregates originate in the ENS at a very early stage of PD,and then possibly ascend via the vagus nerve into the lower brainstem (Figure 2;Braak et al.,2006;Braak and Del Tredici,2008).This “gut origin hypothesis” is supported by the findings of Pan-Montojo and colleagues,who showed that after intragastric administration of the complex I inhibitor and herbicide rotenone in mice,neuropathological changes including PD-like α-synuclein aggregations occurred first in the ENS and later in the substantia nigra pars compacta(Pan-Montojo et al.,2010).Moreover,the progression of α-synuclein aggregations from the ENS to the CNS could be prevented by surgical vagotomy (Pan-Montojo et al.,2012).Notably,GI symptoms,such as constipation and nausea,often precede the motor symptoms of PD by up to a decade,suggesting an early involvement of the gut in the disease process (Poirier et al.,2016).

Figure 2 ｜The progression of PD.

Only a thin layer of enterocytes separates the neurons of the submucosal plexus from the intestinal lumen with its resident microbiome.As a pathomechanism,neuroactive pathogens passing through the gastric epithelial mucosa,for example,could trigger α-synuclein pathologies in neuronal cells of the submucosal plexus in an early phase of PD and these could ascend to the projection neurons of the brain via a retrograde axonal prion-like cell-to-cell transfer.All this together leads to the currently discussed theory that GI complaints are not mere symptoms,but that PD has its origin in the gut in at least some of the patients.More precise knowledge about these pathomechanisms could certainly provide new starting points for medical intervention measures.

Also a dysfunctional microbiome is not only associated with functional GI disorders,but also with altered gut-brain interactions (Tan et al.,2021).In this context,the term“inflammaging” describes a systemic,low-grade chronic inflammation of the gut and brain that develops physiologically with advanced age and is associated with several age-related diseases (Franceschi et al.,2018).Levels of proinflammatory cytokines are also increased in the brains of PD patients and are associated with nigrostriatal damage (Nagatsu and Sawada,2005).A similar increase in inflammatory markers has been correlatively observed in the colon of PD patients (Devos et al.,2013).

A study conducted in 2017 with germ-free (GF) mice suggests a key role of the microbiome in the development process of these inflammations.Mice housed under GF conditions did not exhibit age-related elevated levels of circulating inflammatory mediators.Co-housing these GF mice with conventionally reared aged mice resulted in the colonization of the GF mice with the gut microbiome of the conventional mice and subsequently an increase in pro-inflammatory cytokines.The authors also showed that paracellular permeability in the colon was increased in older wild-type mice.These animals had a higher concentration of proteins of bacterial origin in their plasma,whereas GF mice,in contrast,showed no evidence of increased intestinal permeability with age (Thevaranjan et al.,2017).In summary,these data suggest age-related microbial dysbiosis leading to increased gut permeability and translocation of bacterial components,which in turn results in low-level systemic inflammation.Since it is known that inflammation per se alters gastrointestinal permeability (Bruewer et al.,2003),we speak here of a vicious circle that can eventually lead to PD.

The gut-brain axis in PD: exploring the gut-origin hypothesis and microbiota-based therapies

In recent years,research into PD has increasingly focused on the gut,driven by the concept of the “gut-brain axis” and the emerging “gut-origin hypothesis”.This shift in attention has seen the study of the ENS transition from a focus solely on understanding complex digestive processes to investigating systemic neural states that influence both the PNS and CNS.This shift is primarily due to the well-established bidirectional connection between the CNS’s brainstem region and the ENS.The gut-brain axis,which constitutes a bidirectional communication system between the gut and the central nervous system,plays a pivotal role in this context.It encompasses various components,including the microbiota,the immune system,metabolism,and neural pathways.Recent research indicates that the gut microbiota plays a crucial role in the pathogenesis of neurodegenerative diseases,including PD (Quigley,2017;Peterson,2020;Gubert et al.,2022;Singh et al.,2022).

Dysfunctional signaling along the gut-brain axis during episodes of gut dysbiosis can lead to heightened oxidative stress,inflammation,and disturbances in neurotransmitter levels (Peterson,2020).The gut microbiota exerts its influence on brain function through mechanisms such as modulating the immune system,direct neural signaling,and producing signaling molecules that interact with the host nervous system (Houser and Tansey,2017;Zhang et al.,2022).This role of the gut microbiota in neurodegenerative conditions is further supported by changes in its composition observed in individuals with these diseases (Singh et al.,2021;Gubert et al.,2022).The gut microbiota might function as an intermediary factor between the host and the environment,playing a role in disease onset and progression (Gubert et al.,2022).Consequently,researchers are investigating microbiotabased therapeutic approaches as potential interventions for preventing and modifying neurodegenerative diseases(Bicknell et al.,2023).These approaches encompass the use of probiotics,which are live microorganisms that confer health benefits by modulating the composition and function of the gut microbiota,as well as prebiotics,which are non-digestible food ingredients promoting the growth and activity of beneficial gut bacteria.Additionally,synbiotics,a combination of probiotics and prebiotics,aim to synergistically enhance gut health.Fecal microbiota transplantation,involving the transfer of fecal microbiota from a healthy donor to a recipient,aims to restore the composition and function of the gut microbiota.Dietary interventions that alter dietary patterns to promote the growth of beneficial gut bacteria while reducing harmful ones are also under investigation.Finally,antibiotics are being used selectively to target harmful gut bacteria and reduce inflammation (Peterson,2020;Wu et al.,2020;Gubert et al.,2022).

While these interventions show promise,further research is needed to determine their safety and efficacy in treating neurodegenerative diseases.The close connection between the gut and the brain,along with the pivotal role of the gut microbiota,offers exciting new avenues for therapy development and understanding the origins of diseases like PD.

Neurosteroids: a new approach for prevention and therapy

Based on Braak’s hypothesis,measures to protect the cells and prevent the misfolding and aggregation of α-synuclein in the ENS gain importance.If a neuroactive agent can break through the barrier of the intestinal epithelial mucosa and induce protein misfolding in the neurons of the submucosal plexus and consequently in the brainstem area,then neuroprotection of the ENS is an appropriate and beneficial approach for preventive and therapeutic measures.These measures could include systemic or local application of neuroprotective,neurotrophic,and anti-inflammatory substances in the ENS,since (1) inflammation has already been shown to be a crucial factor in GI permeability and (2) “inflammaging” has been shown to be a major cause of age-related neurological disorders.

In the field of endogenous substances with these positive properties,steroid hormones and especially P4 should be mentioned.Steroid hormones are known as endogenous regulators of inflammation.While glucocorticoids are well established for the treatment of acute and chronic inflammation,P4 is proving to be a more tolerable alternative without the side effects of glucocorticoids,such as hyperglycemia and hypertension (Prete and Bancos,2021;Fedotcheva et al.,2022).It is known that P4 mediates uterine receptivity and is important during pregnancy.However,P4 is equally an endogenous hormone for all sexes and its synthesis has been described in a variety of tissues,including the PNS and CNS (Baulieu and Robel,1990;Giatti et al.,2015).In endometrial cells,P4 regulates and reduces inflammation by down-regulating the expression of Toll-like receptor 4,nuclear factor-κB,and interleukin-6 (Feng et al.,2022).A similar reduction in such inflammatory markers has also been observed in mouse and rat brains (Atif et al.,2020;Gutzeit et al.,2021).Furthermore,P4 improves gut barrier function by reducing gut permeabilityin vivoandin vitro(Zhou et al.,2019).

Within the nervous system,P4 shows positive (neurotrophic,neuroprotective) effects in the CNS,PNS,and ENS (Table 1).Experimental administration of progesterone to juvenile Purkinje cells (PC) in slice cultures of the cerebellum showed positive,growth-promoting effects of the neurosteroid.In PC,P4 caused a highly significant increase in dendrite length,spine number,and spine area compared to untreated controls.However,these effects were limited to PC development,which is consistent with the physiological course of age-dependent endogenous P4 concentration (Wessel et al.,2014).Since the observed effects could be reduced by combining P4 incubation with mifepristone,an antagonist of the classical P4 receptors PR-A and PR-B,it can be assumed that the majority of the growth-promoting effects of P4 in PC are mediated by genomic mechanisms of the classical P4 receptors.However,P4 also leads to PC growth via non-genomic mechanisms mediated by the progesterone receptor membrane component 1 (PGRMC1,non-genomic progesterone receptor) (Wessel et al.,2014).Thus,balanced mechanisms of the genomic and non-genomic progesterone receptor response in these CNS neurons can be assumed.Additionally,in the sensory dorsal root ganglia of the PNS,P4 increases the motility of the neuronal growth cones by causing rapid reorganization of actin filaments of the neuronal cytoskeleton.This highlights the importance of P4 in the physiological maturation process of neuronal circuits as well as its neurotrophic and neuroprotective potential (Olbrich et al.,2013).

Table 1 ｜The effect of P4 treatment on the nervous system

The genomic and non-genomic P4 receptors are also expressed in the ENS.However,expression analyses showed that in the ENS,in contrast to the CNS,thePGRMC1gene has the highest relative expression level across all ages (Stegemann et al.,2023),and no significant changes in P4 receptor expression levels during aging can be observed here either(Jacobsen and Horwitz,2012).In the current study,P4 showed a highly significant neuroprotective effect in rotenone-treated cultured myenteric neurons,with rotenone-induced cell death being reduced by almost half by P4.Additional administration of the PGRMC1 antagonist AG205 attenuated the neuroprotective effect of P4,suggesting a strong involvement of PGRMC1 (Jarras et al.,2020;Stegemann et al.,2023).While the exact molecular mechanisms following PGRMC1 activation remain to be further investigated,these initial data are of particular interest in terms of a potential therapeutic option for neuroprotection in the ENS regarding the gut-origin hypothesis of PD pathogenesis.

Conclusions

Summary of the main findings

This comprehensive review has unveiled the intricate interplay between nutrition,the gut microbiome,steroid hormones,and PD within the context of the gut-brain axis.The main findings can be summarized as follows (Figure 3):

Figure 3 ｜This comprehensive review explores the intricate relationship between progesterone and PD within the context of the gut-brain axis.

1.Nutrition and Gut Microbiome: Nutrition profoundly influences the composition of the gut microbiome,impacting not only the GI system but also the immune system.Early dietary choices exert a lasting impact on health through microbiome modulation.

2.Nutritional Strategies: Certain diets,such as the Mediterranean and ketogenic diets,show the potential in reducing PD risk and improving brain health.Microbiometargeted dietary approaches offer avenues for innovative therapeutic interventions.

3.Steroid Hormones: P4 emerges as a promising neuroprotective agent within the ENS.Its anti-inflammatory properties and presence in the nervous system present opportunities for novel PD therapies.

4.Gut-Origin Hypothesis: The gut-origin hypothesis sheds light on the potential initiation of α-synuclein aggregates in the gut,with subsequent transmission to the brain via the vagus nerve.Early GI symptoms in PD patients underscore the importance of understanding gut-brain interactions.

Challenges and open questions

Despite significant strides,several challenges and open questions remain:

1.Complexity of Gut-Brain Interactions: The multifaceted nature of interactions between nutrition,microbiota,hormones,and PD presents challenges in deciphering precise mechanisms.The bidirectional nature of the gut-brain axis adds layers of complexity.

2.Microbiome-Based Interventions: While microbiome-based interventions hold promise,questions regarding their safety,efficacy,and long-term effects warrant further investigation.Identifying optimal probiotics,prebiotics,and dietary patterns is crucial.

3.Progesterone as a Therapeutic Agent: The translation of P4’s neuroprotective potential into clinical therapies necessitates in-depth research into its mechanisms of action,dosing,and safety profiles.

4.Gut-Origin Hypothesis Validation: Confirming the gut origin of PD pathogenesis and elucidating the precise mechanisms involved require comprehensive studies.The relationship between gut health and neuroinflammation warrants exploration.

The importance of future research in this area

The findings and remaining questions underscore the significance of future research in this area:

1.Precision Nutrition: Investigating individualized dietary approaches based on microbiome and metabolic phenotypes can revolutionize PD prevention and treatment.

2.Microbiome-Based Therapies: Rigorous clinical trials are needed to establish the safety and efficacy of microbiometargeted interventions,potentially opening new avenues for neurodegenerative disease management.

3.Progesterone in PD Therapy: Future research should focus on P4 as a neuroprotective agent,exploring its potential in clinical trials for PD and other neurodegenerative disorders.

4.Gut-Brain Axis Understanding: Advancing our understanding of the gut-brain axis,including its role in neuroinflammation and α-synuclein pathology,will continue to provide vital insights into the origins and treatment of PD.

In conclusion,unraveling the intricate connections between nutrition,the gut microbiome,steroid hormones,and PD within the gut-brain axis framework offers immense promise for improving our understanding of neurodegenerative diseases and advancing innovative therapeutic strategies.Future research efforts in this area have the potential to transform the landscape of PD prevention and treatment.

Author contributions:Conceptualization:PMN,RAN,VM,MV,SS,and CT;writing—original draft preparation:PMN,SS,and CT;writing—review and editing:PMN,RAN,VM,MV,SS,and CT;visualization:PMN and CT;supervision and project administration:SS and CT.All authors have read and agreed to the published version of the manuscript.

Conflicts of interest:The authors declare no conflicts of interest.

Data availability statement:Not applicable.

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