The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not?

We appreciate that Freese and colleagues [FKL] attempt to understand what they refer to as the “inflammation paradox”, i.e. that people may experience high chronic levels of circulating inflammation (as measured by biomarkers such as high sensitivity C-reactive protein (CRP)), yet not succumb to the diseases such as heart disease and diabetes usually attributed to such high exposure in urban settings. We first documented this pattern among Tsimane Amerindians in Bolivia in 2009 when we found no cases of peripheral arterial disease among older adults despite high average levels of CRP, and no relationship between CRP and the continuous ankle-brachial index used to assess peripheral arterial disease risk¹. More recently, we reported minimal coronary artery calcification that progressed 25 years more slowly than in the US,, and again, without any relationship with CRP².
 
FKL assert that the typically high inflammation the Tsimane experience may be protective against non-communicable diseases (NCDs), and that their healthy hearts may not be due simply to their having protective diets, high moderate-to-vigorous activity levels and other lifestyle factors. We interpret their position that high inflammation is protective based on their discussion of field Eifel studies which showed CRP elevations after an attempt to mimic a more traditional “Paleo” lifestyle on a 4 day forest trek with low-carb diet, caloric restriction and semi-fasting. They propose three reasons for why CRP might be elevated under these (and presumably Tsimane conditions), but yet have no relationship with NCDs and their inflammation-related risk factors like smoking and obesity: 1) forest bathing may induce innate immune activity from plants releasing phyto-antibiotics into the atmosphere; 2) trekking in the “natural environment” (but not the city) may induce anticipatory immune defenses; and 3) caloric restriction combined with vigorous activity may have led to “cell depletion” and increased innate immune activity, including CRP, via uric acid byproducts.
 
First, we disagree with their conclusion that a “chronic inflammatory situation in Tsimans [sic]  protects against NCD”. This has never been shown. Rather, we have just shown that Tsimane do not appear to suffer from NCDs like heart disease and diabetes, despite  their  elevated systemic inflammation. Elsewhere, we have proposed that high inflammation may not lead to increased heart disease risk under certain conditions that may be particular for traditional subsistence populations like the Tsimane^3,4. High systemic inflammation might not lead to greater NCD risk when combined with: 1) low LDL, a physically demanding lifestyle and minimal obesity; 2) chronic helminthic infections that: a) modulate immune function toward more anti-inflammatory Th2 activity that helps prevents systemic inflammation from damaging arteries, b) increase basal metabolic rate and lower obesity risk; c) reduce blood lipids such as LDL cholesterol and triglycerides, and blood glucose. Also notable is their limited exposure to tobacco smoke.

Answer: We agree that there are no data showing that chronic inflammation in Tsimans protects them against NCD (correlation is not causation). We have erased this claim. Rather, we agree that the best explantion is probably the absence of typical NCD risk factors. Therefore, the Tsimane are noteworthy for being an example that chronic high inflammation is not sufficient for increasing NCD risk, given that other conditions are satisfied as you mentioned. This is now emphasized in the revision.
 
Second, while the Eifel study results suggest that adopting a more “Paleo”-like lifestyle can improve cardiometabolic biomarkers, we disagree that they show that higher inflammation (or innate immune activity in general) typifies hunter-gatherers or other subsistence populations. While CRP increased by 67% after the four day forest trek of healthy adults, this increase was not statistically significant (see Table 4). Thus, given the small sample size (n=25), these speculations have limited basis and are premature. Moreover, we see other issues with generalizing from the Eifel study. Half of the study participants did not engage in regular physical activity (52% <3 hrs/week). Heavy physical activity could lead to acute increases in inflammation, whereas long-term effects of regular exercise are usually associated with reduced chronic low grade inflammation. It is also possible that during the experiment, some participants incurred minor injuries or acute infections, both of which could result in higher CRP. Psychosocial stress, as might occur under the Eifel study conditions of food restriction for example, can also increase inflammation, especially IL-6, IL-1B and CRP⁵.

Answer: You are correct that high-grade inflammation is not a general hallmark of hunter-gatherer populations, and we apologize if we seem to have made such a statement. Our goal was simply to propose several possible hypotheses fort he observed acute elevations in CRP in the Eifel studies, partly in preparation for a new study that is going to start this summer. We also state in the revision that the data are not able to provide evidence for one of our hypotheses over any other, so that future studies should particularly put these hypotheses to test.

While Tsimane show evidence of chronic, elevated CRP across much of the life course^6,7, it is yet to be determined how representative this pattern is among small-scale subsistence populations. Shuar forager-horticulturalists of Ecuador show elevated CRP only when infected, but otherwise have low baseline CRP levels⁸. A small sample of Hadza hunter-gatherers also showed reasonably low CRP levels (74% of 23 adults had CRP < 3 mg/L)⁹.

Answer: Thank you for pointing this out. We added the references to these studies that indicate that the Tsimane CRP levels are apparently higher than that of other indegenous people.
 
Anticipatory stimulation of the innate immune system in the forest is an interesting idea; even visual exposure to photographs with disease cues (e.g. sneezing) can increase IL-6 by 24% compared to controls shown neutral stimuli¹⁰. However, while short-term changes in other biomarkers like blood lipids and blood glucose may be generalizable from the Eifel study to a long-term study, it is unclear whether any acute innate immune activity observed over a 4 day period would sustain in a longer-term study after habituation. As FKL argue, there are many other reasons CRP can be elevated that have little to do with inflammation, but might still be related to tissue stress or injury¹¹.

Answer: We agree that it is unclear if and when the elevated CRP levels found in the Eifel study participants would have decreased again. However, a similar study has found increased CRP levels after a 10-day trip through the wilderness. This is stated now in the last two sentences of the conclusions section: “In particular it remains to be determined, if, when and how the acute elevations in CRP level resolve if the participants would remain in Paleolithic living conditions. Interestingly, a study similar to the Eifel studies involving a10-day trip through the Pyrenees also reported a significant mild increase in CRP levels after the trip, showing that the acute phase repsonse could be sustained at least up to 10 days (29-30).“