ALL Metrics
-
Views
-
Downloads
Get PDF
Get XML
Cite
Export
Track
Opinion Article
Revised

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

[version 2; peer review: 2 approved, 1 approved with reservations]
PUBLISHED 06 Aug 2018
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

We here describe two apparent paradoxes concerning high CRP levels and NCD risk. One has emerged from observational studies in the Amazon region showing that the indigenous Tsimane in Bolivia appear protected against non-communicable diseases (NCDs) such as obesity, type 2 diabetes, and cardiovascular diseases despite increased inflammatory markers. These findings stand in contrast to Western societies, where an increasing body of evidence demonstrates that low-grade-inflammation is the driver of NCDs. The second paradox has emerged from two field studies (Eifel studies) conducted in 2013 and 2014 with Westerners who returned to a simulated Palaeolithic lifestyle in a National park for 4 days. We had detected elevated inflammation markers, despite otherwise anti-inflammatory effects of these interventions as indicated by metabolic blood parameters. We here propose three hypotheses for this second inflammatory paradox.

Keywords

Tsimane, Low-Grade Inflammation, Eifel studies, Non-communicable diseases

Revised Amendments from Version 1

In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do. Moreover, we have been more careful with our formulations in the revised manuscript, refraining from making any causal claims.
We agree with the reviewers that our hypothesis concerning the forest bathing effect is currently only speculative until further measurements have been made. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Our future research is planned to more specifically address the forest bathing hypothesis.
In context of our third hypothesis, we have included the additional mechanism proposed by the reviewers in our discussion and re-wrote a large part of the third hypothesis. Our revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies.
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. 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.

Finally, 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.

See the authors' detailed response to the review by Colette Berbesque and Baptiste Sadoughi
See the authors' detailed response to the review by Michael Gurven and Caleb Finch

Abbreviations

CRP, C-reactive protein; NCD, non-communicable diseases; NK cells, natural killer cells; LGI, low-grade inflammation; LPS, lipopolysaccharides; NFκB, nuclear-factor-kappa-B

Introduction

Recently, observational studies in the Amazon region showed that the indigenous Tsimane in Bolivia appear protected against non-communicable diseases (NCDs) such as obesity, type 2 diabetes, and cardiovascular diseases, despite increased inflammatory markers1. These findings stand in contrast to Western societies, where an increasing body of evidence demonstrates that low-grade-inflammation (LGI) is the driver of NCDs24.

Report

Compared to US reference values, Tsimane exhibit markedly high levels of eosinophilic and neutrophilic granulocytes, B lymphocytes and natural killer cells. The leukocyte counts of Tsimans (8,600–12,000 cells/μL) are 1.5 times, and lymphocytes 1.2 to 1.6 times higher than in the US population (6,700–7,900 cells/μL)5,6. Eosinophilic granulocytes, primarily indicative of parasitic infections, are 7-fold elevated. Consequently, the immunoglobulin E values are also significantly higher (150–200-fold). Important biomarkers for inflammation, such as neutrophil granulocytes (1.2 to 1.6-fold), blood sedimentation (30 mm/h to 15–20 mm/h) and C-reactive protein (CRP) values (higher from infant to adolescence), are also upregulated6. The high CRP levels in Tsimane are in contrast to other indigenous people such as the Hadza hunter-gatherers in Tansania7 or the Shuar hunter-horticulurists in Ecuador8 who show no obvious signs of chronic low-grade inflammation. Thus, chronically high CRP levels in the Tsimane pose an apparent paradox, as high CRP levels due to LGI in Westernized societies correlate with NCD risk. The paradox could be resolved if one assumes that chronic systemic inflammation is a necessary, but not sufficient component in NCD development if certain other factors are simultaneously present. In particular, in the Tsimane the chronic state of infection is thought to stem from a high prevalence of intestinal worms which would i) decrease the absorption of macronutrient in the gut, ii) increase the amount of type 2 anti-inflammatory T helper cells and iii) raise basal metabolic rate, reducing the risk for obesity9. However, the major protective factor against NCD appears to be their lifestyle which prevents the development of typical NCD risk factors such as insulin resistance and adiposity.

In 2013 and 2014, we carried out two field studies (Eifel studies) with Westerners who returned to a simulated Palaeolithic lifestyle in a National park for 4 days10,11. Contrary to our expectations, in both studies, CRP, the main liver-derived biomarker that displays nonspecific inflammation, had increased by 170% and 67%, respectively. The essential components of these interventions consisted of (i) the conversion to a paleo diet; (ii) the high range of locomotion (15 km/day in the Eifel study 2013, 16.4 km/day in the Eifel study 2014); (iii) a fasting period from 12 to 14 hours per day in conjunction with a low meal frequency resulting in undercaloric energy intake (1567 kcal in the Eifel study 2013, 1747 kcal in the Eifel study 2014). All mentioned factors have been shown to have anti-inflammatory effects1216.

Discussion

There are two interesting observations concerning the indigenous Tsimane in Bolivia and Westeners who returned to a paleolithic lifestyle in the Eifel studies: The former have chronically elevated CRP levels despite being practically free of NCDs, while the latter were found to have acutely elevated CRP levels despite other physiological changes that would usually be interpreted as protective against NCDs. We provide the following hypothetical explanations for the stimulation of the immune system in the Eifel studies, which are likely to influence one another:

  • 1. Phyto-antibiotics (phytoncides), which plants release into the atmosphere to protect themselves against bacteria and insects, could have stimulated the innate immune system17. As studies from Japan and Korea have shown, so-called "forest bathing" (a multi-day hike through a forest) promotes the formation of high levels of natural killer cells (NK cells). This effect persists for up to 30 days after the intervention18,19. In addition, forest bathing also increases the activity of the cytolytic proteins perforin, granzyme A and granulysin in NK cells. Walks in the city, on the other hand, do not change the NK cell population or its activity19. These effects could have contributed to the increase in CRP levels in the Eifel studies, as most of the time participants spent in a forest area.

  • 2. The radical change from a near-sterile to a natural environment may have prompted the innate immune system to anticipate and prophylactically protect the organism against pathogens such as bacteria, parasites, fungi, and other microorganisms. Danger signals, called exogenous pathogen associated molecular patterns and endogenous danger associated molecular patterns, activate the innate immune system via Toll-like receptors, which can trigger a rapid antibacterial inflammatory response. This mechanism of action may have led to the development of an acute phase response. In contrast to LGI, substances such as lipoxins, resolvins and protectins are formed in acute inflammation in order to end the inflammatory process20,21. Since no follow-up measurements were made in the Eifel studies, this hypothesis is currently only speculative.

  • 3. Despite the fact that the participants in the Eifel studies were in good mental and physical health, the level of physical stress due to the high workload combined with calorie restriction conditions could have induced a moderate acute phase response. Indeed, acute and transient elevations of CRP levels, inflammatory cytokines (in particular IL-6) and shifts in leucocyte patterns typically occur after strenuous exercise2224. The latter include elevations in neutrophils and decreases in eopsinophils and lymphocytes, changes that have also been observed in our Eifel study participants10,11. Therefore, this hypothesis appears to be the best confirmed by the data. The acute increase in CRP levels could thereby be caused by several mechanisms including increased catecholamine and cortisol levels23 or endotoxemia through bacterial lipopolysaccharides (LPS) caused by increased cell destruction and gut leakage25. LPS activate the innate immune system via Toll-like receptors and stimulate the activation of nuclear-factor-kappa-B (NFκB) intracellularly, leading to pro-inflammatory cytokine secretion26. A by-product of cell destruction is uric acid, which stimulates the release of CRP in the liver as part of the acute immune response27,28. In turn, CRP stimulates the production of antibodies from B lymphocytes to kill pathogens29. Due to the high range of locomotion in both Eifel studies, uric acid might have played a prominent role in stimulating the immune system. Since uric acid has not been measured, future studies should include this marker to provide a possible confirmation of this hypothesis.

Outlook

The fact that a chronic inflammatory situation in Tsimans persists despite practical non-existence of NCDs, while it is associated with NCDs in Westerners, appears paradoxical. A second apparent paradox concerns the acutely elevated CRP levels in Westeners returning to a Paleolithic lifestyle despite otherwise beneficial metabolic effects usually associated with a decrease in LGI. We have discussed three different hypotheses to solve this second paradox. While the “forest-bathing” and “danger anticipation” hypotheses are currently only speculative due to the lack of relevant measurements, a mild-to-moderate acute-phase response due to the strenuous physical activity is consistent with the available data. However, the data cannot clearly constitute evidence for one of these hypotheses against any other, in part because their likelihood under the “forest-bathing” and “danger anticipation” hypotheses remains to be determined. Finally it remains to be examined if, when and how the acute elevations in CRP levels would resolve if the participants would remain in Paleolithic living conditions. Interestingly, a study similar to the Eifel studies involving a 10-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 days30,31.

Data availability

No data are associated with this article.

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 01 Mar 2018
Comment
Author details Author details
Competing interests
Grant information
Copyright
Download
 
Export To
metrics
Views Downloads
F1000Research - -
PubMed Central
Data from PMC are received and updated monthly.
- -
Citations
CITE
how to cite this article
Freese J, Klement RJ and Lötzerich H. The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2018, 7:252 (https://doi.org/10.12688/f1000research.14052.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 06 Aug 2018
Revised
Views
9
Cite
Reviewer Report 06 Aug 2019
J. Josh Snodgrass, Department of Anthropology, University of Oregon, Eugene, OR, USA 
Approved
VIEWS 9
I have the luxury of reading this article after revisions based on two thorough reviews, both of which raise important points and make excellent suggestions for improvement. The new version of the article has been substantively revised in response to ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Snodgrass JJ. Reviewer Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2018, 7:252 (https://doi.org/10.5256/f1000research.17155.r50908)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Views
10
Cite
Reviewer Report 23 Oct 2018
Michael Gurven, Department of Anthropology, University of California, Santa Barbara, Santa Barbara, CA, USA 
Approved
VIEWS 10
I confirm that I have read this submission and believe that I have an ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Gurven M. Reviewer Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2018, 7:252 (https://doi.org/10.5256/f1000research.17155.r36833)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 01 Mar 2018
Views
31
Cite
Reviewer Report 06 Apr 2018
Colette Berbesque, Centre for Research in Evolutionary, Social and Inter-Disciplinary Anthropology, University of Roehampton, London, UK 
Baptiste Sadoughi, Centre for Research in Evolutionary, Social and Inter-Disciplinary Anthropology, University of Roehampton, London, UK 
Approved with Reservations
VIEWS 31
The authors statement is organised around two discoveries: the highly inflammatory immune profile in Tsimane associated with low prevalence of NCDs, and the increased inflammation in westerners whom participated in a 'Paleo-trek'1. From these observations, FKL reach the conclusion that chronic ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Berbesque C and Sadoughi B. Reviewer Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2018, 7:252 (https://doi.org/10.5256/f1000research.15283.r31345)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 06 Aug 2018
    Jens Freese, Deutsche Sporthochschule Köln, Germany
    06 Aug 2018
    Author Response
    The authors statement is organised around two discoveries: the highly inflammatory immune profile in Tsimane associated with low prevalence of NCDs, and the increased inflammation in westerners whom participated in ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 06 Aug 2018
    Jens Freese, Deutsche Sporthochschule Köln, Germany
    06 Aug 2018
    Author Response
    The authors statement is organised around two discoveries: the highly inflammatory immune profile in Tsimane associated with low prevalence of NCDs, and the increased inflammation in westerners whom participated in ... Continue reading
Views
30
Cite
Reviewer Report 12 Mar 2018
Michael Gurven, Department of Anthropology, University of California, Santa Barbara, Santa Barbara, CA, USA 
Caleb Finch, Leonard Davis School of Gerontology & Dornsife College, University of Southern California, Los Angeles, CA, USA 
Approved with Reservations
VIEWS 30
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)), ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Gurven M and Finch C. Reviewer Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Research 2018, 7:252 (https://doi.org/10.5256/f1000research.15283.r31343)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 06 Aug 2018
    Jens Freese, Deutsche Sporthochschule Köln, Germany
    06 Aug 2018
    Author Response
    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 ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 06 Aug 2018
    Jens Freese, Deutsche Sporthochschule Köln, Germany
    06 Aug 2018
    Author Response
    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 ... Continue reading

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 01 Mar 2018
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
Sign In
If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password.

The email address should be the one you originally registered with F1000.

Email address not valid, please try again

You registered with F1000 via Google, so we cannot reset your password.

To sign in, please click here.

If you still need help with your Google account password, please click here.

You registered with F1000 via Facebook, so we cannot reset your password.

To sign in, please click here.

If you still need help with your Facebook account password, please click here.

Code not correct, please try again
Email us for further assistance.
Server error, please try again.