Category Archives: Side Effects

In my last post, I noted that

So far, all the negative experiences [from adoption of our diet] I am aware of have come from low-carb dieters who had difficulty after adding carbs and/or cutting protein….

It’s interesting that the same dietary change – adding “safe starches” to a low-carb Paleo diet – made some people feel better and others worse.

In thinking about why adding starches can cause short-term trouble for some people, my first thought was a fascinating post from two years ago by Peter Dobromylskyj of Hyperlipid. Peter noted:

Bacterial endotoxin is a breakdown product of the cell wall of gram negative bacteria. It’s a lipopolysaccharide and even quite small amounts of it are extremely unpleasant….

Now the scary thing is that eating a high fat meal, probably based on any fat which generates chylomicrons, markedly increases your uptake of endotoxin from your gut, which is obviously full of gram negative bacteria. Eating short chain fatty acids or carbohydrate [1] does not have this effect.

Endotoxins are fat-soluble, and so fat carries them into the body. The paper Peter cited actually found an increase in blood endotoxin levels after people were fed a high-fat meal:

In humans, no significant relation was observed between cardiovascular disease risk factors, carbohydrate and protein intakes, and plasma LPS concentration. Conversely, positive correlations were observed with fat and energy intakes. [1]

The same effect was found in mice:

Compared with the control mice, mice fed a high-energy diet showed an increase in plasma LPS. However, in mice fed a high-carbohydrate diet, the increase in plasma LPS was blunted compared with mice fed a high-fat diet.

The conclusion:

Experimental data suggest that fat was more efficient in transporting bacterial LPS from the gut lumen into the bloodstream. [1]

Does this mean that one should avoid dietary fat?  No, because it turns out the body regulates the amount of endotoxin entering the body. So a high-fat diet causes the immune system to exert greater control over gut bacteria. Peter writes:

Then came a fascinating random paper [2] through my wife’s journal club meetings … It’s about superinfection with resistant bacteria when broad spectrum antibiotics are used. This is a routine problem for anyone in medicine, especially patients. The concept is very simple, you kill off the susceptible commensal bacteria in the gut and resistant pathogens have no competition, so they have a field day and superinfection causes severe problems for the unlucky patient.

Simple, straightforward and wrong.

It turns out that the immune system, that is the innate immune system (of course), continuously monitors the contents of the gut by looking at endotoxin production. Lots of bacteria mean lots of endotoxin and an active, on-guard innate immune system. Kill off 99% of your gut bacteria and exdotoxin production drops. The innate immune system goes on vacation and clostridium difficile gets in and wipes out your granny.

Simple administration of oral endotoxin to the experimental mice stopped this effect completely.

Apparently, the human body evolved to favor having a certain population of commensal gut flora. When the population is too low, immune defenses are lowered to allow gut bacteria to multiply. When the population is too high, antimicrobial peptides are released into the gut to control pathogen numbers.

Thus, during gut infections adding probiotic bacteria may help defeat pathogenic infections by causing the body to increase its immune defenses. The body is actually trying to control the numbers of probiotic bacteria, but in doing so it makes compounds that kill pathogens.

Removal of tiny numbers of probiotic bacteria can lead to a huge multiplication of pathogens:

Administration of the broad-spectrum antibiotic combination metronidazole, neomycin and vancomycin (MNV), to which vancomycin-resistant Enterococcus (VRE) is resistant, markedly increases colonization of the small intestine, caecum and colon with VRE…. It remains unclear, however, why elimination of the relatively sparse microbial flora of the small intestine increases the number of VRE by over 100–1,000-fold. [2]

It’s possible that this effect may be able to work in reverse – that addition of the small number of bacteria in a probiotic capsule can diminish the much larger population of an acute infection by 100-fold. I’ve noticed that swallowing probiotic capsules can be extremely effective against food poisoning. If you ever get diarrhea from a bad meal, take handfuls of probiotics every few minutes. You’ll be cured remarkably quickly.

The Gut of a Zero-Carb Dieter

On a zero-carb diet – especially an entirely plant-free diet like the one Charles Washington eats – lack of food will cause the population of gut bacteria to dwindle.

As in a gut depopulated of bacteria by antibiotics, this diet will cause the gut to let down its immune defenses. The body will reduce its production of antimicrobial peptides in order to help gut bacteria survive.

Perversely, this may make any pathogens that enter the body with food more likely to enter the body. It also may allow pathogens to gain a foothold in the gut. Thus, heightened infectious disease risk could be another long-term danger of zero-carb diets.

What Happens When A Zero-Carb Dieter Reintroduces Starches?

When a zero-carb dieter starts eating plant foods, suddenly gut bacteria have a lot of food, and can multiply many-fold. Bacteria can double their numbers in 20 minutes, and yeast in a few hours. That means that bacterial populations can increase 8-fold in an hour, 4000-fold in 4 hours, and ten million fold in 8 hours. Yeast can increase 4000-fold in 24 hours.

So it doesn’t take long – the very first day – before gut bacteria have multiplied by huge proportions. In the course of their fermentation, they’ll release a lot of gas, causing some bowel distress.

And along with greater numbers comes greater endotoxin release. Any dietary fats carry these endotoxins into the body. This rise in endotoxin load triggers an immune response that includes release of antimicrobial peptides, killing gut bacteria and releasing more endotoxins.

This rise in endotoxin levels and the resulting immune response may resemble a brief illness. Some known effects of a sudden rise in systemic lipopolysaccharide levels:

• Depression [3] and depressive-like behavior [4].
• Impaired athleticism [5]. 
• Reduced appetite [6, 7].
• Fever, vasoconstriction and endothelial dysfunction. [8]

Of course these effects would be only temporary. In a matter of days to a week, the immune system should re-establish an equilibrium with the gut flora and the new diet. Gas and bloating in the gut should be reduced (unless pathogens have been able to establish an enduring infection first). Endotoxin levels in the body should return to the evolutionary optimum. Higher production of antimicrobial peptides will maintain a limited gut bacterial population, even though carb intake has increased.

My Experience

My own experience is consistent with some of these expectations. When I went from zero-carb to including carbs – in my case, the change was adding fruit only, starches didn’t start for another year – my abdomen became bloated and I had gas. It was remarkable:  the very first day I ate fruit, my belly bloated up. It seemed to leave me with a lasting infection, because both the bloating and various digestive problems lasted several years. Probably the scurvy that I also had at that time was a big contributor; until I fixed the scurvy I also had gallbladder problems, and developed diverticulitis during this period, diagnosed by a barium enema.

I believe the main factor in the bloating was a colonic yeast/fungal infection that may or may not be completely gone today (it is certainly much diminished). The bloating was increased whenever I developed fungal skin infections. I suspect the yeast took over my colon while my immune defenses were depressed on the zero-carb diet and vitamin C deficiency, and multiplied immensely as soon as they had access to plant foods.

Conclusion

This hypothesis matches some but not all of the first-couple-of-days symptoms experienced by Don Matesz and his commenter SamAbroad when they cut protein and increased starches. SamAbroad became “hungry and cranky”; Don noted “decline in mood and … increase in hunger and intestinal gas and a disruption of bowel function.” In short:

• Gas, bloating, intestinal distress.
• Cranky mood.
• Hunger.

The first two are consistent with a rise in endotoxin levels. The last isn’t.

However, I can imagine a few reasons why a shift from meat to starches may have made them hungry:

• Protein is notably satiating, one reason why high-protein diets are often effective for weight loss. Mixed carb and fat, on the other hand, makes a good dessert. As we have all witnessed, many people say they are stuffed after dinner but get hungry again when they see desserts.
• Or maybe the calories lost from the reduction in meat were not fully replaced. Plant foods have far fewer calories per pound than meat, and many people overestimate how many calories are found in plant foods. In cutting meat from

The body should adjust appetite to the diet, but this may not happen in the first few days. In short-term (3-day) trials of food mix alteration, people who increased carbs ate more food than people who increased protein. [9]

I don’t know if these explanations are correct in the specific cases of Don and SamAbroad. (Indeed, I was very surprised Don had any trouble at all, since he already eats our safe starches and I am pretty sure he also eats within our recommended optimal range of macronutrients — hat tip to commenter Beth Mazur of WeightMaven.org for a link to one of Don’s meal analyses in which he ate our recommended calorie ratio.) However, I think many people who have been on zero-carb diets can expect short-term gut distress when they first restore carbs to the diet.

In people with healthy gut flora, this should disappear in a few days. In others, like me, who have pathogenic gut populations, a gut infection may become entrenched and take longer to get rid of. Still, overall I think the inclusion of dietary carbs, and the resulting enhancement of intestinal barrier immunity, is likely to lead to long-term improvement in the body’s protection against infectious diseases that enter through the gut.

References

[1] Amar J et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr. 2008 May;87(5):1219-23. http://pmid.us/18469242.

[2] Brandl K et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature. 2008 Oct 9;455(7214):804-7. http://pmid.us/18724361.

[3] Weidenfeld J, Yirmiya R. Effects of bacterial endotoxin on the glucocorticoid feedback regulation of adrenocortical response to stress. Neuroimmunomodulation. 1996 Nov-Dec;3(6):352-7. http://pmid.us/9266546.

[4] Fu X et al. Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflammation. 2010 Aug 2;7:43.  http://pmid.us/20678226.

[5] Sparkman NL et al. Effects of intraperitoneal lipopolysaccharide on Morris maze performance in year-old and 2-month-old female C57BL/6J mice. Behav Brain Res. 2005 Apr 15;159(1):145-51.  http://pmid.us/15795008.

[6] Stengel A et al. Lipopolysaccharide differentially decreases plasma acyl and desacyl ghrelin levels in rats: potential role of the circulating ghrelin-acylating enzyme GOAT. Peptides. 2010 Sep;31(9):1689-96.  http://pmid.us/20599577.

[7] Rorato R et al. Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats. Exp Physiol. 2009 Mar;94(3):371-9. http://pmid.us/19074588.

[8] Feng SY et al. Acute and chronic effects of endotoxin on cerebral circulation in lambs. Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R760-6. http://pmid.us/20071615.

[9] Coelho JS et al. Selective carbohydrate or protein restriction: effects on subsequent food intake and cravings. Appetite. 2006 Nov;47(3):352-60. http://pmid.us/16844265.