H pylori Linked to Lower MS Risk in Women

Pauline Anderson

January 22, 2015

Helicobacter pylori seropositivity is significantly lower in women with multiple sclerosis (MS) than in female healthy controls, suggesting a possible protective effect of these bacteria, a new study shows.

Interestingly, the study, the largest ever to evaluate the association between H pylori infection and MS, did not find such a trend in men.

The new study provides "objective evidence for many of the postulated environmental risk factors," author Allan Kermode, MD, head, Department of Neurology and Clinical Neurophysiology, Centre for Neuromuscular and Neurological Disorders, Australian Neuromuscular Research Institute, Perth, Australia, told Medscape Medical News. "This now opens an important window into MS pathogenesis."

The research was published online January 19 in the Journal of Neurology, Neurosurgery & Psychiatry.

Increase in Infection

H pylori are gram-negative bacteria that reside in the stomach of more than half of the human population. H pylori infection is linked to peptic ulcer disease, and the connection has changed the way this condition is treated.

H pylori infection has steadily decreased in western populations in recent years, largely attributed to higher hygiene standards and widespread use of antibiotics. At the same time, the incidence of MS has increased, mainly because of more cases among women.

Although there are other possible explanations for H pylori being lower in patients with MS, study authors argue in favour of the "hygiene hypothesis," where infections in early life may prime the immune system and suppress autoimmune conditions in later life.

"It's most likely that helicobacter colonization is a surrogate marker for baseline levels of exposure to environmental pathogens and organisms during childhood," Dr Kermode said.

The analysis included 550 white patients, mostly female (75%), with an average age of 47.7 years, who were enrolled in the Perth Demyelinating Disease Database with a diagnosis of MS. It also included 299 carefully selected community-based sex- and age-matched controls of Anglo-Celtic descent.

Researchers performed anti-H pylori serology on both groups and used an enzyme immunoassay to detect specific IgG antibodies to H pylori.

The rate of H pylori seropositivity was lower in patients with MS than in controls (16% vs 21%), with the difference pertaining almost exclusively to women (14% vs 22%; P = .027) but not men (19% vs 20%; P = 1.0).

After adjustment for age at onset, year of birth, and disease duration, seropositive women had lower disability scores than seronegative women, while the reverse was true for men.

Most MS is relapsing-remitting (RRMS) or secondary progressive (SPMS), and most patients with these MS types are women. In contrast, the sex ratio for primary progressive MS (PPMS) is 1:1. In this study, the patients with PPMS were a much smaller group than the RRMS or SPMS groups.

But these patients with PPMS represented "the nail that sticks out" in the study, said Dr Kermode. After adjustment for other variables, a significant interaction was seen between sex and PPMS status (P = .037), with a significant increase in seroprevalence rates for PPMS cases compared with non-PPMS cases among women (P = .026), but not men (P = .88).

"The seroprevalence risk is curious in that if you have MS but are positive then you are more likely to have PPMS than RRMS," said Dr Kermode. "Could this be because being seronegative pushes a female MS case into the RRMS group, whereas positive cases have a much less inflammatory form of MS that presents much later and does not relapse?"

If that's the case, he added, it would fit the hygiene hypothesis in that infections such as H pylori early in life reduce any autoinflammatory tendencies. "PPMS has much less inflammation than RRMS/SPMS, and some people believe that it might have a different pathogenesis."

Hygiene Hypothesis

In many ways, the hygiene hypothesis in MS makes sense. Research shows that environmental influences, including socioeconomic status — which could affect sanitation levels — have a profound effect on the subsequent risk for MS.

Researchers have tried various strategies to test the hygiene hypothesis in MS, including looking at birth order. In an accompanying editorial, Professor Jun-ichi Kira, from the Neurological Institute at Kyushu University, Fukuoka, Japan, cited one study published in 2005 that observed that residents with younger siblings during early life had significantly decreased MS occurrence later in life.

According to the theory, "exposure to infant siblings can increase the opportunity to encounter infection during early life leading to a robust development of the immune regulatory system that can suppress immune effector responses," writes Professor Kira.

For Dr Kermode, investigating the role of H pylori seropositivity "seemed to be a very obvious strategy" to obtain objective data on the hygiene hypothesis. "Helicobacter is typically acquired in childhood and correlates directly with hygiene," he said.

The prevalence of H pylori infection in Australian adults is even lower than in other developed countries. Australia also has relatively high rates of MS.

Historically, the sex ratio in MS was equal, but over the last 100 years, the prevalence of MS has increased markedly; most of this increase has occurred in women. In Australia, the sex ratio of women to men is now about 3:1.

"The fact that over the same period prevalence of Helicobacter in western countries has declined markedly is a tantalizing observation," said Dr Kermode.

That the relationship between H pylori and MS exists only in women, who presumably are exposed to the same environmental conditions as men, "is arguably one of the most fascinating observations of our study," said Dr Kermode.

At this stage, though, scientific knowledge can't explain either the changing sex ratios in MS or the strong H pylori association in women but not men. "But our study provides useful navigation to direct further research," said Dr Kermode.

The relationship uncovered by the study may apply to other immune disorders, said Dr Kermode. "There is already evidence of an inverse association between Helicobacter colonization and allergic disorders, and of parasitic infections and MS, so I would not be surprised if this relationship exists for other disorders of presumed autoimmune origin."

As for a potential therapeutic application of the findings, research is under way elsewhere to develop H pylori cultures that don't cause peptic ulcer disease. "This is a fascinating area of research," commented Dr Kermode. "Modified H pylori could be used as a vehicle to continuously deliver various specific peptide therapies to an individual patient."

Asked to comment on these new findings, Robert Lisak, MD, professor, neurology, Wayne State University School of Medicine, Detroit, Michigan, and president, Consortium of Multiple Sclerosis Centers, pointed out that the study didn't include titers against other bacterial or viral agents in patients or controls in the study.

"So the same findings might have been found to one or more other bacteria, viruses, or other infectious agents," said Dr Lisak.

As the authors suggest, the data support the hygiene hypothesis, said Dr Lisak, "with differences in types of infections and age of infection in different populations influencing the type of T cell immune responses an individual tends to mount to many different immunologic stimuli."

However, he added, "the data do not demonstrate a direct protective effect of H pylori infection from developing MS or modulating MS."

Dr Kermode received speaker honoraria and scientific advisory board fees from Bayer, Biogen Idec, Novartis, Sanofi-Aventis, Merck, Sanofi-Genzyme, and Innate Immunotherapeutics. Professor Kira is a consultant for Biogen Idec Japan and has received honoraria from Bayer Healthcare and funding for a trip from Bayer Healthcare and Biogen Idec Japan. He is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan, and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan.

J Neurol Neurosurg Psychiatry. Published online January 19, 2015. Abstract Editorial

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