Remyelination in multiple sclerosis, along with its immunology and association with gut dysbiosis, lifestyle, and environmental factors

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease that damages the myelin sheath around the axons of the central nervous system. While there are periods of inflammation and remyelination in MS, the latter can sometimes be insufficient and lead to the formation of lesions in the brain and spinal cord. Environmental factors such as vitamin D deficiency, viral or bacterial infections, tobacco smoking, and anxiety have been shown to play a role in the development of MS. Dysbiosis, where the composition of the microbiome changes, may also be involved in the pathogenesis of MS by affecting the gut’s microbial population and negatively impacting the integrity of the epithelia. While the cause of MS remains unknown, genetic susceptibility, and immunological dysregulation are believed to play a key role in the development of the disease. Further research is needed to fully understand the complex interplay between genetic, environmental, and microbial factors in the pathogenesis of MS.

Introduction

Highlights

• The ability of axons to carry action potentials in a fast-paced manner is provided by the myelin sheath. Our paper aimed to provide an overview of the remyelination inadequacy occurring in multiple sclerosis (MS), hindering the activity of such axons to function properly, resulting in a higher rate of progressive axonal atrophy.

• The manuscript also provides an overview of recent factors that have been linked and attributed to the development of MS, including environmental factors, vitamin D deficiency, viral or bacterial infections, tobacco smoking, and anxiety.

• Dysbiosis, characterized by changes in the composition of the gut microbiome, may play a role in the pathogenesis of MS by impacting the gut’s microbial population and negatively affecting the integrity of the epithelia. A major section of this manuscript investigated the role of gut microbiota and the potential benefits they could provide in MS patients.

• Genetic susceptibility and immunological dysregulation are considered important factors in the development of MS, although the exact cause of the disease remains unknown.

• Further research is necessary to gain a comprehensive understanding of the complex interactions between genetic, environmental, and microbial factors in the development of MS.

Multiple sclerosis (MS) is an inflammatory disease that damages the protective layer around the axon of the central nervous system (CNS) by lymphocytic infiltration. As a progressive disease, there are periods of inflammation followed by periods of remyelination that can sometimes be excessive. This can result in lesions being formed in the brain and spinal cord. A typical pathogenomic picture of MS usually presents as brief episodes of neurological impairment in the early stages and eventually alters the normal physiological neural function and may cause permanent disabling impact. During paraclinical examinations of CSF through lumbar puncture, evoked electrical potentials, and intrathecal creation of oligoclonal antibodies can be detected, as well as disordered axonal growth and inflammatory lesions.

The immune system targets the myelin sheath that surrounds and protects neurons, causing numerous neurological signs, including demyelination and axonal loss¹. People with relapsing MS tend to be diagnosed between the ages of 20 and 50, with the incidence peaking at 28 years of age. As far as autoimmune disorders are concerned, the odds of girls developing them are higher than those of males. Since Charcot first described MS at the end of the 19th century, the ratio has changed from 1:1 to 3:1². Additionally, it appears that the sex ratio varies by region³. The causative agent of the disease remains unknown⁴, even though genetic predisposition may play a role in 1/3 of cases. The imperfect causal influence of genetic susceptibility makes it possible for additional factors, such as environmental circumstances, to interact with genetic susceptibility (Fig. 1).

Figure 1.

Gut dysbiosis in multiple sclerosis – the bacteriae population affected.

Myelin sheath provides axons with the ability to carry action potentials quickly and efficiently; it also possesses a robust regenerative capacity, which allows demyelinated axons to efficiently remyelinate in the majority of time. However, MS is not one of those times, as remyelination inadequacy results in a higher rate of progressive axonal atrophy, especially with large demyelinated lesions that mostly or entirely fail to remyelinate⁵.

There is still a debate over whether MS is neurological or autoimmune in origin, despite the majority of genetic profiling showing that immune-mediated markers are activated during illness¹. It is now believed that inflammation and perhaps immunological dysregulation plays a key role in the development of this disease, no matter its etiology. Stressors for MS include but are not restricted to, vitamin D deficiency, anxiety, tobacco smoking, viral or bacterial infections, and food^6–8. Genetic risk factors for MS have also been identified as possible risk factors. In the current understanding of the gut environment, dysbiosis, where the composition of the microbiome changes, may play a role in causing disease. Dysbiosis can impact immune reactions to the microbiota, but it can also negatively impact the integrity of the epithelia. These barriers form cellular barriers necessary to preserve the health of the intestine and the nervous system. The comparison of the gut’s microbial population appears to be significantly impacted by a variety of factors that have been linked to MS and may act as disease triggers⁷.

Remyelination in multiple sclerosis

Remyelination is a regenerative response in which newly formed oligodendrocytes help in the formation of the new myelin sheath around denuded axons^5,9–12. The action potential is propagated via voltage-gated sodium and potassium channels present in the nodes of Ranvier by saltatory conduction^13,14. The myelin loss leads to slow conduction of action potential and sometimes, latency and; complete absence of action potential resulting in conduction block¹⁵. This saltatory conduction and clinical functioning of nerve fiber is gained by remyelination^16,17.

Histopathological studies have found that remyelination occurs in some people with MS¹⁸. Oligodendrocytes provide lactate for metabolism and energy for neutrons^19–21. It is becoming more and clearer that myelin remodeling, which promotes learning and plasticity, is a dynamic process in which both freshly generated and pre-existing oligodendrocytes remodel myelin²².

Dynamic myelin imaging with positron emission tomography provides support for the high inter-subject variability in remyelination capacity, and when combined with data showing that people with higher levels of remyelination have lower levels of disability, it emphasizes the therapeutic potential of a remyelinating therapy^23,24. In order to identify druggable targets to improve this process, efforts have been made to understand the mechanics of remyelination and why this process fails in MS. Remyelination depends on adult oligodendrocyte progenitor cells (aOPCs), derived from neonatal oligodendrocyte progenitor cells, which have been demonstrated through genetic fate mapping to be the cells in charge of producing the majority of new oligodendrocytes in the adult nervous system^15–27.

A coordinated phase of activation, migration, proliferation, and differentiation must be followed by aOPCs after injury to myelinated regions, and this process ends with the production of new myelin sheaths²⁶. When the process is examined in animal models, the fact that the ultimate outcome is a compacted layer of myelin that is thinner and shorter than those generated during developing myelination is frequently utilized to detect remyelination histologically²⁸.

Remyelination might be stalled due to problems anywhere between the courses; insufficiency of proregenerative factors, or inhibitory factor excess, as can be found in MS lesions, along with the inherent constitution of aOPCs¹. It has been proven in the past that aOPCs do go to damage sites and disperse uniformly to promote remyelination²⁹; however, they most likely move a short distance³⁰. In light of the fact that some MS patients remyelinate more effectively than others^23,31, it is obvious that a treatment plan that only works to improve differentiation may not always be enough to address remyelination in a group of diverse MS patients. The interaction between oligodendrocytes and other glial cells is also seen. Reactive astrocytes secrete inhibitors of remyelination like Endothelin-1³², particularly A1 reactive astrocytes³³ that lead to the death of oligodendrocytes, should be given importance in understanding remyelination and its potential therapeutic targets.

Parallel to this, evidence suggesting that axonal action potentials regulate protein production in OPCs points to an underlying symbiosis between the neuron and the cells that myelinate it³⁴. OPCs may differentiate in the CNS even in the absence of axons^35,36, and they can myelinate inert substrates that resemble axons in culture^37,38. The capacity of oligodendrocytes to develop and myelinate axons is; however, controlled by axon diameter and activity, suggesting that intact axons are necessary in vivo³⁹.

To enhance remyelination, it will thus likely be necessary to combine medications that operate on several processes; these combinations will work best when there is a sufficiently maintained demyelinated axon. This last aspect serves as the justification for many phase 2 studies that first target individuals with recurrent remitting MS since it is believed that these individuals will have less axonal degeneration.

Environmental and lifestyle factors, and immunology

The exact cause of the disease remains unknown; it is mostly a combination of genetic factors frequently seen in patients with an affected first-degree relative by a certain major histocompatibility complex like HLA-DRB1⁴⁰. The lifetime risk of MS in monozygotic twins if one of them develops the condition is about 25%; thus, the risk is also influenced by environmental factors like geographical location, colder climates, the microbiome of the gut and reduces sunlight exposure leading to vitamin D deficiency. Other causes include infections with Epstein–Barr virus (EBV)^41,42 which results in molecular mimicry by which antigens present on axons become targets for the immune system giving rise to MS attacks⁴³.

The pathophysiology of MS is based upon the activation of T-cells, B-cells, and macrophages, which causes a Type IV cell-mediated hypersensitivity reaction in the brain and the spinal cord. This reaction leads to the destruction of oligodendrocytes protecting the axons thus leading to various symptoms seen in MS as resultant of failure of signal transmission between axons^44,45. The predisposing factors which activate these T-cells also help them in breaking through the blood–brain barrier. This first attack creates a vicious inflammatory cycle which leads to further activation of T-helper cells of the immune system, which produces cytokines to activate more T-cells, B-cells, and macrophages to make their way to the CNS. The aftermath of the attack is seen as lesions on an MRI. Multiple environmental and lifestyle factors have been associated with an altered immune response and subsequent effects on the gut:

(1) Obesity: A high BMI has been associated with an increased risk of an earlier age of MS onset, a higher rate of relapse, and a decrease in disease-modifying therapy responsiveness⁴⁵. White adipose tissue acts as an endocrine organ in addition to its energy-storing function as it secrets (TNF)-a, IL-6, or leptin. The latter was shown to favor Th1 and Th17 reactions while suppressing Treg cells thus leading to metaflammation and an increasing suspicion of its direct effect on autoimmunity⁴⁶.

(2) Fatty acids: They were shown to have an effect on autoimmunity irrespective of body weight depending on their chain length. Moderate or long-chain fatty acids were shown to increase the Th1 and Th17 levels while suppressing Treg cells. Short-chain fatty acids (SCFAs), which are mostly dietary fiber fermentation products of the gut commensal bacteria, have demonstrated an opposite effect by suppressing Th1 and Th17 levels while promoting Treg cells⁴⁶.

(3) Hygiene hypothesis: It basically states that exposure to particular microorganisms and helminths during infancy and early childhood improves immune regulation and prevents unnecessary overreaction to harmless stimuli that could eventually lead to allergies and autoimmune diseases like MS. The underexposure to these microorganisms and helminths that once was a normal part of the gut microbiota has paved the way to an altered composition of the gut microbiome, thus leading to dysbiosis and an immune-regulatory deficit, which plays a major role in the recent increase of autoimmune disease incidence. MS has shown a much lower prevalence in countries where helminth infestations were common and an increased incidence with increased sanitation. It also has been recorded that MS coexisting with helminthic infection has led to a decrease in disease progression due to increased Treg that releases IL-10 and TGF-β, while an exacerbation immediately follows infection treatment^47,48.

(4) Geographical location: It is closely related to the hygiene hypothesis. A higher incidence and prevalence in urban areas than in rural areas have been recorded⁴⁹. It is also influenced by genetic different susceptibilities among different ethnic groups as it is of high incidence amongst Sardinians and Palestinians while it is rare amongst Asians⁵⁰.

(5) Decreased sunlight exposure and vitamin D deficiency: It induces FoxP3+ Treg cell production and reduces T-cells⁴¹. MS prevalence is inversely correlated with the duration and intensity of UVB as it increases with latitude away from the equator⁵⁰.

(6) Smoking: The duration and intensity of smoking were associated with more severity and rapid progression of the disease^49,50. Gut microbiota dysbiosis may also arise as the microbiome composition is altered to a large extent with increasing microbial diversity up to 5 years following smoking cessation; however, it reverses after 10 years following cessation.

(7) Infections: Measles, rubella, mumps, and chickenpox viruses have been heavily studied due to their prevalence amongst children but mostly controversial results were recorded. However, patients with a history of EBV infection showed an increased risk of developing MS compared to their seronegative counterparts. Patients with MS have also been found to have anti-EBV antibodies or have the signs of EBV reactivation with some having the virus within acute lesions in the brain. The hypothesis of molecular mimicry has been presented to explain this, stating that T-cells that recognize EBV antigens react to CNS antigens⁵⁰.

(8) Salt: A high salt diet increased classical M1 macrophage activation and the expression of proinflammatory mediators while it decreased M2 macrophages activation and decreased their ability to suppress proinflammatory T-cells⁴⁶.

Gut microbiome and microbial agents in MS

The surface of our body’s epithelial barrier is home to a wide range of microorganisms, including bacteria, fungus, archaea, protozoa, and viruses, which make up the human microbiome^51,52. Moreover, the gut microbiome is composed of ~3×1013 bacteria, the majority of which are symbiotic with the host. The microbiota can have an impact on a variety of physiological processes as it not only modulates the gastrointestinal tract but also has a significant impact on the development and function of the immune system and the CNS^53–55.

Recent studies have shown that the development and progression of neurological illnesses are linked to dysbiosis, an imbalance in the gut microflora. Characterization of the microbiome–host cross-talk pathways also sheds light on potential new treatment plans to treat neurological disorders like MS⁵⁵.

Several microbial agents have been implicated in the development of MS and other autoimmune diseases. Researchers have failed to conclusively prove that the EBV is an etiologic agent of MS, despite comparing CNS-derived antibodies against the EBV with antibodies against other neurotropic viruses in children and adults with MS onset⁵⁶. It may; however, reduce susceptibility to the condition by altering its immunogenicity. Increasing immunization procedures, prolonged antibiotic use, and a clean environment may change how intestinal pathogenic bacteria colonize, according to the hygiene theory. By mismatching proinflammatory TH1 and TH17 cells with anti-inflammatory TH2 and regulatory cells, these circumstances may contribute to autoimmune disorders.

In the gut, commensal bacteria, such as Bacteroides fragilis, have lately been linked to the hygiene hypothesis, which has previously been linked to parasitic illnesses caused by helminths. In experimental autoimmune encephalomyelitis (EAE), A-polysaccharide from B. fragilis has been shown to restrain Th17 activity while it induces an increase in Treg cells through toll-like receptor 2 action^47,57. For some time, viruses like measles, HTLV-1, rabies, coronavirus, herpes simplex virus, and EBV have been hypothesized to share a link to causing MS⁵⁸. Herpes simplex virus-6 (HHV-6) DNA has been found in the cerebrospinal fluid of MS patients with lesions⁵⁹. While EBV nuclear antigen and myelin basic protein share a genetic sequence that may function as a trigger for the development of MS.

Commensals and multiple sclerosis

Approximately 10¹³ bacteria are present in the human gut and they support a variety of physiologic processes. Inflammatory illnesses like MS may occur as a result of an alteration in the normal healthy gut flora as discussed above. In order to treat MS and other disorders, gut commensals may offer interesting therapeutic possibilities. Researchers have presented the discovery of Prevotella histicola, a human gut-derived commensal bacterium that can inhibit experimental autoimmune encephalomyelitis (EAE) in a mouse model that is transgenic for the HLA class II antigen. P. histicola regulates innate immune responses and suppresses disease by lowering proinflammatory Th1 and Th17 cells level and by raising the level of +FoxP3+ regulatory T-cells, tolerogenic dendritic cells, and suppressive macrophages⁶⁰.

Akkermansia is another commensal shown to improve EAE. An increased level of Akkermansia in patients with MS has been recorded which could be regarded as a beneficial compensatory response⁶¹. Also, Clostridiale was found to be abundant in MS patients irrespective of ethnicity. Especially Clostridium perfringens as it secretes epsilon toxin, which binds to the blood vessels thus increasing the permeability of the blood–brain barrier, also it was shown to have an effect on Myelin and Lymphocyte protein MAL, thus impacting the survival of oligodendrocytes. It also disrupts the metabolism of tryptophan, which impairs 5HT production and its beneficial effects⁶¹.

The availability of commensals in the gut exerts favorable metabolic effects on the host gut. Dietary fibers are broken down by gut microorganisms into metabolites, which have a variety of molecular and cellular roles in the host’s physiology and immune response. These dietary fiber fermentation mechanisms are linked to fermenting bacteria in the colon, such as those from the groups of Clostridium and Bacteroides. The bacterial fermentation of complex fiber-derived nondigestible carbohydrates yields SCFAs, including acetate, propionate, and butyrate. Without the gut microbiome, fibers would pass through the GI tract unused. Additionally, SCFAs improve the host’s immune system by controlling immune cells’ gene expression and directing them toward a more regulatory phenotype, which reduces oxidative stress. The IL-10 knockout concept of spontaneous colitis was used to emphasize the significance of gut-derived metabolites. Intervention with a fiber-rich meal lessened the disruption in mice with severe intestinal epithelial barrier disruption.

Increases in intestinal acetate, propionate, and butyrate levels, a reduction in the infiltration of inflammatory cells in the lamina propria, and increased frequencies of T-regs all followed the diet’s positive effects⁶². Therefore, critical metabolites linked to gastrointestinal integrity as well as the stimulation of immunomodulatory responses may be influenced by gut microorganisms. The gut microbes may influence immune balance in the body by affecting the equilibrium between immune functions that are elicited to enhance inflammation and those that are intended to control the extent of the immune reaction according to the experimental autoimmune encephalomyelitis model. Experimental models of autoimmunity have shown that segmented filamentous bacteria (SFB), inhabitant of the mouse gut, have a significant impact on the severity of EAE.

A major mechanism by which SFB seems to increase disease severity is through the stimulation of Th17 cells by the gut. Germ-free mice that are disease-resistant to EAE become susceptible to the disease by being monocolonized with SFB due to the activation of Th17 cells⁶³. Toll-like receptor 2 was found to be able to identify the lipopolysaccharide antigen of Porphyromonas gingivalis, which induced neuroinflammation⁶⁴. When compared to stool samples from healthy donors, many studies show a considerable decrease in the relative abundance of particular Clostridium clusters in individuals with recurrent remitting MS⁶⁵. The experimental data points to the stimulation of Th17 cells by gut bacteria, suggesting that dysbiosis may have an impact on the population of proinflammatory cytokines with autoreactive capacity (Fig. 2). While Lactobacillus and Bifidobacterium strains do control the degree of severity of EAE, P. gingivalis exacerbates the condition by amplifying glial stimulation and promoting proinflammatory responses to worsen EAE^64,66.

Figure 2.

Common factors influencing altering both the gut microorganisms as well as the pathogenesis of multiple sclerosis.

A blend of Lactobacillus prevents mice from contracting EAE, while Bifidobacterium animalis lowers EAE in Lewis rats⁶⁷. The amalgam of three different strains of L. plantarum decreased the severity of established EAE in mice administered prophylactically using L. paracasei as well as L. plantarum. The severity of EAE is also reduced by the probiotics Pediococcus acidilactici variant R037 and Lactococcus lactis modified, which expresses Heat shock protein 65 (Hsp65)^68,69.

Two recently published research demonstrate the functional significance of the MS gut microbiome as evaluated by fecal transplantation studies employing recipient germ-free animals despite the lack of a causal relationship^70,71. According to Berer’s study, germ-free mice exhibit a lower vulnerability to MS than mice kept in normal housing. Compared to recipient mice that received fecal matter isolated from their homozygotic siblings, who were not diagnosed with MS and were regarded as healthy in their study, the incidence of illness in transgenic mice that acquire sporadic EAE was higher in this study⁷⁰.

The findings emphasized the significance of CD4+ T-cells that produce IL-10 in the immunomodulatory effects of the intestinal microbiota. According to Cekanaviciute’s study, recipients of C57 germ-free mice were given the feces of MS sufferers or that of healthy donors. When compared to the control, mice who got fecal content from MS patients experienced an EAE that was considerably more severe than those mice who received fecal content from healthy subjects, in whose patient EAE was observed to be less severe⁷¹. The bacteriae population having a role in the MS is demonstrated below in Figure 1.

The regulation of experimental autoimmune disorders, including EAE, has been linked to oral tolerance⁷². Salmonella strains that have undergone genetic mutagenesis have been effectively employed to develop tolerance and resistance in EAE⁷³. After a single oral dosage, Salmonella enterica serovar Typhimurium protects against EAE in a preventive and therapeutic manner through a mechanism that is dependent on FoxP3+ T-reg cells and TGF-^74,75. The protection offered by T-reg cells produced by Salmonella-CFA is eliminated by in vivo TGF- neutralization⁷⁶. These findings imply a link between the immune reactions triggered in the stomach and any potential immunological effects in the CNS. The gut microbiota is a two-way system. The host’s immunological or physiological response to microbiota influences the maintenance of gut homeostasis and the avoidance of dysbiosis by the host. In the Gut-associated lymphoid tissue (GALT) of mice with EAE, a rise in the frequencies of TH1, TH17, and IL-17+ T-cells is seen as early as 7 days after the disease is induced⁷⁷. Additionally, proinflammatory cytokines are produced in greater quantities by the antigen-presenting cells extracted from the GALT of EAE mice. Additionally, it suggests that the intestinal barrier’s integrity can also get compromised⁷⁷. Moreover, the B. fragilis therapy enhances the barrier’s integrity⁷⁸.

The intestinal barrier integrity, which is maintained by gut microbes, is also impacted by the absence of microbial species in germ-free mice^79,80. In the setting of CNS inflammation, various gut–brain axis routes have been put forth. Food intake and dietary patterns are influenced by signaling peptides that are released by the CNS⁷⁹ endocrine pathways and regulate nutrition intake. According to a recent analysis by Cryan and colleagues, the autonomic nervous system and the hypothalamus–pituitary–adrenal axis serve as important regulatory components of the brain–gut axis that are impacted by several circumstances, including stress and diet⁸⁰. The microbial communities in the gut may be impacted by these regulatory systems.

The secretion of metabolites like SCFA, immunologically active antigens like peptidoglycan, LPS, and PSA, and endocrine substances like 5-hydroxytryptamine generated by enteroendocrine cells by gut microorganisms modulate brain activity in turn⁸¹. Autoreactive macrophages attack the CNS in MS as a result of inflammatory cytokines. IL-17 and Th17 cells play a major etiological role in MS. Patients receiving interferon (IFN)- and glatiramer acetate compared with MS exacerbations have higher levels of TH17 cells (CCR6+, CD161+) in their peripheral blood mononuclear cells. In EAE and MS, T-reg cells may be able to regulate inflammation in the CNS due to their anti-inflammatory properties as discussed above of how it normally regulates inflammation, which are also amplified by approved MS therapies such as IFN-beta, glatiramer acetate, and the drug alemtuzumab being tested⁸². The pathogenesis of gut dysbiosis in MS has been depicted in Figures 2 and 3.

Figure 3.

Pathogenesis of gut dysbiosis in multiple sclerosis.

Conclusion

In conclusion, MS is a complex disease that involves inflammation and damage to the myelin sheath surrounding axons in the CNS. It is a progressive disease that affects people between the ages of 20 and 50 and has a higher incidence in females. The causative agent of the disease remains unknown, although genetic predisposition may play a role in some cases. The imperfect causal influence of genetic susceptibility makes it possible for additional factors, such as environmental circumstances, to interact with genetic susceptibility. Dysbiosis in the gut microbiome has also been linked to MS and may act as a disease trigger. While there is still a debate over whether MS is neurological or autoimmune in origin, it is now believed that inflammation and immunological dysregulation play a key role in the development of the disease, regardless of its etiology. The identification of these risk factors may lead to better prevention and treatment options for those living with MS.

Limitations

There were a few limitations in our study that need to be documented for transparency and a better understanding of the research. Since the role of the gut microbiome in MS has emerged as a topic of interest nowadays with very few trials on the role of the specific microorganisms in MS, a lot of information from various papers was conflicting, which posed a difficulty in framing the review. An example of the above statement is that in certain papers, Limosilactobacillus reuteri was shown to be improving the health of patients of MS, whereas in some it has been shown to worsen it. Global rising interest in this topic and lack of free-text availability is also one of the limitations that risks information bias.

Ethical approval

Ethical approval was not required for this review.

Consent for publication

None.

Sources of funding

None.

Author contribution

P.P.: conceptualization, methodology, writing – original draft preparation; P.I.: methodology, writing – original draft preparation; B.N.: visualization, writing – original draft preparation; S.K.: validation, writing – original draft preparation; M.D.M.M.: visualization, writing – original draft preparation, review, and editing; H.T.: validation, writing – review, and editing; P.: validation, writing – review, and editing; N.V.: validation, writing – original draft preparation; S.T.A.: writing – review and editing; A.D.M.M.: writing, review, and editing; O.A.H.: supervision, writing – original draft preparation.

Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest.

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Guarantor

Priyadarshi Prajjwal and Pugazhendi Inban.

Data availability statement

No data is available for this review.

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Not commissioned, externally peer-reviewed.