Restriction diets can be very useful when trying to manage symptoms related to the gut. We see this in people who have SIBO with a low FODMAP diet, people who have IBS in an SCD diet, and the Keto diet seems to be helping out people with a variety of issues. But just because something helps you manage symptoms in the short term doesn’t necessarily make it a great long term solution free of problems.
An excellent example of this is the use of PPIs in people with gastritis. Sure, decreasing acid exposure to a damaged stomach wall will decrease symptoms, but it doesn’t typically address the underlying issue. So, people take them for months on end to manage symptoms and end up paying later down the road.
I kind of see the same thing happening with oxalates. On paper, a low oxalate diet makes perfect sense if you buy in to the paradigm most put forth on the topic. Oxalates are a toxin that plants such as spinach, beets, nuts, potatoes and sweet potatoes use to defend against us that circulate throughout the body poisoning cells and destroying mitochondria.
The problem is, the data on this is shaky at best, typically in petri dishes, and when we take a look at how oxalate behaves in the body it just seems highly unlikely that consuming oxalates are:
- B)The primary cause of any problem
But to be clear, they are an issue for a significant number of people and decreasing oxalate intake is an intelligent way to start the process of healing a gut that is sensitive to oxalate. But it’s only the first step and something you should move beyond to address the underlying cause.
Note: I recently published a bit of a rundown on how we process oxalate on youtube. It would probably be useful, but not necessary, to check it out before continuing. Click here to check it out if you haven’t already.
Are oxalates toxins?
This one is pretty easy to quash right away. If oxalates were a human toxin, one would expect to see mortality increase in a population as people consume more of the foods that contain it. With regard to oxalate, nuts are loaded with them. But as nut intake increases, mortality actually decreases. This is the opposite effect you’d see with a toxin.
Similarly, legumes are also high in oxalate, but higher consumption is associated with lower mortality risk. It’s not a large effect, but if they were a toxin mortality would increase. Soy, another high oxalate food, shows no increase or decrease in mortality with increased intake. So it’s hard to really take oxalate as a toxin seriously. Mercury, lead, arsenic, and even alcohol are toxins.
This isn’t to say that people can’t have problems with oxalate. People with primary hyperoxaluria have an inborn defect of glyoxylate metabolism that causes them to produce too much oxalate in the body, which elevates the amount of oxalate in the urine. These people are much more likely to form kidney stones and can have problems throughout the body when calcium oxalate stones form.
Secondary/enteric hyperoxaluria occurs via excess absorption from the gut. But addressing why this is happening (Leaky gut, inflammation, high fat diet, low calcium intake) should be the major part of the solution, not simply relying on dropping oxalate intake to zero.
We have very efficient means of eliminating oxalate in both the stool and urine providing we’re not making tons of it in our body, absorbing tons of it, or providing an environment that converts all of it to calcium oxalates stones. Which is easy enough to do and much more effective.
Removal of oxalate from tissues
As I mentioned, we have a pretty great system for getting rid of oxalate. Oxalate is pumped out of cells via a cytoplasmic transporter known as Solute Carrier Family 26 Member 6(SLC26A6) that exchanges chloride outside of the cell for oxalate, sulfate, or bicarbonate inside the cell. In other words, when oxalate enters, SLC26A6 kicks it to the curb if there is adequate extracellular chloride.
SLC26A6 is expressed basically everywhere throughout the body, with very high expression in the brain, bone marrow, immune system, lung liver, gallbladder, gut, kidney, reproductive tissues, and skin. In the intestine it plays a pivotal role in reducing oxalate absorption, and another transporter pulls oxalate out of the blood and in to cells of the gut.
When oxalate from the diet or blood enters enterocytes and colonocytes, SLC26A6 sends the oxalate right back in to the gut in a process called secretion. This prevents absorption in to the blood and removes excess oxalate from the body.
Oxalate absorption throughout the gut varies with low absorption in the small intestine and proximal colon and high absorption in the distal colon. But this isn’t because oxalate doesn’t enter the cells in the small intestine, it does. The small intestine and proximal colon have a high expression of SLC26A6 that pumps oxalate, along with some of the oxalate we produce in the liver, back in to the gut. Thus, these portions of the gut are cause a net oxalate secretion back in to it, while the distal colon has net absorption…sort of. Back to that in a minute
So increased oxalate absorption, as seen in secondary/enteric hyperoxaluria probably has something to do with SLC26A^, right? Absolutely. In a nice little study in mice, obese mice excreted 3.3x more oxalate in their urine than healthy controls. This was not due to changes in diet because the mice were pair-fed, meaning their diets were identical.
Removing oxalate from the diet in the obese mice corrected their hyperoxaluria, which indicates that the excess oxalate was coming from absorption from the gut and not from production in the body. The obese mice had an 80% reduction in SLC26A6 activity in their jejunum, the middle portion of the small intestine, when compared to the healthy mice. This led to net oxalate absorption in the jejunum of obese mice whereas the healthy mice had net oxalate secretion back in to the gut. Must be the genes, right? Not so much.
Treating healthy jejunal tissue with the same inflammatory soup that one would experience with obesity leading to excess lipopolysaccharide(LPS) in the gut dramatically decreased expression of SLC26A6. This decreased jejunal secretion by 46%, converting the jejunum in to a net oxalate absorber. AND I MUST EMPHASIZE THIS: INFLAMMATION CAUSED THE OXALATE PROBLEM, THE OXALATE PROBLEM DIDN’T CAUSE THE INFLAMMATION!!!
Now, it’s important to point out that this transporter works in bascially same way everywhere. So systemic inflammation induced by LPS likely decreases SLC26A6 in all of the tissues where it’s expressed; it’s the same inflammatory soup. So, in systemic inflammation, you’d expect to see oxalate accumulate more rapidly in tissues such as the brain, kidney, lung, skin, and reproductive tissues where SLC26A6 is highly expressed.
Insights from kidney stone formers
While people who form kidney stones aren’t the only people who have issues with oxalate, it can be argued that they have the most severe issues outside of PH, which is more about production than absorption. When we look at kidney stone formers, men and older women who consume the most oxalate have a 22% and 21% increased risk of forming stones when compared to the lowest. There was no increase in risk from oxalate or spinach intake in young women.
To put this in to perspective, men who weigh more than 220lbs have a 44% higher risk when compared to men who weigh 150lbs. Women who fit the same bill have a 90% increased risk. Having a HgA1c indicative of pre-diabetes increases risk by 68% and HgA1c indicative of diabetes increases risk by 182%.
When we look at the physiology behind stone formation it makes perfect sense. Obese people and those with Type 2 diabetes are more at risk for leaky gut, chronic inflammation, and a greater proportion of M1 to M2 macrophages. Both accumulate more LPS in their gut, leaky gut increases absorption of LPS which causes the inflammation and macrophage polarization that lock oxalate into tissues and form calcium oxalate stones.
LPS also promotes an environment where more oxalate can be formed in the body. Type 2 diabetics and people on their way to Type 2 diabetes create more glyoxylate, a precursor to oxalate. When the liver is exposed to LPS, autophagy is altered leading to an accumulation of enzymes that break down glucose, including lactate dehydrogenase(LDH). You wouldn’t necessarily see this in obesity as in the mouse model above. It’s more of a byproduct of the Type 2 diabetes-induced glyoxylate formation and conversion to oxalate. But how?
A recent study in mice showed that LDH was the primary route of oxalate production in the liver, the organ which creates all the oxalate. Knocking down LDH in the liver of mice with primary hyperoxaluria(PH) 1 & 2 caused a dramatic drop in urinary oxalate and decreased calcium oxalate stone formation. Based on all of this data, tackling obesity and/or type 2 diabetes would yield 2-9x the results reducing oxalate in the diet would and all the mechanisms match up.
In my personal opinion, probably the biggest culprit that isn’t Type 2 diabetes is leaky gut induced accumulation of LPS in the blood. Address that, and you’ve addressed the problem. This also helps explain why a low oxalate diet works for autism. Data has shown that children with autism have much higher plasma and urinary oxalate levels than healthy children.
But, children with autism also have leaky gut, which would cause increased oxalate absorption and also explain why they have a more than 5-fold elevation in lipopolysaccharide-binding protein, a marker of LPS absorption than healthy controls. It also explains the chronic inflammatory state and may ultimately be the reason oxalates are a problem.
So the most pragmatic approach is to address the leaky gut at some point, not maintain a low oxalate diet ad infinitum. Our intestine is exquisitely designed to handle oxalate with transporters that pump it back in to the gut as are most of our organs, and it’s unlikely that oxalate is triggering leaky gut.
But we’re not finished. We have a little friend in our colon who can provide us with a little assistance from time to time. If you’ve dabbled with a low oxalate diet for any significant amount of time I’m sure you’ve heard of her: Oxalobacter formigenes.
Oxalobacter formigenes: our oxalate degrading friend
Anyone who has even thought about doing a low oxalate diet has heard of Oxalobacter formigenes. Many believed that the primary way it helps with oxalate is by degrading the oxalate we eat. It’s not.
Oxalate secretion can also happen in the colon, and guess which critter we find nestled up right next to this the SLC26A6 transporter. You got it, Oxalobacter formigenes. But O. formigenes isn’t just chilling there to passively grab a snack. She’s also secreting proteins that upregulate the transporter that pulls oxalate out of the blood and in to the gut, to the tune of 2.4x. Cool!
But let’s not forget that inflammation is going to decrease this by 80%, meaning eliminating inflammation will increase SLC26A6 4x as much, almost double what colonization with O. formigenes will.
So now you’re probably asking yourself, what if I don’t have O. formigenes? Well, good question. I don’t think it’s all that big of a deal unless you’re pumping out oxalates, and it appears that exposing oneself to a diet with oxalate in it is the best way to ensure you have O. formigenes.
Based on the study just mentioned, a low oxalate diet will pretty much wipe them out, oxalate consumption needs to be maintained in order to maintain O. formigenes colonization. And who knows what’s going to happen when you have inflammation reducing SLC26A6 based oxalate to O. formigenes by 80%.
But, is it hard to colonize with O. formigenes if you weren’t born with it. Good news, you weren’t born with it so you can probably get it.
Prevalence of O. formigenes in US and hunter gatherer Mothers
Everyone who believes that oxalates are toxic explain away the high consumption of high oxalate foods in hunter gatherer populations and the lack crippling pain and digestive problems to their colonization with O. formigenes. But there’s a problem with that theory.
Despite those populations having a higher prevalence of O. formigenes colonization, it’s still only 60-80% of them. So why aren’t the other 20-40% of them doubled over in pain from their relatively high toxic oxalate consumption? Could it be because they aren’t overweight and diabetic?
But what about mother and children here in the US? While O. formigenes colonization is much lower here, it’s not something we take from Mother to child from birth nor do hunter gatherers. Children in the US AND in hunter gatherer populations aren’t colonized with O. formigenes at birth. In the US children, colonization didn’t begin until 1 year of age, while in the hunter gatherer populations the earliest was 3 months and 9 months in Amerindians and Hadza, respectively. However, the general trend in all groups was no colonization until 1 year of age.
So how would these children get colonized with O. formigenes if they weren’t born with it. If, as mentioned above, oxalate consumption is the primary determinant of O. formigenes colonization, these infants must have been exposed to oxalate from some source. Given that hunter gatherers don’t shop at CVS for formula, the mothers must have been passing oxalate to the child via breast milk. Kind of odd for a mother to pass a human toxin along to their child in breast milk. Particularly one that’s been consumed at very high levels for the vast majority of primate evolution.
Additionally, in the US cohort, there was no relationship between child colonization and whether or not the mother was colonized, birthing method, or antibiotic exposure. Children born from mothers who were negative for O. formigenes could still be colonized with O. formigenes up to 2 years of age, when the study stopped.
Taking all of the data in to consideration, oxalate is most definitely not a human toxin. Indeed, if oxalate were toxic to us, Mothers wouldn’t pass it ot their non-colonized babies and there wouldn’t be a beneficial response in doing so.
It is also abundantly clear that the modern human lifestyle which drives obesity, Type 2 diabetes, hyperglycemia, leaky gut, and chronic inflammation is the primary driver of oxalate problems. While lowering oxalate in the diet may provide symptomatic relief, there is little doubt that doing so chronically will decrease colonization with O. formigenes and make things worse in the long run. Regardless, O. formigenes colonization probably only provides modest benefit anyways since 20-40% of hunter gatherers, who have a high oxalate diet, aren’t colonized with O. formigenes.
The real problem with addressing these issues with a low oxalate diet is that you are ignoring the actual cause of the problem. And by ignoring the problem you are likely making it much worse and more difficult to correct. We know several drivers of leaky gut and most of them are correctable by modifying your behavior. I’ve seen this over and over with the people I’ve worked with.
Other factors can alo be involved. Persistent viral and bacterial infections, microbial dysbiosis, heavy metal toxicity, and even some things outside of our control such as our genetic predisposition to inflammatory bowel disease and other genetic factors, including primary hyperoxaluria. But, ignoring the lifestyle component only makes these things worse, and you have no control over genetic predispositions.
Thus, while a low oxalate diet may be useful in the short term to manage the symptoms associated with secondary/enteric hyperoxaluria, anything short of identifying and addressing the actual cause will likely cause problems further down the road.
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