Could H pylori Be Protective Against Multiple Sclerosis?

Allan G Kermode MBBS MD FRACP FRCP Clinical Professor of Neuroimmunology, Murdoch University Clinical Professor of Neurology, University of Western Australia Head, Department of Neurology and Clinical Neurophysiology SCGH Centre for Neuromuscular and Neurological Disorders Australian Neuromuscular Research Institute Sir Charles Gairdner Hospital Perth WA Australia Institute of Immunology and Infectious Diseases Murdoch University, Western Australia MedicalResearch.com Interview with:
Allan G Kermode MBBS MD FRACP FRCP

Clinical Professor of Neuroimmunology, Murdoch University
Clinical Professor of Neurology, University of Western Australia
Head, Department of Neurology and Clinical Neurophysiology SCGH
Centre for Neuromuscular and Neurological Disorders
Australian Neuromuscular Research Institute Sir Charles Gairdner Hospital Perth WA Australia Institute of Immunology and Infectious Diseases
Murdoch University, Western Australia

MedicalResearch: You found that H. pylori sero-positivity was significantly lower in female patients with MS than in female healthy controls, but you didn’t find such a trend in men with Multiple Sclerosis… Briefly, what might explain this association between H. pylori and Multiple Sclerosis in women? (i.e the hygiene hypothesis I suppose?).

Prof. Kemode: There are a number of possible explanations, but we believe that the most likely is that helicobacter colonisation is a surrogate marker for the baseline levels of exposure to environmental pathogens and organisms during childhood. We have argued this point of view in our manuscript. It should be emphasised that perhaps not all exposure to infectious agents need necessarily be pathogenic, and the concept of the protobiome is an important one. Every healthy (and unhealthy) individual is host to very many organisms, with the gut having the widest diversity. Other explanations for the association might include that there is some specific antigenic interaction occurring promoting specific immune tolerance to CNS antigens, but I believe that this conclusion would be drawing a very long bow with our current stage of knowledge regarding Multiple Sclerosis.

MedicalResearch: Why does this relationship exist in women but not in men? (presumably, they are exposed to the same sanitation, hygiene etc.)

Prof. Kemode: This is arguably one of the most fascinating observations of our study. Historically the sex ratio in Multiple Sclerosis was equal, yet in the last 100 years the prevalence of Multiple Sclerosis has increased markedly and the majority of this increase has occurred in women such that in Australia the sex ratio F:M approximates 3:1. The fact that over the same period prevalence of helicobacter in Western countries has declined markedly is a tantalising observation. At this stage scientific knowledge has not explained the changing sex ratios in Multiple Sclerosis nor can we yet explain the strong helicobacter association in females but not males in our study, but our study provides useful navigation to direct further research.

MedicalResearch: Is this relationship between Multiple Sclerosis in women and H pylori stronger for certain types of Multiple Sclerosis? If so which types and why might this be the case?

Prof. Kemode: The relationship was strongest for initially relapsing forms of MS (which also includes secondary progressive forms) and this group forms the majority of MS cases in any western cohort. I might mention that in my personal opinion the phenotyping of Multiple Sclerosis is an evolving area and at present relatively soft science, so whilst we grouped cases using current consensus definitions I would not be surprised if future definitions differ.

MedicalResearch: Would this relationship just exist in Multiple Sclerosis or would it also play out in other autoimmune diseases?

Prof. Kemode: As we alluded to in our manuscript, there is already evidence of an inverse association between helicobacter colonisation and allergic disorders, and of parasitic infections and Multiple Sclerosis, so I would not be surprised if this relationship exists for other disorders of presumed autoimmune origin.

MedicalResearch: What made you want to pursue the connection between H. pylori and MS?

Prof. Kemode: Identified epidemiological risk factors for Multiple Sclerosis have shown that environmental influences have profound influences on the subsequent risk of Multiple Sclerosis, including socio-economic status within a given country. Similarly, these influences have been shown to exert their major effect during childhood. A variety of epidemiological methods have found convergent results on these issues. To attempt to test the hygiene hypothesis in Multiple Sclerosis other researchers have tried various strategies including looking at birth order in families, but looking at helicobacter seropositivity seemed to me to be a very obvious strategy to obtain quite objective data on the hygiene hypothesis. Helicobacter is typically acquired in childhood and correlates directly with hygiene.

MedicalResearch: You said that the prevalence of H. pylori infection in Australian adults is lower than that in other developed countries. So is the Multiple Sclerosis rate in Australia higher than elsewhere (which should be the case if H. pylori protects against this disease)?

Prof. Kemode: Australia does indeed have high rates of Multiple Sclerosis corrected for latitude. Australia is also a well-developed Western country with very high GDP per capita.

MedicalResearch: Do your study results imply that people at high risk for Multiple Sclerosis should try to somehow get infected with H pylori (how? by exposing themselves to an unsanitary environment?).

Prof. Kemode: I think that this conclusion cannot be inferred from our work at present, as we cannot be sure if the helicobacter serology is merely a marker for their environmental risk factors or alternatively influences risk directly.

MedicalResearch: What are the pharmaceutical implications of your study? For example, could a therapy be developed that would mimic H pylori?

Prof. Kemode: Work in this area is already well advanced by Prof. Barry Marshall and his group. Already it is known that certain H pylori may cause peptic ulcer disease, yet many cultures do not. H pylori itself could be used therapeutically so we may not need to “mimic” its effects. Moreover, modified H pylori could be used as a vehicle to continuously deliver various specific peptide therapies to an individual. This is a fascinating area of research.

MedicalResearch: What is your main message to neurologists from this study?

Prof. Kemode: That question can be answered on many levels, and philosophically I would say always think laterally and always question dogma. However, with respect to this manuscript we now have objective evidence for many of the postulated environmental risk factors and this now opens an important window into Multiple Sclerosis pathogenesis.

MedicalResearch: Just noticed something that is a bit confusing….
You said in the paper that after adjusting for other variables, there was a significant interaction between gender and primary progressive (PP) Multiple Sclerosis status, with a significant increase in seroprevalance rates for primary progressive cases compared with non-PP cases in women but not men…. Then in your responses, you said that the relationship was strongest for initially relapsing forms of MS (which includes secondary progressive forms).

Prof. Kemode: Yes, the way we had to present the data for the journal is a little confusing unfortunately, as it is always necessary in manuscript of this type to be economical in interpretation. The strongest association is for seronegativity increasing Multiple Sclerosis risk overall (p=0.005) and in females particularly (p=0.002), of which RRMS and SPMS are the majority and females also in the majority because of the sex ratio of prevalence.

The primary progressive group is the “nail that sticks out” – the sex ratio for PP is 1:1, and the numbers are much smaller than for the RRMS/SPMS group. The seroprevalence risk is also curious, in that if you have MS but are positive then you are MORE likely to have PPMS than RRMS. Could this be because being seronegative “pushes” a female Multiple Sclerosis case into the RRMS group, whereas positive cases have a much less inflammatory form of MS that presents much later and does not relapse (PPMS)? If so, this would be also consistent with the hygiene hypothesis in that infections (such as helicobacter) early in life reduces any auto-inflammatory tendencies. PPMS has much less inflammation than RRMS/SPMS, and some believe perhaps it has a different pathogenesis. We did not have the opportunity to further develop this line of thought in our manuscript as the concept would require a few extra paragraphs.

Citation:

Helicobacter pylori infection as a protective factor against multiple sclerosis in females

Marzena J Fabis Pedrini, Alexandra Seewann, Kirsten A Bennett, Alex J T Wood, Ian James, Jason Burton, Barry J Marshall, William M Carroll Allan G Kermode

J Neurol Neurosurg Psychiatry jnnp-2014-309495Published Online First: 19 January 2015 doi:10.1136/jnnp-2014-309495