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BERLIN – Among a host of potential risk factors for multiple sclerosis (MS), one emerging risk factor – dietary sodium – has accumulating evidence, bolstered by new imaging techniques and emerging research about the mediating effect of the gut microbiome.
“The word is still out on salt – there’s still some work to do; we are not where we stand with smoking or obesity” and the association with MS, said Ralf Linker, MD, speaking at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
For all potential emerging risk factors for MS, there’s an attractive hypothesis and, often, epidemiologic data, Dr. Linker said. “There are probably good [epidemiologic] data in multiple sclerosis for vitamin D, smoking, obesity, and probably also alcohol,” he said. “The therapeutic consequence, however, is much less clear, the best example of that being, of course, vitamin D.”
“The attractive risk factor is not enough to be a hypothesis, although some people seem to believe that nowadays,” said Dr. Linker, chair of the department of neurology at Friedrich-Alexander University, Erlangen, Germany. “Probably it’s better to start with some basic science and some experimental data to get an idea of the mechanism.”
“Today, we need clear associations with clear markers, well-defined cohorts, and proper epidemiological data telling us whether this is a real risk factor. ... If you look at the clinicians – and there are many among us in the room here – your ultimate goal, of course, is to use this as an intervention.”
For salt intake, there’s a clear overlap between high salt consumption in Westernized diets and increasing incidence of MS. The association also holds for many other autoimmune diseases, Dr. Linker added.
“The next step is experimental evidence,” Dr. Linker said. In a rodent model of experimental autoimmune encephalomyelitis (EAE), rats with high salt intake had a worse clinical course, compared with control rats fed a usual diet (Nature. 2013 Apr 25;496[7446]:518-22).
“There were a lot of follow-up studies on that,” with identification of multiple immune cells that are up- or down-regulated via distinct pathways in a high-salt environment, Dr. Linker said.
More recently, Dr. Linker was a coinvestigator in work showing that healthy humans placed on a high-salt diet had significant increases in T-helper 17 (Th17) cells after just 2 weeks of an additional 6 g of table salt daily over a baseline 2-4 g/day (Nature. 2017 Nov 30;551[7682]:585-9).
“You can also translate it to a more realistic setting,” where individuals who ate fast food four or more times weekly had significantly higher Th17 cell counts than did those who ate less fast food, he noted in reference to unpublished data.
Looking specifically at MS, a single-center study found that increased sodium intake correlated with increased MS clinical disease activity, with the highest sodium intake (more than 4.8 g/day) associated with higher incidence of MS exacerbations. Those in the highest tier of sodium intake also had a higher lesion load, with 3.65 more T2 lesions seen on MRI scans for each gram of salt consumed above average amounts of 2-4.8 g/day (J Neurol Neurosurg Psychiatry. 2015 Jan;86[1]:26-31).
On the other hand, Dr. Linker said, “There have been recent very well-conducted studies in very well-defined cohorts casting doubt on this translation to multiple sclerosis.” In particular, an examination of data from over 70,000 participants in the Nurse’s Health Study showed no association between MS risk and dietary salt assessed by a nutritional questionnaire (Neurology. 2017 Sep 26;89[13]:1322-9). “There was no hint that the diagnosis was linked in any way with salt exposure,” Dr. Linker said.
In the BENEFIT study, both a spot urine sample and a food questionnaire were used, and patients were grouped into quintiles of sodium intake. For demyelinating events and MS diagnosis, the curves for all quintiles were “completely overlapping,” with no sign of increased risk of MS with higher sodium intake (Ann Neurol. 2017;82:20-9).
An important caveat to the null findings in these analyses is the known poor agreement between self-report of salt intake and actual sodium load, Dr. Linker noted. Renal sodium excretion can vary widely despite fixed salt intake, so spot urine and even 24-hour urine collection don’t guarantee accuracy, he said, citing studies from space travel emulations that show wide day-to-day excursions in sodium excretion with a fixed diet.
A promising tool for accurate assessment of sodium load may be sodium-23 skin spectroscopy using MRI, because skin tissue binds sodium in a stable, nonosmotic fashion. Dr. Linker and his colleagues have recently found that skin sodium levels, measured at the calf, are higher in individuals with relapsing-remitting MS. “Indeed, the sodium level in the skin of the MS patients was significantly higher than in the controls” who did not have MS, he said of the study that matched 20 patients with MS with 20 healthy controls. The MRI studies were assessed by radiologists blinded to the disease status of participants.
The increase is seen in only free sodium and seen in skin, but not muscle tissue, Dr. Linker said.
Using MRI spectroscopy with a powerful 7-Tesla magnet, Dr. Linker and his colleagues returned to the rodent EAE model, also finding increased sodium in the skin. Mass spectrometry findings were similar in other rodent autoimmune models, he said. The differences were not seen for sodium in other organs, or for potassium levels in the skin.
“The most difficult point,” Dr. Linker said, is “can we use this therapeutically somehow? Of course, you can put your patients on a salt-free or very low-salt diet, but it’s not very tasty, of course, and adherence would be probably very, very low.”
The microbiome may play a modulating role that adds to the sodium-MS story and provides a potential therapeutic option. In mice, a high-salt diet was associated with marked and rapid depletion of Lactobacillus species in the mouse gut microbiome. In healthy humans as well, the drop in lactobacilli was quick and profound when 6 g/day of salt was added to the diet, Dr. Linker said (P = .0053 versus the control diet of 2-4 g sodium/day).
Working backward with the same healthy cohort, repletion of Lactobacillus by probiotic supplementation normalized systolic blood pressure, which had become elevated with increased dietary sodium. Further, Lactobacillus repletion downregulated Th17 cells to levels seen before the high-sodium diet, even when dietary sodium stayed high.
“This was even transferred to multiple sclerosis,” in work recently published by another group, Dr. Linker said. For patients with MS who consumed a Lactobacillus-containing probiotic, investigators could “clearly show, besides effects on the microbiome itself, that there were effects on antigen-presenting cells in MS patients.” Intermediate monocytes decreased, as did dendritic cells, in the small study that involved both healthy controls and MS patients who received a probiotic and then underwent a washout period. Stool and blood samples were collected in both groups to compare values with and without probiotic administration.
A question from the audience looked back at historic data: 100 or more years ago, salt was used extensively for food preservation in many parts of the world, so dietary sodium intake is thought to have been higher. The incidence of MS, though, was lower then. Dr. Linker pointed out that food preservation practices varied widely, and that a host of other variables make assessment of past or present associations difficult. “It’s hard to argue that salt is the one and only risk factor; I would strongly doubt that.”
Still, he said, this early work invites more study, with a target of establishing whether probiotic supplementation could be used as “add-on therapy to established immune drugs.”
Dr. Linker has received honoraria and research support from Bayer, Biogen, Genzyme, Merck Serono, Novartis, and TEVA.
SOURCE: Linker R. ECTRIMS 2018, Scientific Session 7.
BERLIN – Among a host of potential risk factors for multiple sclerosis (MS), one emerging risk factor – dietary sodium – has accumulating evidence, bolstered by new imaging techniques and emerging research about the mediating effect of the gut microbiome.
“The word is still out on salt – there’s still some work to do; we are not where we stand with smoking or obesity” and the association with MS, said Ralf Linker, MD, speaking at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
For all potential emerging risk factors for MS, there’s an attractive hypothesis and, often, epidemiologic data, Dr. Linker said. “There are probably good [epidemiologic] data in multiple sclerosis for vitamin D, smoking, obesity, and probably also alcohol,” he said. “The therapeutic consequence, however, is much less clear, the best example of that being, of course, vitamin D.”
“The attractive risk factor is not enough to be a hypothesis, although some people seem to believe that nowadays,” said Dr. Linker, chair of the department of neurology at Friedrich-Alexander University, Erlangen, Germany. “Probably it’s better to start with some basic science and some experimental data to get an idea of the mechanism.”
“Today, we need clear associations with clear markers, well-defined cohorts, and proper epidemiological data telling us whether this is a real risk factor. ... If you look at the clinicians – and there are many among us in the room here – your ultimate goal, of course, is to use this as an intervention.”
For salt intake, there’s a clear overlap between high salt consumption in Westernized diets and increasing incidence of MS. The association also holds for many other autoimmune diseases, Dr. Linker added.
“The next step is experimental evidence,” Dr. Linker said. In a rodent model of experimental autoimmune encephalomyelitis (EAE), rats with high salt intake had a worse clinical course, compared with control rats fed a usual diet (Nature. 2013 Apr 25;496[7446]:518-22).
“There were a lot of follow-up studies on that,” with identification of multiple immune cells that are up- or down-regulated via distinct pathways in a high-salt environment, Dr. Linker said.
More recently, Dr. Linker was a coinvestigator in work showing that healthy humans placed on a high-salt diet had significant increases in T-helper 17 (Th17) cells after just 2 weeks of an additional 6 g of table salt daily over a baseline 2-4 g/day (Nature. 2017 Nov 30;551[7682]:585-9).
“You can also translate it to a more realistic setting,” where individuals who ate fast food four or more times weekly had significantly higher Th17 cell counts than did those who ate less fast food, he noted in reference to unpublished data.
Looking specifically at MS, a single-center study found that increased sodium intake correlated with increased MS clinical disease activity, with the highest sodium intake (more than 4.8 g/day) associated with higher incidence of MS exacerbations. Those in the highest tier of sodium intake also had a higher lesion load, with 3.65 more T2 lesions seen on MRI scans for each gram of salt consumed above average amounts of 2-4.8 g/day (J Neurol Neurosurg Psychiatry. 2015 Jan;86[1]:26-31).
On the other hand, Dr. Linker said, “There have been recent very well-conducted studies in very well-defined cohorts casting doubt on this translation to multiple sclerosis.” In particular, an examination of data from over 70,000 participants in the Nurse’s Health Study showed no association between MS risk and dietary salt assessed by a nutritional questionnaire (Neurology. 2017 Sep 26;89[13]:1322-9). “There was no hint that the diagnosis was linked in any way with salt exposure,” Dr. Linker said.
In the BENEFIT study, both a spot urine sample and a food questionnaire were used, and patients were grouped into quintiles of sodium intake. For demyelinating events and MS diagnosis, the curves for all quintiles were “completely overlapping,” with no sign of increased risk of MS with higher sodium intake (Ann Neurol. 2017;82:20-9).
An important caveat to the null findings in these analyses is the known poor agreement between self-report of salt intake and actual sodium load, Dr. Linker noted. Renal sodium excretion can vary widely despite fixed salt intake, so spot urine and even 24-hour urine collection don’t guarantee accuracy, he said, citing studies from space travel emulations that show wide day-to-day excursions in sodium excretion with a fixed diet.
A promising tool for accurate assessment of sodium load may be sodium-23 skin spectroscopy using MRI, because skin tissue binds sodium in a stable, nonosmotic fashion. Dr. Linker and his colleagues have recently found that skin sodium levels, measured at the calf, are higher in individuals with relapsing-remitting MS. “Indeed, the sodium level in the skin of the MS patients was significantly higher than in the controls” who did not have MS, he said of the study that matched 20 patients with MS with 20 healthy controls. The MRI studies were assessed by radiologists blinded to the disease status of participants.
The increase is seen in only free sodium and seen in skin, but not muscle tissue, Dr. Linker said.
Using MRI spectroscopy with a powerful 7-Tesla magnet, Dr. Linker and his colleagues returned to the rodent EAE model, also finding increased sodium in the skin. Mass spectrometry findings were similar in other rodent autoimmune models, he said. The differences were not seen for sodium in other organs, or for potassium levels in the skin.
“The most difficult point,” Dr. Linker said, is “can we use this therapeutically somehow? Of course, you can put your patients on a salt-free or very low-salt diet, but it’s not very tasty, of course, and adherence would be probably very, very low.”
The microbiome may play a modulating role that adds to the sodium-MS story and provides a potential therapeutic option. In mice, a high-salt diet was associated with marked and rapid depletion of Lactobacillus species in the mouse gut microbiome. In healthy humans as well, the drop in lactobacilli was quick and profound when 6 g/day of salt was added to the diet, Dr. Linker said (P = .0053 versus the control diet of 2-4 g sodium/day).
Working backward with the same healthy cohort, repletion of Lactobacillus by probiotic supplementation normalized systolic blood pressure, which had become elevated with increased dietary sodium. Further, Lactobacillus repletion downregulated Th17 cells to levels seen before the high-sodium diet, even when dietary sodium stayed high.
“This was even transferred to multiple sclerosis,” in work recently published by another group, Dr. Linker said. For patients with MS who consumed a Lactobacillus-containing probiotic, investigators could “clearly show, besides effects on the microbiome itself, that there were effects on antigen-presenting cells in MS patients.” Intermediate monocytes decreased, as did dendritic cells, in the small study that involved both healthy controls and MS patients who received a probiotic and then underwent a washout period. Stool and blood samples were collected in both groups to compare values with and without probiotic administration.
A question from the audience looked back at historic data: 100 or more years ago, salt was used extensively for food preservation in many parts of the world, so dietary sodium intake is thought to have been higher. The incidence of MS, though, was lower then. Dr. Linker pointed out that food preservation practices varied widely, and that a host of other variables make assessment of past or present associations difficult. “It’s hard to argue that salt is the one and only risk factor; I would strongly doubt that.”
Still, he said, this early work invites more study, with a target of establishing whether probiotic supplementation could be used as “add-on therapy to established immune drugs.”
Dr. Linker has received honoraria and research support from Bayer, Biogen, Genzyme, Merck Serono, Novartis, and TEVA.
SOURCE: Linker R. ECTRIMS 2018, Scientific Session 7.
BERLIN – Among a host of potential risk factors for multiple sclerosis (MS), one emerging risk factor – dietary sodium – has accumulating evidence, bolstered by new imaging techniques and emerging research about the mediating effect of the gut microbiome.
“The word is still out on salt – there’s still some work to do; we are not where we stand with smoking or obesity” and the association with MS, said Ralf Linker, MD, speaking at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
For all potential emerging risk factors for MS, there’s an attractive hypothesis and, often, epidemiologic data, Dr. Linker said. “There are probably good [epidemiologic] data in multiple sclerosis for vitamin D, smoking, obesity, and probably also alcohol,” he said. “The therapeutic consequence, however, is much less clear, the best example of that being, of course, vitamin D.”
“The attractive risk factor is not enough to be a hypothesis, although some people seem to believe that nowadays,” said Dr. Linker, chair of the department of neurology at Friedrich-Alexander University, Erlangen, Germany. “Probably it’s better to start with some basic science and some experimental data to get an idea of the mechanism.”
“Today, we need clear associations with clear markers, well-defined cohorts, and proper epidemiological data telling us whether this is a real risk factor. ... If you look at the clinicians – and there are many among us in the room here – your ultimate goal, of course, is to use this as an intervention.”
For salt intake, there’s a clear overlap between high salt consumption in Westernized diets and increasing incidence of MS. The association also holds for many other autoimmune diseases, Dr. Linker added.
“The next step is experimental evidence,” Dr. Linker said. In a rodent model of experimental autoimmune encephalomyelitis (EAE), rats with high salt intake had a worse clinical course, compared with control rats fed a usual diet (Nature. 2013 Apr 25;496[7446]:518-22).
“There were a lot of follow-up studies on that,” with identification of multiple immune cells that are up- or down-regulated via distinct pathways in a high-salt environment, Dr. Linker said.
More recently, Dr. Linker was a coinvestigator in work showing that healthy humans placed on a high-salt diet had significant increases in T-helper 17 (Th17) cells after just 2 weeks of an additional 6 g of table salt daily over a baseline 2-4 g/day (Nature. 2017 Nov 30;551[7682]:585-9).
“You can also translate it to a more realistic setting,” where individuals who ate fast food four or more times weekly had significantly higher Th17 cell counts than did those who ate less fast food, he noted in reference to unpublished data.
Looking specifically at MS, a single-center study found that increased sodium intake correlated with increased MS clinical disease activity, with the highest sodium intake (more than 4.8 g/day) associated with higher incidence of MS exacerbations. Those in the highest tier of sodium intake also had a higher lesion load, with 3.65 more T2 lesions seen on MRI scans for each gram of salt consumed above average amounts of 2-4.8 g/day (J Neurol Neurosurg Psychiatry. 2015 Jan;86[1]:26-31).
On the other hand, Dr. Linker said, “There have been recent very well-conducted studies in very well-defined cohorts casting doubt on this translation to multiple sclerosis.” In particular, an examination of data from over 70,000 participants in the Nurse’s Health Study showed no association between MS risk and dietary salt assessed by a nutritional questionnaire (Neurology. 2017 Sep 26;89[13]:1322-9). “There was no hint that the diagnosis was linked in any way with salt exposure,” Dr. Linker said.
In the BENEFIT study, both a spot urine sample and a food questionnaire were used, and patients were grouped into quintiles of sodium intake. For demyelinating events and MS diagnosis, the curves for all quintiles were “completely overlapping,” with no sign of increased risk of MS with higher sodium intake (Ann Neurol. 2017;82:20-9).
An important caveat to the null findings in these analyses is the known poor agreement between self-report of salt intake and actual sodium load, Dr. Linker noted. Renal sodium excretion can vary widely despite fixed salt intake, so spot urine and even 24-hour urine collection don’t guarantee accuracy, he said, citing studies from space travel emulations that show wide day-to-day excursions in sodium excretion with a fixed diet.
A promising tool for accurate assessment of sodium load may be sodium-23 skin spectroscopy using MRI, because skin tissue binds sodium in a stable, nonosmotic fashion. Dr. Linker and his colleagues have recently found that skin sodium levels, measured at the calf, are higher in individuals with relapsing-remitting MS. “Indeed, the sodium level in the skin of the MS patients was significantly higher than in the controls” who did not have MS, he said of the study that matched 20 patients with MS with 20 healthy controls. The MRI studies were assessed by radiologists blinded to the disease status of participants.
The increase is seen in only free sodium and seen in skin, but not muscle tissue, Dr. Linker said.
Using MRI spectroscopy with a powerful 7-Tesla magnet, Dr. Linker and his colleagues returned to the rodent EAE model, also finding increased sodium in the skin. Mass spectrometry findings were similar in other rodent autoimmune models, he said. The differences were not seen for sodium in other organs, or for potassium levels in the skin.
“The most difficult point,” Dr. Linker said, is “can we use this therapeutically somehow? Of course, you can put your patients on a salt-free or very low-salt diet, but it’s not very tasty, of course, and adherence would be probably very, very low.”
The microbiome may play a modulating role that adds to the sodium-MS story and provides a potential therapeutic option. In mice, a high-salt diet was associated with marked and rapid depletion of Lactobacillus species in the mouse gut microbiome. In healthy humans as well, the drop in lactobacilli was quick and profound when 6 g/day of salt was added to the diet, Dr. Linker said (P = .0053 versus the control diet of 2-4 g sodium/day).
Working backward with the same healthy cohort, repletion of Lactobacillus by probiotic supplementation normalized systolic blood pressure, which had become elevated with increased dietary sodium. Further, Lactobacillus repletion downregulated Th17 cells to levels seen before the high-sodium diet, even when dietary sodium stayed high.
“This was even transferred to multiple sclerosis,” in work recently published by another group, Dr. Linker said. For patients with MS who consumed a Lactobacillus-containing probiotic, investigators could “clearly show, besides effects on the microbiome itself, that there were effects on antigen-presenting cells in MS patients.” Intermediate monocytes decreased, as did dendritic cells, in the small study that involved both healthy controls and MS patients who received a probiotic and then underwent a washout period. Stool and blood samples were collected in both groups to compare values with and without probiotic administration.
A question from the audience looked back at historic data: 100 or more years ago, salt was used extensively for food preservation in many parts of the world, so dietary sodium intake is thought to have been higher. The incidence of MS, though, was lower then. Dr. Linker pointed out that food preservation practices varied widely, and that a host of other variables make assessment of past or present associations difficult. “It’s hard to argue that salt is the one and only risk factor; I would strongly doubt that.”
Still, he said, this early work invites more study, with a target of establishing whether probiotic supplementation could be used as “add-on therapy to established immune drugs.”
Dr. Linker has received honoraria and research support from Bayer, Biogen, Genzyme, Merck Serono, Novartis, and TEVA.
SOURCE: Linker R. ECTRIMS 2018, Scientific Session 7.
EXPERT ANALYSIS FROM ECTRIMS 2018