Category Archives: Disease - Page 19

What’s the Trouble With Sweet Potatoes?

Posted by on January 11, 2011 166 comments

We’re continuing with a series on people who have reported something going wrong when they tested some variation of the Perfect Health Diet. (The first post summarized experiences, good and bad; the second looked at difficulties suddenly adding carbohydrates to a very low-carb diet.)

The next issue was reported by Chris Masterjohn; he had trouble with sweet potatoes:

Although sweet potatoes are considered a safe starch on the Perfect Health Diet, they are not very safe for me. When I discovered how yummy sweet potato fries are, I started eating several sweet potatoes per day. Within a few days, I was limping and my neck was stiff. By the end of the week, my limp was extreme. I looked online to see if I was eating anything high in oxalates, and sure enough, sweet potatoes are loaded with them. My symptoms dramatically improved after one day off sweet potatoes and were gone the second day.

Chris’s commenter Lisa also had trouble with sweet potatoes:

I’ve been very achy since I started eating sweet potatoes daily. Why would some of us be maladapted to oxalates?… I’m wondering if after a long stint of LC/paleo eating I’ve become intolerant to oxalates or to starch in general.

Clearly sweet potatoes are not safe for everyone. What might be causing the trouble?

Fructose and Fiber as Possible Confounders

One factor to consider is that there are different varieties of sweet potato. We eat an Asian sweet potato variety which is not nearly as sweet as conventional American sweet potatoes; it has a yellow flesh and a chestnut flavor. It is botanically a yam, not a sweet potato. It looks like this (via “my super sweet twenty-six”):

Like so many modern foods, the standard American sweet potato has been bred for sweetness. Here is data from http://nutritiondata.com comparing 100 g of potatoes, yams, sweet potatoes, and grapes for sugar, starch, and fiber content:

Food Sugar (g) Starch (g) Fiber (g)
Potato 1.2 17.3 2.2
Yam 0.5 23.1 3.9
Sweet potato 6.5 7.5 3.3
Grapes 15.5 0.0 0.9

All have similar calories. Yams are largely sugar-free, but sweet potatoes are intermediate between grapes and potatoes in both sugar and starch content. They are sort of half fruit, half starch.

Thus, it is conceivable that sweet potatoes could trigger an issue like fructose malabsorption; or that fructose or fiber might feed certain gut infections that would not be similarly fed by potatoes.

Oxalate

Chris believed his problem was due to oxalate. Sweet potatoes do contain oxalate, although they are not the only plant foods which do.

In fact, by far the largest source of oxalate in the American diet is spinach. Spinach by itself accounts for over 40% of all oxalate consumed by Americans; potatoes for about 10%. [1] Wheat bran has high levels of oxalate.

Why are oxalates troublesome?  Some people have sensitivities to oxalate. Rarely, genetic defects in the enzymes that degrade oxalate cause a disease called primary hyperoxaluria; this disease afflicts 1 to 3 people in a million.  Other conditions can elevate calcium or oxalate in the urine and increase the risk of calcium oxalate kidney stones. This is especially likely in people who are deficient in magnesium or who don’t eat citrate. [2]

Another pathway by which oxalate might cause trouble is via fungal infections. Candida and other fungi form calcium oxalate crystals in tissue [3,4]; fungi appear to be responsible for the yellow-brown calcium oxalate biofilms which form on stone monuments. [5]

But the literature suggests that oxalate sensitivities are rare. If oxalate sensitivity is present, then it should manifest itself when eating spinach, wheat bran, and other oxalate rich foods. Since Chris has praised spinach and wheat recently, I wonder if it is really the oxalate that caused his trouble.

Phytoalexins

Another possibility is a class of toxins called phytoalexins.

Ordinarily, sweet potatoes are largely toxin free. But when attacked by fungus or molds, sweet potatoes generate a variety of food toxins. As two papers describe them:

Sweet potatoes contain phytoalexins that can cause lung edema and are hepatotoxic to mice. At least one of these, 4-ipomeanol, can cause extensive lung clara cell necrosis and can increase the severity of pneumonia in mice. Some phytoalexins in sweet potatoes are hepatotoxic and nephrotoxic to mice. [6]

Ipomeanine (IPN), 4-ipomeanol (4-IPO), 1-ipomeanol (1-IPO), and 1,4-ipomeadiol (DIOL) are toxic 3-substituted furans found in mold-damaged sweet potatoes. IPN and 4-IPO are the most toxic, but all produce pulmonary toxicity in cattle and rodents, and 4-IPO induces hepatotoxicity in humans. [7]

Cattle will die if fed mold-damaged sweetpotatoes:

Unfortunate bovine fatalities occurring after ingestion of mold-damaged sweetpotatoes preclude the use of the culled tubers in livestock feed. In cattle, mold-damaged sweetpotatoes induce an acute respiratory distress syndrome resulting in asphyxiation. [8]

Toxins may be present even if mold damage is not visible:

Fermentation of 6 weeks duration was observed to inadequately eliminate the lung, liver, and kidney toxicity caused by mold-damaged sweetpotatoes. In fact, fermentation exacerbated the hepatotoxicity of mold-damaged sweetpotatoes. This is also the first demonstration that sweetpotato regions lacking visible mold damage can induce lung and kidney injury … [8]

Allergies

Sweet potatoes are generally considered to be one of the least allergenic of foods. However, infants sometimes do have sensitivities to sweet potato. This may reflect an immature gut flora in the infants; perhaps specific bacterial species — possibly including the oxalate-digesting Oxalobacter [9] — make sweet potatoes tolerable? If so, it raises the possibility that adults with incomplete gut flora might also have sweet potato sensitivities.

There is also the possibility of allergies to mold toxins in infected sweet potatoes.

Food Sensitivities as a Diagnostic Tool

Food sensitivities can sometimes be helpful in diagnosing certain health conditions:

  • Leaky gut. People with a leaky gut will have many food sensitivities; people with a healthy gut will have few.
  • Small bowel infections. People with infections of the small intestine will usually have a negative reaction to fructose.
  • Colonic infections. People with infections of the colon may react badly to fiber, and obtain relief on low-fiber diets.

There is a chance that oxalate may benefit fungal infections, so I suppose an oxalate sensitivity could be diagnostic for that, although in my experience fungal infections are usually slow-reacting to food and the response is rarely obvious.

Conclusion

In our book [p 121] we note that all plants make pesticidal toxins. Thus, no plant food can be guaranteed to be safe.

Normally, levels of pesticidal toxins are low in sweet potatoes. But it’s always desirable to inspect sweet potatoes for visible damage, and to discard any that are discolored or show other evidence of toxin production.

I confess to being puzzled as to how sweet potatoes caused Chris’s symptoms. If he tolerates spinach and wheat bran, it seems unlikely that the oxalate in sweet potatoes would be responsible. He might wish to test various foods and try to narrow down the source of his sensitivity.

For our part, we may cease listing sweet potatoes among our “safe starches” and specify yams instead, since a “safe starch” should probably be low in fructose.

References

[1] Taylor EN, Curhan GC. Oxalate intake and the risk for nephrolithiasis. J Am Soc Nephrol. 2007 Jul;18(7):2198-204. http://pmid.us/17538185.

[2] McConnell N et al. Risk factors for developing renal stones in inflammatory bowel disease. BJU Int. 2002 Jun;89(9):835-41. http://pmid.us/12010224.

[3] Takeuchi H et al. Detection by light microscopy of Candida in thin sections of bladder stone. Urology. 1989 Dec;34(6):385-7. http://pmid.us/2688263.

[4] Muntz FH. Oxalate-producing pulmonary aspergillosis in an alpaca. Vet Pathol. 1999 Nov;36(6):631-2. http://pmid.us/10568451.

[5] Pinna D. Fungal physiology and the formation of calcium oxalate films on stone monuments. Aerobiologia. 1993 9(2-3):157-167. http://www.springerlink.com/content/n72l71352t1r0r04/.

[6] Beier RC. Natural pesticides and bioactive components in foods. Rev Environ Contam Toxicol. 1990;113:47-137. http://pmid.us/2404325.

[7] Chen LJ et al. Metabolism of furans in vitro: ipomeanine and 4-ipomeanol. Chem Res Toxicol. 2006 Oct;19(10):1320-9. http://pmid.us/17040101.

[8] Thibodeau MS et al. Effect of fermentation on Sweetpotato (Ipomoea batatas) toxicity in mice. J Agric Food Chem. 2004 Jan 28;52(2):380-4. http://pmid.us/14733525. B76FN5FG89GM

[9] Hatch M et al. Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of Primary Hyperoxaluria following intestinal colonization with Oxalobacter. Am J Physiol Gastrointest Liver Physiol. 2010 Dec 16. [Epub ahead of print]. http://pmid.us/21163900.

Chronic Disease: Don’t Ever Give Up

Posted by on December 28, 2010 49 comments

Two days before Christmas, Amy left a heart-rending comment:

My dad has Alzheimers and was just put in a nursing home because my mom can’t handle taking care of him anymore. He shouldn’t be there and I believe there’s still hope for recovery in him…. What are your thoughts in this situation?

You can visit the comment to see my immediate response. But I thought I’d say a bit more here.

Don’t Ever Give Up

Two erroneous beliefs encourage people to give up too quickly.

  • Many diseases are wrongly considered to be inevitable and natural consequences of aging. Aging, unlike disease, is considered to be incurable.
  • The ineffectiveness of conventional medicine makes us think that cures are impossible. But I believe that dietary, nutritional, and antimicrobial therapies can effectively treat many of the diseases of aging, including Alzheimer’s.

As regular readers know, I had a chronic illness that seemed to progress relentlessly – until I started fixing my diet. It took another 5 years, but I eventually found a cure.

I think my case was far from unique. Many chronic illnesses can be cured. The path to recovery is not yet well mapped, and may require considerable experimentation. But I think we know enough now to see the general direction. It is worth embarking on the journey. And worth adopting the motto of Jim Valvano: “Don’t give up. Don’t ever give up.”

Fasting and the Ketogenic Diet for Migraines

Posted by on December 21, 2010 82 comments

We’ve previously argued that people with migraines should try a ketogenic diet. There are two reasons: (1) ketones can evade certain mitochondrial defects which might cause migraines, and (2) ketones reduce glutamate levels, and glutamate toxicity is implicated in migraines.

Reader Rob Sacks has had lifelong migraine headaches. As an experiment he turned to desperate measures – a long fast. Here’s his story:

I fasted for 30 days.   When I say “fast” I mean that I stopped eating all food.   I consumed only water and occasionally sea salt and potassium tablets.

As part of the fast I stopped taking Imitrex which I had been using almost daily to control my migraines.   I did this because I thought Imitrex was increasing the number of migraines due to a rebound effect.   I also stopped consuming caffeine to which I was addicted.

As the fast went on, my migraines lasted for shorter periods of time, and they became less painful. 

By day 23 I became free of headaches.  There was still some sort of migraine activity — I could often feel the sensations that in all my previous life, had always been followed by a headache — but no headache resulted.   Judging from what I could feel, there is a cascade of events that leads to a migraine, and the metabolic changes induced by the fast were interrupting the cascade at a certain point.

I was quite happy with this result and continued the fast as long as I could in the hopes that this would increase the chances that the change would be permanent.

Unfortunately, after the fast ended, the headaches gradually came back. I think this happened because after the first few post-fast meals, I made no effort to keep my diet ketogenic. An intense craving for fruit developed and once the danger of refeeding syndrome seemed to be over, I gave in. This was interesting because before the fast I had been on low carb diets since 2007 and hadn’t craved carbs in years.

When I saw the gains slipping away, I fasted again for two days to get back into ketosis as quickly as possible. Then I started following a diet similar to those used by neurologists at Johns Hopkins to treat children with epilepsy, with calorie restriction, frequent meals, and a ratio of fat to protein (by weight) of four to one. After two days of this diet, my headaches stopped again. That was only 48 hours ago but I’m sure the diet is working because I challenged myself last night with a sure-fire migraine trigger by staying up past my bedtime to watch the eclipse. Normally this would create a debilitating headache, but the only result was a slight migrainy feeling that was easily controlled with two aspirin. Before the fast, aspirin had no apparent effect on my migraines.

The next step will be to try more moderate diets and find the least extreme one that controls the headaches.

The fast proved that migraine headaches can be stopped by the metabolic changes induced by fasting.  Hopefully I can find a way to make that same metabolic state occur permanently.

Incidentally, the fast had some unexpected beneficial effects.  A bad varicose vein is dramatically improved, and a teary eye problem (which I think was caused by a clogged tear duct, and which I previously controlled with large amounts of vitamin C) has resolved almost completely.

I think this kind of experimentation is extremely important. Through experiments like Rob’s we can learn more about the causes of these seemingly incurable health conditions and find dietary and nutritional methods for healing or mitigating them. Experiments in lab mice are important, but the mice don’t tell us what they’re experiencing!

Rob lost 22 pounds during his 30-day fast, equivalent to 2200 calories per day if taken equally from protein and fat. Such an extended loss of lean tissue can be quite dangerous. If he had taken coconut oil or medium chain triglycerides during his fast, he would have conserved lean tissue mass and might have actually increasing ketone availability.

Fortunately it looks like ketogenic dieting is the key to Rob’s migraine relief, so extreme fasting should not be necessary.

Fasting does have therapeutic actions apart from its elevation of ketones. For instance, it promotes autophagy. It is possible that the fasting, not the ketones, was responsible for Rob’s cure of his varicose vein and teary eyes.

Rob might wish to experiment with protein restriction and other techniques for autophagy promotion, in order to see if they might also be beneficial in addition to ketosis.

Also, experimenting with micronutrients is important. Magnesium and riboflavin are often helpful for migraines.

Good luck Rob! Keep us posted.

Tryptophan Poisoning and Chronic Infections

Posted by on December 21, 2010 14 comments

On Friday I discussed a recent paper showing that a high-tryptophan diet caused mice, after 4 to 12 weeks, to start harming themselves by tearing out fur from their bellies and forepaws. The mice also developed ulcerative dermatitis – open sores on their skin. [1]

I closed with a promise that on Monday I would suggest some reasons why a high tryptophan diet might cause these diseases.

However …

C57BL/6 Mice Are Prone to Ulcerative Dermatitis

The breed of mice used in the study, C57BL/6 mice, are an inbred strain featuring some genetic mutations which make them prone to ulcerative dermatitis and compulsive behavior.

Upon looking into the literature, it seems that if you look at these mice cross-wise they get ulcerative dermatitis.

For instance, vitamin A causes ulcerative dermatitis in these mice because of mutations that impair the disposal of excess retinol:

A number of C57BL/6 (B6) substrains are commonly used by scientists for basic biomedical research. One of several B6 strain-specific background diseases is focal alopecia that may resolve or progress to severe, ulcerative dermatitis…. Four B6 substrains tested have a polymorphism in alcohol dehydrogenase 4 (Adh4) that reduces its activity and potentially affects removal of excess retinol. Using immunohistochemistry, differential expression of epithelial retinol dehydrogenase (DHRS9) was detected, which may partially explain anecdotal reports of frequency differences between B6 substrains. The combination of these 2 defects has the potential to make high dietary vitamin A levels toxic in some B6 substrains … [2]

Malnourishment seems to lead to spontaneous development of ulcerative dermatitis. The cause may be oxidative stress, since supplemental vitamin E cures the ulcerative dermatitis:

In this study, we fed a standard NIH-31 diet fortified with vitamin E to C57BL/6 mice and strains of mice with a C57BL/6 background that had spontaneously developed ulcerative dermatitis (UD)…. Of 71 mice, 32 (45%) had complete lesion re-epithelialization with hair regrowth. Complete lesion repair was not influenced by sex, age, or coat color. The average time to complete lesion repair ranged from 2 to 5 weeks, and there was no correlation with sex or coat color. The positive response to vitamin E suggests that protection from oxidative injury may play a role in the resolution of UD lesions … [3]

When scientists studying cancer applied a carcinogenic toxin to the skin of these mice, they developed not cancer but – you guessed it – ulcerative dermatitis:

In this study, heterozygous p53-deficient (p53(+/-)) mice … and wild-type (WT) litter mates were subjected to a two-stage skin carcinogenesis protocol with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Instead of skin carcinomas, however, the chemical treatment protocol caused ulcerous skin lesions, and 89% of mice fed ad libitum died from infection/septicemia. When WT mice were restricted to 60% of the average calorie intake of the respective ad libitum group, however, only 33% developed such lesions, and the CR mice survived twice as long on average as the ad libitum mice. [4]

It’s interesting that calorie restriction reduces the ulcerative dermatitis rate. Note that the mice went on to die of sepsis from an unknown infection; this suggests that these mice probably had some chronic pre-existing infection that was laying dormant, but emerged to become acute when the mouse was stressed by the toxins.

So far we’ve seen that malnutrition (lack of antioxidants) and exposure to toxins (vitamin A, carcionogens) can cause ulcerative dermatitis. Our three major causes of disease are malnutrition, toxins, and pathogens, so to complete our survey we should check whether infections cause ulcerative dermatitis in these mice.

Indeed they do. The most common infection in laboratory mice is fur mites, and fur mite infections induce ulcerative dermatitis in all strains of C57BL mice. [5]

Since diseases become more common with age, we shouldn’t be surprised to see that the rate of spontaneous ulcerative dermatitis rise with age in these mice:

A spontaneous, severely pruritic ulcerative dermatitis was initially observed in 33/201 (16.4%) aged C57BL/6NNia mice obtained from the National Institute of Aging. This ulcerative dermatitis also developed in 21/98 (21%) aged C57BL/6 mice in a subsequent experimental group obtained from the same source. The average age of onset in the initial group was 20 months. These animals were negative for ectoparasite infestation and primary bacterial or fungal infection. The lesions varied from acute epidermal excoriation and ulceration to chronic ulceration with marked dermal fibrosis…. The elucidation of the pathogenesis of this disease is important because of the significant percentage of animals affected … [6]

Given that there are so many possible triggers of ulcerative dermatitis in these mice, I decided to shift the topic of this post a bit, and focus on the specific possibility that chronic infections might play a role.

Lab Mice Are At Risk For Chronic Infections

As I’ve said many times, everyone gets chronic infections. The world is saturated in germs, and sooner or later the ones that can maintain persistent infections take up residence in all of us. So health is determined by the relative balance of power between immune system and pathogens, not by exposure.

Lab mice are at heightened risk for chronic infections because of their living conditions. In the case of the tryptophan-poisoned mice, here’s a description of their accommodations:

All subjects were adult (over 6 months of age) C57BL/6 mice, bred from C57BL/6J progenitors, and housed with same-sex siblings…. Lights were on a 14-10-h light-dark cycle. Mice were caged in standard shoebox cages (12.7 cm high, 433 cm2 floor area) with wire lids…. Ages ranged from 24-66 weeks of age (mean, 47 weeks). The number of mice per cage was variable, ranging from 2-4 mice per cage. [1]

These shoebox cages are small: 433 cm2 floor area translates to roughly 15 by 29 cm or 6 by 11 inches. The lid is 5 inches high. With four mice to a cage, each mouse gets a 3 by 5 inch area.

There is little room to exercise. Crowding is stressful.

Moreover, there is no natural sunlight, and therefore no vitamin D production.

All of these factors tend to impair immune function. Their casein, cornstarch, and soybean oil diets can’t be helpful to immune function either.

Cages are generally fairly closely packed in animal facilities. The mice generally cannot touch mice in adjacent cages, but respiratory pathogens and fur mites spread easily. If one mouse in a facility gets fur mites, usually all the others get infected soon afterward, and the whole room has to be quarantined.

Note also that the mice are old enough – 6 to 15 months – to have had extensive exposure to any chronic pathogens carried by either their mouse neighbors or their human handlers.

So it wouldn’t be surprising if the lab mice in this study had chronic infections.

Chlamydiae Infections in Lab Mice

C. pneumoniae is a zoonotic bacterium that crossed from reptiles to mammals about 60 million years ago and can infect both humans and animals.

Unfortunately, nobody seems to have bothered to see if C. pneumoniae is commonly present in “healthy” lab mice. However, in test tubes C. pneumoniae infects mouse brain cells just fine:

Inspired by the suggested associations between neurological diseases and infections, we determined the susceptibility of brain cells to Chlamydia pneumoniae (Cpn). Murine astrocyte (C8D1A), neuronal (NB41A3) and microglial (BV-2) cell lines were inoculated with Cpn…. Our data demonstrate that the neuronal cell line is highly sensitive to Cpn, produces viable progeny and is prone to die after infection by necrosis. Cpn tropism was similar in an astrocyte cell line, apart from the higher production of extracellular Cpn and less pronounced necrosis. In contrast, the microglial cell line is highly resistant to Cpn as the immunohistochemical signs almost completely disappeared after 24 h. Nevertheless, significant Cpn DNA amounts could be detected, suggesting Cpn persistence. [7]

So in the mouse glial cells which were most resistant, C. pneumoniae could maintain infections even if it didn’t do much. In mouse neurons and astrocytes, C. pneumoniae was able to reproduce freely and would eventually kill the cells.

In a different mouse microglial cell line, EOC-20, C. pneumoniae replicates rapidly, increasing 9-fold in 3 days. [8] So it appears that C. pneumoniae can infect all the major cell types of the mouse brain.

In humans, C. pneumoniae generally reaches the brain by first infecting the blood vessels that feed the brain. In our C57BL/6 mice, C. pneumoniae can create a vascular infection after a single dose in the nose:

In C57BL/6J mice on a nonatherogenic diet, C. pneumoniae were detected in the aorta only 2 weeks after a single intranasal inoculation in 8% of mice. The persistence of C. pneumoniae in atheromas suggests a tropism of C. pneumoniae to the lesion. [9]

Repeated inoculation of C57BL/6J mice resulted in inflammatory changes in the heart and aorta in 8 of 40 of mice … [10]

In a ranking of mouse strains in susceptibility to C. pneumoniae infection, C57BL/6 mice occupy a middle position:

The first mouse models for C. pneumoniae infection … used several mouse strains that differed in susceptibility to infection. Swiss Webster mice and NIH/S mice were highly susceptible, followed by C57BL/6 mice, whereas BALB/c mice were least susceptible. [11]

C. pneumoniae infection typically begins with a brief, mild respiratory infection that is followed by spread of the pathogen to other organs via infected white blood cells and establishment of a persistent infection:

Infection of mice with C. pneumoniae resulted in a self-limiting pneumonia [30–32,77]. Depending on the dose given, mice displayed symptoms, like dyspnea, weakness and weight loss. The symptoms reached a maximum within 2 to 4 days and rarely lasted longer than 1 week….

Isolation of viable C. pneumoniae organisms from the lungs was generally possible up to 4 weeks after infection and occasionally up to 6 weeks [31,32,42,47,49,52,54,66,72]. However, C. pneumoniae antigens and DNA were detected in the lungs for a much longer period, up to 20 weeks after infection [42]. The presence of C. pneumoniae antigens in the lungs was limited to macrophages in alveoli and bronchus-associated lymphoid tissue [63]. These findings suggested a latent persistence of the organisms, which was confirmed by reactivation of pulmonary infection using cortisone-induced immunosuppression experiments [50,51]….

C. pneumoniae infection was not limited to the respiratory tract only. Following local infection, spreading of C. pneumoniae to multiple organs throughout the body was detected by PCR and immunohistochemical staining up to 20 weeks [42]. The dissemination was probably mediated by peripheral blood monocytes as they were positive both by PCR and isolation in some studies, whereas blood plasma was negative [38,47]. [11]

Interferon Gamma and the Immune Defense Against Chlamydiae

In both humans and mice, immune defense against Chlamydiae is mediated principally by interferon gamma. Mice that lack interferon gamma or its receptor suffer prolonged severe infections:

The central role of IFN-? in clearance is evidenced by prolonged infections that occur in IFN-?, and IFN-? receptor-, deficient mice (10, 11). [12]

Infant mice exposed to Chlamydiae die within 2 weeks if they lack interferon gamma:

Importantly, infected mice deficient in IFN-gamma or IFN-gamma receptor demonstrated enhanced chlamydial dissemination, and 100% of animals died by 2 wk postchallenge. [13]

Might Chlamydia Infection Have a Connection to Compulsive Behavior and Ulcerative Dermatitis?

I started looking into these Chlamydia infection papers to see if they might explain why C57BL/6 mice given high levels of tryptophan might develop compulsive behavior and ulcerative dermatitis.

It’s possible. The logic goes like this.

First, tryptophan is crucial to Chlamydial growth; it is a precursor to niacin, the key vitamin of bacterial metabolism, and is also essential to a number of Chlamydial proteins. So a high-tryptophan diet will promote Chlamydiae infections.

Chlamydiae trigger the innate immune response mediated by interferon gamma.

So interferon gamma will be elevated in Chlamydiae-infected mice. Interestingly, the only study I found that gave interferon gamma directly to mice found that it caused ulcerative dermatitis:

Daily subcutaneous doses of 0.02, 0.2, or 2 mg/kg/d of recombinant murine interferon-gamma (rmuIFN-gamma) were given to mice on postnatal days 8 through 60 … Males given 0.2 and 2 mg/kg/d had swelling and ulcerative dermatitis around the urogenital area, which were observed after sexual contact and attributed to a bacterial infection. [14]

What about the compulsive behavior? Well, in mice one of the principal effects of interferon gamma is to stimulate the release nitric oxide (NO):

Gamma interferon (IFN-gamma)-induced effector mechanisms have potent antichlamydial activities that are critical to host defense. The most prominent and well-studied effectors are indoleamine dioxygenase (IDO) and nitric oxide (NO) synthase. The relative contributions of these mechanisms as inhibitors of chlamydial in vitro growth have been extensively studied using different host cells, induction mechanisms, and chlamydial strains with conflicting results. Here, we have undertaken a comparative analysis of cytokine- and lipopolysaccharide (LPS)-induced IDO and NO using an extensive assortment of human and murine host cells infected with human and murine chlamydial strains. Following cytokine (IFN-gamma or tumor necrosis factor alpha) and/or LPS treatment, the majority of human cell lines induced IDO but failed to produce NO. Conversely, the majority of mouse cell lines studied produced NO, not IDO. [15]

That’s interesting, because nitric oxide (NO) induces compulsive behavior in mice. A standard measure of obsessive-compulsive behavior in mice is marble burying. Nitric oxide increases marble burying:

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive-compulsive disorder, patients with obsessive-compulsive disorder exhibit higher plasma nitrate levels, and drugs useful in obsessive-compulsive disorder influence nitric oxide, we hypothesized that nitric oxide may have some role in obsessive-compulsive behavior. We used marble-burying behavior of mice as the animal model of obsessive-compulsive disorder, and nitric oxide levels in brain homogenate were measured using amperometric nitric oxide-selective sensor method. Intraperitoneal administration of nitric oxide enhancers … significantly increased marble-burying behavior as well as brain nitrites levels, whereas treatment with 7-nitroindazole-neuronal nitric oxide synthase inhibitor (20-40 mg/kg, i.p.) or paroxetine-selective serotonin reuptake inhibitor (5-10 mg/kg, i.p.) dose dependently attenuated marble-burying behavior and nitrites levels in brain…. In conclusion, obsessive compulsive behavior in mice appears related to nitric oxide in brain … [16]

Giving mice arginine, which raises NO levels, reverses the effect of SSRI antidepressants:

enhancement of NO synthesis by l-arginine reversed the effect of SSRI antidepressants, further demonstrating the role of NO in regulating the marble-burying behavior [17]

In rats allowed access to cocaine, blocking NO production decreased their self-administration of the drug. [18] This raises the possibility that Chlamydiae infection, leading to increase NO production, would increase self-administration of cocaine.

So if your pet mice are addicted to cocaine, maybe you should give them antibiotics!

Conclusion

Chronic infections are widespread in both humans and animals, and can have odd effects on behavior and health. Yet researchers have barely begun to detect their existence, much less trace their effects.

I don’t know whether chronic infections were involved in the apparent poisoning of C57BL/6 mice by tryptophan. But, since tryptophan is a very strong promoter of bacterial growth, and bacterial infections trigger interferon gamma and nitric oxide release which can induce ulcerative dermatitis and compulsive behavior in this breed, the possibility can’t be ruled out.

References

[1] Dufour BD et al. Nutritional up-regulation of serotonin paradoxically induces compulsive behavior. Nutr Neurosci. 2010 Dec;13(6):256-64. http://pmid.us/21040623.

[2] Sundberg JP et al. Primary Follicular Dystrophy With Scarring Dermatitis in C57BL/6 Mouse Substrains Resembles Central Centrifugal Cicatricial Alopecia in Humans. Vet Pathol. 2010 Sep 22. [Epub ahead of print]. http://pmid.us/20861494.

[3] Lawson GW et al. Vitamin E as a treatment for ulcerative dermatitis in C57BL/6 mice and strains with a C57BL/6 background. Contemp Top Lab Anim Sci. 2005 May;44(3):18-21.  http://pmid.us/15934718.

[4] Perkins SN et al. Calorie restriction reduces ulcerative dermatitis and infection-related mortality in p53-deficient and wild-type mice. J Invest Dermatol. 1998 Aug;111(2):292-6. http://pmid.us/9699732.

[5] Dawson DV et al. Genetic control of susceptibility to mite-associated ulcerative dermatitis. Lab Anim Sci. 1986 Jun;36(3):262-7. http://pmid.us/3724051.

[6] Andrews AG et al. Immune complex vasculitis with secondary ulcerative dermatitis in aged C57BL/6NNia mice. Vet Pathol. 1994 May;31(3):293-300. http://pmid.us/8053123.

 [7] Boelen E et al. Chlamydia pneumoniae infection of brain cells: an in vitro study. Neurobiol Aging. 2007 Apr;28(4):524-32. http://pmid.us/16621171.

[8] Ikejima H et al. Chlamydia pneumoniae infection of microglial cells in vitro: a model of microbial infection for neurological disease. J Med Microbiol. 2006 Jul;55(Pt 7):947-52. http://pmid.us/16772424.

[9] Moazed TC et al. Murine models of Chlamydia pneumoniae infection and atherosclerosis. J Infect Dis. 1997 Apr;175(4):883-90. http://pmid.us/9086145.

[10] Campbell LA et al. Mouse models of C. pneumoniae infection and atherosclerosis. J Infect Dis. 2000 Jun;181 Suppl 3:S508-13. http://pmid.us/10839749.

[11] de Kruif MD et al. Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research. Cardiovasc Res. 2005 Feb 1;65(2):317-27. http://pmid.us/15639470.

[12] Kaiko GE et al. Chlamydia muridarum infection subverts dendritic cell function to promote Th2 immunity and airways hyperreactivity. J Immunol. 2008 Feb 15;180(4):2225-32. http://pmid.us/18250429.

[13] Jupelli M et al. Endogenous IFN-gamma production is induced and required for protective immunity against pulmonary chlamydial infection in neonatal mice. J Immunol. 2008 Mar 15;180(6):4148-55. http://pmid.us/18322226.

[14] Bussiere JL et al. Reproductive effects of chronic administration of murine interferon-gamma. Reprod Toxicol. 1996 Sep-Oct;10(5):379-91. http://pmid.us/8888410.

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