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Freese J, Klement RJ and Lötzerich H. The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]. F1000Research 2018, 7:252
(doi: 10.12688/f1000research.14052.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Opinion Article
The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]
Jens Freese1 Rainer Johannes Klement
https://orcid.org/0000-0003-1401-4270
2
Helmut Lötzerich1
Jens Freese1 Rainer Johannes Klement
https://orcid.org/0000-0003-1401-4270
2
Helmut Lötzerich1
PUBLISHED 01 Mar 2018
Author details Author details
1 Institute of Outdoor Sports and Environmental Science, German Sports University Cologne, Cologne, 50933, Germany
2 Department of Radiotherapy and Radiation Oncology, Leopoldina Hospital Schweinfurt, Schweinfurt, 97422, Germany

Jens Freese
Roles: Writing – Original Draft Preparation
Rainer Johannes Klement
Roles: Writing – Review & Editing
Helmut Lötzerich
Roles: Supervision

OPEN PEER REVIEW
REFEREE STATUS

Abstract

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 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. 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 days and detected elevated inflammation markers, analogous to the conditions of the Tsimane. We here propose three hypotheses for this inflammatory paradox.
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Tsimane, Low-Grade Inflammation, Eifel studies, Non-communicable diseases

Corresponding Author(s)
Jens Freese ( info@dr-freese.com)
Corresponding author: Jens Freese
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2018 Freese J et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
CAVALLI Black JUST Handbag CAVALLI JUST How to cite: Freese J, Klement RJ and Lötzerich H. The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]. F1000Research 2018, 7:252 (doi: 10.12688/f1000research.14052.1) First published: 01 Mar 2018, 7:252 (doi: 10.12688/f1000research.14052.1) Latest published: 06 Aug 2018, 7:252 (doi: 10.12688/f1000research.14052.2)
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of this article available.

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. Also striking is the relatively high basal metabolism of the Tsimane compared to the US population. Gurven et al.7 argue that the elevated metabolic rate occurs to cover the energetic costs of an activated immune system in the tropical wilderness. This assumption indicates that 70% of this population is permanently infected with parasites. Despite elevated inflammation, this might be the reason why Tsimane are protected from NCD, because intestinal worms not only absorb fat that would then no longer be available to the host, but also increase the amount of type 2 anti-inflammatory T helper cells7.

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 days8,9. Contrary to our expectations, in both studies, CRP, the main liver-derived biomarker that displays nonspecific inflammation, had increased significantly. 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 effects1014.

Discussion

Since it cannot be assumed that civilized humans display major parasitic infections like the Tsimane, we provide the following hypothetical explanations for the stimulation of the immune system in the Eifel studies, which are likely to influence one another:

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  • 1. Phyto-antibiotics (phytoncides), which plants release into the atmosphere to protect themselves against bacteria and insects, could have stimulated the innate immune system15. 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 intervention16,17. 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 activity17. 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 inflammation and resolution of a (chronic) LGI. In contrast to LGI, substances such as lipoxins, resolvins and protectins are formed in acute inflammation in order to end the inflammatory process18,19. 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 increased cell depletion. It is well known that the destruction of cell structures, e.g. in burns, viral and bacterial infections or after high volume or intensity training, increases the endogenous load of lipopolysaccharides (LPS)20. LPS activate the innate immune system via Toll-like receptors and stimulate the activation of nuclear-factor-kappa-B (NFκB) intracellularly. NFκB on the one hand increases pro-inflammatory cytokine secretion and on the other hand inhibits the insulin signalling cascade. As a result, macrophages, and other immune cells switch from oxidative phosphorylation to anaerobic glycolysis. This metabolic reprogramming of M2 to M1 macrophages occurs to trigger a rapid antibacterial inflammatory response to pathogens21. A by-product of cell destruction is uric acid, which stimulates the release of CRP in the liver as part of the acute immune response22,23. In turn, CRP stimulates the production of antibodies from B lymphocytes to kill pathogens24. Due to the high range of locomotion in both Eifel studies, uric acid might have played the leading 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 protects against NCD, while it increases the incidence in LGI in Westerners, should be investigated in further studies with the hypotheses proposed here.

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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References

Author details Author details
1 Institute of Outdoor Sports and Environmental Science, German Sports University Cologne, Cologne, 50933, Germany
2 Department of Radiotherapy and Radiation Oncology, Leopoldina Hospital Schweinfurt, Schweinfurt, 97422, Germany

Jens Freese
Handbag JUST CAVALLI Black JUST CAVALLI Roles: Writing – Original Draft Preparation
Rainer Johannes Klement
Roles: Writing – Review & Editing
Helmut Lötzerich
Roles: Supervision

Article Versions (2)
version 2
Revised
Published: 06 Aug 2018, 7:252
Published: 01 Mar 2018, 7:252
Copyright
© 2018 Freese J et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Freese J, Klement RJ and Lötzerich H. The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations] F1000Research 2018, 7:252 (doi: 10.12688/f1000research.14052.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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How to cite this report:
Berbesque C and Sadoughi B. Referee Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]. F1000Research 2018, 7:252
(doi: 10.5256/f1000research.15283.r31345)
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Referee 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
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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
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 inflammation in the Tsimane protects against NCDs and propose explanations for why this might be the case. We will discuss this assumption in the following sections.
 
First, we disagree with the assumption that Tsimane people stand as an adequate model for the study of the relationship between Low-grade inflammation (LGI) and non-communicable diseases (NCDs). LGI, associated with coronary diseases and other NCDs in westerners, is usually not triggered by specific stimuli such as infection or injury 2, but strongly associated with other risk factors such as stressful situations 3 and excess of adipose tissue 4. Tismanes are less mobile than most hunter-gatherers, such as the Hadza - who demonstrate low CPR 5. This increased sedentisation may be part of the reason they face a heavy parasitic load and bacterial infections 6 likely responsible for their hightened inflammatory response 7, along with low levels of cholesterol, LDL and HDL. It is also noteworthy that the major comparative study on Tsimane immune function failed to show that after childhood there was any significant increase in CRP, a major low-grade inflammatory marker 7. The hypothesis that the parasitic burden triggering Th2 response may enhance anti-inflammatory cytokine levels and thus protect against NCDs is interesting. However, the absence of major NCDs risk factors, such as chronic stress, insulin-resistance and elevated fatty acid levels, brings into question the underlying assumption that the Tsimane may face common NCDs. 

Finally, we strongly reject the authors' conclusion that inflammation may protect against NCDs in Tsimane. Indeed, CRP levels were found to be a positive predictor of non-null coronary artery calcium scores 8, suggesting CRP might actually be predictive of atherosclerosis, a major NCD, in Tsimane as well.
 
According to the authors, the inflammatory state of the Tsimane could be partly explained by environmental factors also responsible for the pro-inflammatory profile observed in the participants of the Eifel experiment. We will review and discuss two of the hypotheses proposed by FKL to explain this result.
 
First, a ‘forest bathing’ effect would have enhanced innate immune response and therefore result in an increase in CRP levels. Although we do not wish to undermine the potential role of the ‘forest bathing’ effect, to the best of our knowledge no evidence so far suggests that it could have an impact on CRP levels. Most studies focus on NK cells, cortisol levels and bio-markers of endothelial function. As CRP elevation in the Eifel participants failed to reach significance and NK cells were not measured, the ‘forest bathing’ effect remains speculative.
 
Second, as suggested by the authors, exposure to exogenous pathogen associated-molecules could have caused a shift towards Th1 response in Eifel participants. However, there is no evidence to support the assumption that this shift was 'prophylactic' as participants may have well indeed face acute infection from small wounds or respiratory pathogens in a forest environment. In order to strengthen their theoretical argument, the authors could provide references regarding the resolution of chronic inflammation following an episode of acute inflammation.
 
Finally, we would like to suggest another potential origin for the pro-inflammatory immune profile in the Eifel participants. It seems participants exhibit the typical leukocyte count induced by stress and exercise 9: neutrophilia, lymphopenia and eosinopenia. Such leukocyte pattern is supposedly the result of cortisol-induced cell-migration into peripheral tissue 10 and does not fit with Tsimane leukocyte pattern 7. Furthermore, exercise-induced response has been shown to gradually decrease in trained athletes. Long-term training is eventually followed by the release of anti-inflammatory cytokines 11 , 12. Such difference between initial-shock immune response to intense exercise, as undertaken by untrained Eifel participants, and long-term immune adaptation to physical activity brings into question the reliability of the leukogram patterns measured on the fourth day of trek in the Eifel study. A shift towards a more anti-inflammatory pattern could therefore be expected in the Eifel participants after acclimatisation to this new lifestyle, regardless of environmental factors. It is therefore highly speculative that the Eifel participants’ immune profile would be a good model for the immune pattern of a Paleo-population.
  • Is the topic of the opinion article discussed accurately in the context of the current literature?

    Partly

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  • Are all factual statements correct and adequately supported by citations?

    Yes

  • Are arguments sufficiently supported by evidence from the published literature?

    Partly

  • Are the conclusions drawn balanced and justified on the basis of the presented arguments?

    No

References

1. Freese J, Pardi D, Ruiz-Núñez B, Schwarz S, Heynck R, Renner R, Zimmer P, Lötzerich H: Back to the Future. Metabolic Effects of a 4-Day Outdoor Trip Under Simulated Paleolithic Conditions – New Insights from The Eifel Study. Journal of Evolution and Health. 2016; 1 (1). Publisher Full Text
2. Rohleder N: Stimulation of systemic low-grade inflammation by psychosocial stress.Psychosom Med. 2014; 76 (3): 181-9 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
3. Hänsel A, Hong S, Cámara RJ, von Känel R: Inflammation as a psychophysiological biomarker in chronic psychosocial stress.Neurosci Biobehav Rev. 2010; 35 (1): 115-21 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
4. Festa A, D'Agostino R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM: The relation of body fat mass and distribution to markers of chronic inflammation.Int J Obes Relat Metab Disord. 2001; 25 (10): 1407-15 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
5. Raichlen DA, Pontzer H, Harris JA, Mabulla AZ, Marlowe FW, Josh Snodgrass J, Eick G, Colette Berbesque J, Sancilio A, Wood BM: Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers.Am J Hum Biol. 2017; 29 (2). Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
6. Page AE, Viguier S, Dyble M, Smith D, Chaudhary N, Salali GD, Thompson J, Vinicius L, Mace R, Migliano AB: Reproductive trade-offs in extant hunter-gatherers suggest adaptive mechanism for the Neolithic expansion.Proc Natl Acad Sci U S A. 2016; 113 (17): 4694-9 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
7. Blackwell AD, Trumble BC, Maldonado Suarez I, Stieglitz J, Beheim B, Snodgrass JJ, Kaplan H, Gurven M: Immune function in Amazonian horticulturalists.Ann Hum Biol. 2016; 43 (4): 382-96 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
8. Kaplan H, Thompson R, Trumble B, Wann L, Allam A, Beheim B, Frohlich B, Sutherland M, Sutherland J, Stieglitz J, Rodriguez D, Michalik D, Rowan C, Lombardi G, Bedi R, Garcia A, Min J, Narula J, Finch C, Gurven M, Thomas G: Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet. 2017; 389 (10080): 1730-1739 Publisher Full Text
9. Suzuki K, Yamada M, Kurakake S, Okamura N, Yamaya K, Liu Q, Kudoh S, Kowatari K, Nakaji S, Sugawara K: Circulating cytokines and hormones with immunosuppressive but neutrophil-priming potentials rise after endurance exercise in humans.Eur J Appl Physiol. 2000; 81 (4): 281-7 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
10. Davis A, Maney D, Maerz J: The use of leukocyte profiles to measure stress in vertebrates: a review for ecologists. Functional Ecology. 2008; 22 (5): 760-772 Publisher Full Text
11. Suzuki K, Totsuka M, Nakaji S, Yamada M, Kudoh S, Liu Q, Sugawara K, Yamaya K, Sato K: Endurance exercise causes interaction among stress hormones, cytokines, neutrophil dynamics, and muscle damage.J Appl Physiol (1985). 1999; 87 (4): 1360-7 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
12. Weinhold M, Shimabukuro-Vornhagen A, Franke A, Theurich S, Wahl P, Hallek M, Schmidt A, Schinköthe T, Mester J, von Bergwelt-Baildon M, Bloch W: Physical exercise modulates the homeostasis of human regulatory T cells.J Allergy Clin Immunol. 2016; 137 (5): 1607-1610.e8 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Leather Crossbody Tote Handbag Furla Black qXxtwa

Competing Interests: No competing interests were disclosed.

We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.
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Berbesque C and Sadoughi B. Referee Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]. F1000Research 2018, 7:252 (doi: 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 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'POLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. From these observations, FKL reach the conclusion that chronic inflammation in the Tsimane protects against NCDs and propose explanations for why this might be the case. We will discuss this assumption in the following sections.
     
    First, we disagree with the assumption that Tsimane people stand as an adequate model for the study of the relationship between Low-grade inflammation (LGI) and non-communicable diseases (NCDs). LGI, associated with coronary diseases and other NCDs in westerners, is usually not triggered by specific stimuli such as infection or injury2, but strongly associated with other risk factors such as stressful situations3 and excess of adipose tissueHandbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. Tismanes are less mobile than most hunter-gatherers, such as the Hadza - who demonstrate low CPRClassic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd. This increased sedentisation may be part of the reason they face a heavy parasitic load and bacterial infections6 likely responsible for their hightened inflammatory response7, along with low levels of cholesterol, LDL and HDL. It is also noteworthy that the major comparative study on Tsimane immune function failed to show that after childhood there was any significant increase in CRP, a major low-grade inflammatory marker7. The hypothesis that the parasitic burden triggering Th2 response may enhance anti-inflammatory cytokine levels and thus protect against NCDs is interesting. However, the absence of major NCDs risk factors, such as chronic stress, insulin-resistance and elevated fatty acid levels, brings into question the underlying assumption that the Tsimane may face common NCDs. 

    Answer: We apologize if we seemed to have suggested the Tsimane as an adequate model for studying the connection between LGI and NCD. This was not our aim. Rather, our aim was to point out the Tsimane as an interesting case of indigenous people who are apparently free from the NCD that plague the Western societies despite having chronically elevated CRP levels. This should make clear that they are not an adequate model, but rather an exceptional case worth further studying. In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do, agreeing with your argument above. This is probably the best explanantion for their low incidence of NCDs.

    Finally, we strongly reject the authors' conclusion that inflammation may protect against NCDs in Tsimane. Indeed, CRP levels were found to be a positive predictor of non-null coronary artery calcium scores8, suggesting CRP might actually be predictive of atherosclerosis, a major NCD, in Tsimane as well.

    Answer: We are sorry for making causal claims where the data do not clearly support any. We have been more careful with our formulations in the revised manuscript, refraining from making any causal claims.
     
    According to the authors, the inflammatory state of the Tsimane could be partly explained by environmental factors also responsible for the pro-inflammatory profile observed in the participants of the Eifel experiment. We will review and discuss two of the hypotheses proposed by FKL to explain this result.
     
    First, a ‘forest bathing’ effect would have enhanced innate immune response and therefore result in an increase in CRP levels. Although we do not wish to undermine the potential role of the ‘forest bathing’ effect, to the best of our knowledge no evidence so far suggests that it could have an impact on CRP levels. Most studies focus on NK cells, cortisol levels and bio-markers of endothelial function. As CRP elevation in the Eifel participants failed to reach significance and NK cells were not measured, the ‘forest bathing’ effect remains speculative.

    Answer: We agree that this hypothesis is currently only speculative until further measurements have been made which are able to distinguish it from other hypotheses such as the acute phase response due to strenuous physical activity. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Nevertheless, we consider them possible explanations that should be considered in data interpretation. Our future research is planned to more specifically address the forest bathing hypothesis.
     
    Second, as suggested by the authors, exposure to exogenous pathogen associated-molecules could have caused a shift towards Th1 response in Eifel participants. However, there is no evidence to support the assumption that this shift was 'prophylactic' as participants may have well indeed face acute infection from small wounds or respiratory pathogens in a forest environment. In order to strengthen their theoretical argument, the authors could provide references regarding the resolution of chronic inflammation following an episode of acute inflammation.

    Answer: We had already noted that this hypothesis is currently only speculative. However, since we are mainly interested in explaining the acute rise of CRP levels, we have deleted any hypothesizing that this acute phase response could have led to the resolution of chronic LGI. An example for the resolution of chronic inflammation after acute stimulation of the immune system (although not neccessarily translatable to all NCDs) is the spontaneous remission of cancer after an acute episode of fever that is now more or less officially acknowledged (e.g. Jessy T (2011): Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med; 2(1): 43–49). Other examples from medical practice include treatment of chronic tendonitis through re-injury or using low-dose ionizing radiation to treat chronic inflammatory conditions.
     
    Finally, we would like to suggest another potential origin for the pro-inflammatory immune profile in the Eifel participants. It seems participants exhibit the typical leukocyte count induced by stress and exercise9: neutrophilia, lymphopenia and eosinopenia. Such leukocyte pattern is supposedly the result of cortisol-induced cell-migration into peripheral tissue10 and does not fit with Tsimane leukocyte pattern7. Furthermore, exercise-induced response has been shown to gradually decrease in trained athletes. Long-term training is eventually followed by the release of anti-inflammatory cytokines11,12. Such difference between initial-shock immune response to intense exercise, as undertaken by untrained Eifel participants, and long-term immune adaptation to physical activity brings into question the reliability of the leukogram patterns measured on the fourth day of trek in the Eifel study. A shift towards a more anti-inflammatory pattern could therefore be expected in the Eifel participants after acclimatisation to this new lifestyle, regardless of environmental factors. It is therefore highly speculative that the Eifel participants’ immune profile would be a good model for the immune pattern of a Paleo-population.

    Answer: Thank you for these thoughts which go along the lines of our third hypothesis, namely that the sudden physical activity increase would be responsible for the acute CRP increase. We have included this additional mechanism in our discussion and re-wrote a large part of the third hypothesis. We think that the revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies. In no way did we intent to propose that the immune profile of the latter is a good model for the former. 

    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' POLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. From these observations, FKL reach the conclusion that chronic inflammation in the Tsimane protects against NCDs and propose explanations for why this might be the case. We will discuss this assumption in the following sections.
     
    First, we disagree with the assumption that Tsimane people stand as an adequate model for the study of the relationship between Low-grade inflammation (LGI) and non-communicable diseases (NCDs). LGI, associated with coronary diseases and other NCDs in westerners, is usually not triggered by specific stimuli such as infection or injury 2, but strongly associated with other risk factors such as stressful situations 3 and excess of adipose tissue Handbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. Tismanes are less mobile than most hunter-gatherers, such as the Hadza - who demonstrate low CPR Classic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd. This increased sedentisation may be part of the reason they face a heavy parasitic load and bacterial infections 6 likely responsible for their hightened inflammatory response 7, along with low levels of cholesterol, LDL and HDL. It is also noteworthy that the major comparative study on Tsimane immune function failed to show that after childhood there was any significant increase in CRP, a major low-grade inflammatory marker 7Pink Handbag Handbag ROCHAS Handbag ROCHAS Handbag ROCHAS Pink ROCHAS Pink 5fwqA6W. The hypothesis that the parasitic burden triggering Th2 response may enhance anti-inflammatory cytokine levels and thus protect against NCDs is interesting. However, the absence of major NCDs risk factors, such as chronic stress, insulin-resistance and elevated fatty acid levels, brings into question the underlying assumption that the Tsimane may face common NCDs. 

    Answer: We apologize if we seemed to have suggested the Tsimane as an adequate model for studying the connection between LGI and NCD. This was not our aim. Rather, our aim was to point out the Tsimane as an interesting case of indigenous people who are apparently free from the NCD that plague the Western societies despite having chronically elevated CRP levels. This should make clear that they are not an adequate model, but rather an exceptional case worth further studying. In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do, agreeing with your argument above. This is probably the best explanantion for their low incidence of NCDs.

    Finally, we strongly reject the authors' conclusion that inflammation may protect against NCDs in Tsimane. Indeed, CRP levels were found to be a positive predictor of non-null coronary artery calcium scores 8, suggesting CRP might actually be predictive of atherosclerosis, a major NCD, in Tsimane as well.

    Answer: We are sorry for making causal claims where the data do not clearly support any. We have been more careful with our formulations in the revised manuscript, refraining from making any causal claims.
     
    According to the authors, the inflammatory state of the Tsimane could be partly explained by environmental factors also responsible for the pro-inflammatory profile observed in the participants of the Eifel experiment. We will review and discuss two of the hypotheses proposed by FKL to explain this result.
     
    First, a ‘forest bathing’ effect would have enhanced innate immune response and therefore result in an increase in CRP levels. Although we do not wish to undermine the potential role of the ‘forest bathing’ effect, to the best of our knowledge no evidence so far suggests that it could have an impact on CRP levels. Most studies focus on NK cells, cortisol levels and bio-markers of endothelial function. As CRP elevation in the Eifel participants failed to reach significance and NK cells were not measured, the ‘forest bathing’ effect remains speculative.

    Answer: We agree that this hypothesis is currently only speculative until further measurements have been made which are able to distinguish it from other hypotheses such as the acute phase response due to strenuous physical activity. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Nevertheless, we consider them possible explanations that should be considered in data interpretation. Our future research is planned to more specifically address the forest bathing hypothesis.
     
    Second, as suggested by the authors, exposure to exogenous pathogen associated-molecules could have caused a shift towards Th1 response in Eifel participants. However, there is no evidence to support the assumption that this shift was 'prophylactic' as participants may have well indeed face acute infection from small wounds or respiratory pathogens in a forest environment. In order to strengthen their theoretical argument, the authors could provide references regarding the resolution of chronic inflammation following an episode of acute inflammation.

    Answer: We had already noted that this hypothesis is currently only speculative. However, since we are mainly interested in explaining the acute rise of CRP levels, we have deleted any hypothesizing that this acute phase response could have led to the resolution of chronic LGI. An example for the resolution of chronic inflammation after acute stimulation of the immune system (although not neccessarily translatable to all NCDs) is the spontaneous remission of cancer after an acute episode of fever that is now more or less officially acknowledged (e.g. Jessy T (2011): Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med; 2(1): 43–49). Other examples from medical practice include treatment of chronic tendonitis through re-injury or using low-dose ionizing radiation to treat chronic inflammatory conditions.
     
    Finally, we would like to suggest another potential origin for the pro-inflammatory immune profile in the Eifel participants. It seems participants exhibit the typical leukocyte count induced by stress and exercise 9: neutrophilia, lymphopenia and eosinopenia. Such leukocyte pattern is supposedly the result of cortisol-induced cell-migration into peripheral tissue 10 and does not fit with Tsimane leukocyte pattern 7. Furthermore, exercise-induced response has been shown to gradually decrease in trained athletes. Long-term training is eventually followed by the release of anti-inflammatory cytokines 11 , 12. Such difference between initial-shock immune response to intense exercise, as undertaken by untrained Eifel participants, and long-term immune adaptation to physical activity brings into question the reliability of the leukogram patterns measured on the fourth day of trek in the Eifel study. A shift towards a more anti-inflammatory pattern could therefore be expected in the Eifel participants after acclimatisation to this new lifestyle, regardless of environmental factors. It is therefore highly speculative that the Eifel participants’ immune profile would be a good model for the immune pattern of a Paleo-population.

    Answer: Thank you for these thoughts which go along the lines of our third hypothesis, namely that the sudden physical activity increase would be responsible for the acute CRP increase. We have included this additional mechanism in our discussion and re-wrote a large part of the third hypothesis. We think that the revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies. In no way did we intent to propose that the immune profile of the latter is a good model for the former. 

    Competing Interests: No competing interests were disclosed. Close
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 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'POLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. From these observations, FKL reach the conclusion that chronic inflammation in the Tsimane protects against NCDs and propose explanations for why this might be the case. We will discuss this assumption in the following sections.
     
    First, we disagree with the assumption that Tsimane people stand as an adequate model for the study of the relationship between Low-grade inflammation (LGI) and non-communicable diseases (NCDs). LGI, associated with coronary diseases and other NCDs in westerners, is usually not triggered by specific stimuli such as infection or injury2, but strongly associated with other risk factors such as stressful situations3 and excess of adipose tissueHandbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. Tismanes are less mobile than most hunter-gatherers, such as the Hadza - who demonstrate low CPRClassic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd. This increased sedentisation may be part of the reason they face a heavy parasitic load and bacterial infections6 likely responsible for their hightened inflammatory response7, along with low levels of cholesterol, LDL and HDL. It is also noteworthy that the major comparative study on Tsimane immune function failed to show that after childhood there was any significant increase in CRP, a major low-grade inflammatory marker7. The hypothesis that the parasitic burden triggering Th2 response may enhance anti-inflammatory cytokine levels and thus protect against NCDs is interesting. However, the absence of major NCDs risk factors, such as chronic stress, insulin-resistance and elevated fatty acid levels, brings into question the underlying assumption that the Tsimane may face common NCDs. 

    Answer: We apologize if we seemed to have suggested the Tsimane as an adequate model for studying the connection between LGI and NCD. This was not our aim. Rather, our aim was to point out the Tsimane as an interesting case of indigenous people who are apparently free from the NCD that plague the Western societies despite having chronically elevated CRP levels. This should make clear that they are not an adequate model, but rather an exceptional case worth further studying. In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do, agreeing with your argument above. This is probably the best explanantion for their low incidence of NCDs.

    Finally, we strongly reject the authors' conclusion that inflammation may protect against NCDs in Tsimane. Indeed, CRP levels were found to be a positive predictor of non-null coronary artery calcium scores8, suggesting CRP might actually be predictive of atherosclerosis, a major NCD, in Tsimane as well.

    Answer: We are sorry for making causal claims where the data do not clearly support any. We have been more careful with our formulations in the revised manuscript, refraining from making any causal claims.
     
    According to the authors, the inflammatory state of the Tsimane could be partly explained by environmental factors also responsible for the pro-inflammatory profile observed in the participants of the Eifel experiment. We will review and discuss two of the hypotheses proposed by FKL to explain this result.
     
    First, a ‘forest bathing’ effect would have enhanced innate immune response and therefore result in an increase in CRP levels. Although we do not wish to undermine the potential role of the ‘forest bathing’ effect, to the best of our knowledge no evidence so far suggests that it could have an impact on CRP levels. Most studies focus on NK cells, cortisol levels and bio-markers of endothelial function. As CRP elevation in the Eifel participants failed to reach significance and NK cells were not measured, the ‘forest bathing’ effect remains speculative.

    Answer: We agree that this hypothesis is currently only speculative until further measurements have been made which are able to distinguish it from other hypotheses such as the acute phase response due to strenuous physical activity. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Nevertheless, we consider them possible explanations that should be considered in data interpretation. Our future research is planned to more specifically address the forest bathing hypothesis.
     
    Second, as suggested by the authors, exposure to exogenous pathogen associated-molecules could have caused a shift towards Th1 response in Eifel participants. However, there is no evidence to support the assumption that this shift was 'prophylactic' as participants may have well indeed face acute infection from small wounds or respiratory pathogens in a forest environment. In order to strengthen their theoretical argument, the authors could provide references regarding the resolution of chronic inflammation following an episode of acute inflammation.

    Answer: We had already noted that this hypothesis is currently only speculative. However, since we are mainly interested in explaining the acute rise of CRP levels, we have deleted any hypothesizing that this acute phase response could have led to the resolution of chronic LGI. An example for the resolution of chronic inflammation after acute stimulation of the immune system (although not neccessarily translatable to all NCDs) is the spontaneous remission of cancer after an acute episode of fever that is now more or less officially acknowledged (e.g. Jessy T (2011): Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med; 2(1): 43–49). Other examples from medical practice include treatment of chronic tendonitis through re-injury or using low-dose ionizing radiation to treat chronic inflammatory conditions.
     
    Finally, we would like to suggest another potential origin for the pro-inflammatory immune profile in the Eifel participants. It seems participants exhibit the typical leukocyte count induced by stress and exercise9: neutrophilia, lymphopenia and eosinopenia. Such leukocyte pattern is supposedly the result of cortisol-induced cell-migration into peripheral tissue10 and does not fit with Tsimane leukocyte pattern7. Furthermore, exercise-induced response has been shown to gradually decrease in trained athletes. Long-term training is eventually followed by the release of anti-inflammatory cytokines11,12. Such difference between initial-shock immune response to intense exercise, as undertaken by untrained Eifel participants, and long-term immune adaptation to physical activity brings into question the reliability of the leukogram patterns measured on the fourth day of trek in the Eifel study. A shift towards a more anti-inflammatory pattern could therefore be expected in the Eifel participants after acclimatisation to this new lifestyle, regardless of environmental factors. It is therefore highly speculative that the Eifel participants’ immune profile would be a good model for the immune pattern of a Paleo-population.
    Handbag Black JUST CAVALLI CAVALLI JUST

    Answer: Thank you for these thoughts which go along the lines of our third hypothesis, namely that the sudden physical activity increase would be responsible for the acute CRP increase. We have included this additional mechanism in our discussion and re-wrote a large part of the third hypothesis. We think that the revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies. In no way did we intent to propose that the immune profile of the latter is a good model for the former. 

    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' POLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. From these observations, FKL reach the conclusion that chronic inflammation in the Tsimane protects against NCDs and propose explanations for why this might be the case. We will discuss this assumption in the following sections.
     
    First, we disagree with the assumption that Tsimane people stand as an adequate model for the study of the relationship between Low-grade inflammation (LGI) and non-communicable diseases (NCDs). LGI, associated with coronary diseases and other NCDs in westerners, is usually not triggered by specific stimuli such as infection or injury 2, but strongly associated with other risk factors such as stressful situations 3 and excess of adipose tissue Handbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. Tismanes are less mobile than most hunter-gatherers, such as the Hadza - who demonstrate low CPR Classic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd. This increased sedentisation may be part of the reason they face a heavy parasitic load and bacterial infections 6 likely responsible for their hightened inflammatory response 7, along with low levels of cholesterol, LDL and HDL. It is also noteworthy that the major comparative study on Tsimane immune function failed to show that after childhood there was any significant increase in CRP, a major low-grade inflammatory marker 7. The hypothesis that the parasitic burden triggering Th2 response may enhance anti-inflammatory cytokine levels and thus protect against NCDs is interesting. However, the absence of major NCDs risk factors, such as chronic stress, insulin-resistance and elevated fatty acid levels, brings into question the underlying assumption that the Tsimane may face common NCDs. 

    Answer: We apologize if we seemed to have suggested the Tsimane as an adequate model for studying the connection between LGI and NCD. This was not our aim. Rather, our aim was to point out the Tsimane as an interesting case of indigenous people who are apparently free from the NCD that plague the Western societies despite having chronically elevated CRP levels. This should make clear that they are not an adequate model, but rather an exceptional case worth further studying. In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do, agreeing with your argument above. This is probably the best explanantion for their low incidence of NCDs.

    Finally, we strongly reject the authors' conclusion that inflammation may protect against NCDs in Tsimane. Indeed, CRP levels were found to be a positive predictor of non-null coronary artery calcium scores 8, suggesting CRP might actually be predictive of atherosclerosis, a major NCD, in Tsimane as well.

    Answer: We are sorry for making causal claims where the data do not clearly support any. We have been more careful with our formulations in the revised manuscript, refraining from making any causal claims.
     
    According to the authors, the inflammatory state of the Tsimane could be partly explained by environmental factors also responsible for the pro-inflammatory profile observed in the participants of the Eifel experiment. We will review and discuss two of the hypotheses proposed by FKL to explain this result.
     
    First, a ‘forest bathing’ effect would have enhanced innate immune response and therefore result in an increase in CRP levels. Although we do not wish to undermine the potential role of the ‘forest bathing’ effect, to the best of our knowledge no evidence so far suggests that it could have an impact on CRP levels. Most studies focus on NK cells, cortisol levels and bio-markers of endothelial function. As CRP elevation in the Eifel participants failed to reach significance and NK cells were not measured, the ‘forest bathing’ effect remains speculative.

    Answer: We agree that this hypothesis is currently only speculative until further measurements have been made which are able to distinguish it from other hypotheses such as the acute phase response due to strenuous physical activity. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Nevertheless, we consider them possible explanations that should be considered in data interpretation. Our future research is planned to more specifically address the forest bathing hypothesis.
     
    Second, as suggested by the authors, exposure to exogenous pathogen associated-molecules could have caused a shift towards Th1 response in Eifel participants. However, there is no evidence to support the assumption that this shift was 'prophylactic' as participants may have well indeed face acute infection from small wounds or respiratory pathogens in a forest environment. In order to strengthen their theoretical argument, the authors could provide references regarding the resolution of chronic inflammation following an episode of acute inflammation.

    Answer: We had already noted that this hypothesis is currently only speculative. However, since we are mainly interested in explaining the acute rise of CRP levels, we have deleted any hypothesizing that this acute phase response could have led to the resolution of chronic LGI. An example for the resolution of chronic inflammation after acute stimulation of the immune system (although not neccessarily translatable to all NCDs) is the spontaneous remission of cancer after an acute episode of fever that is now more or less officially acknowledged (e.g. Jessy T (2011): Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med; 2(1): 43–49). Other examples from medical practice include treatment of chronic tendonitis through re-injury or using low-dose ionizing radiation to treat chronic inflammatory conditions.
     
    Finally, we would like to suggest another potential origin for the pro-inflammatory immune profile in the Eifel participants. It seems participants exhibit the typical leukocyte count induced by stress and exercise 9: neutrophilia, lymphopenia and eosinopenia. Such leukocyte pattern is supposedly the result of cortisol-induced cell-migration into peripheral tissue 10 and does not fit with Tsimane leukocyte pattern 7. Furthermore, exercise-induced response has been shown to gradually decrease in trained athletes. Long-term training is eventually followed by the release of anti-inflammatory cytokines 11 , 12. Such difference between initial-shock immune response to intense exercise, as undertaken by untrained Eifel participants, and long-term immune adaptation to physical activity brings into question the reliability of the leukogram patterns measured on the fourth day of trek in the Eifel study. A shift towards a more anti-inflammatory pattern could therefore be expected in the Eifel participants after acclimatisation to this new lifestyle, regardless of environmental factors. It is therefore highly speculative that the Eifel participants’ immune profile would be a good model for the immune pattern of a Paleo-population.

    Answer: Thank you for these thoughts which go along the lines of our third hypothesis, namely that the sudden physical activity increase would be responsible for the acute CRP increase. We have included this additional mechanism in our discussion and re-wrote a large part of the third hypothesis. We think that the revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies. In no way did we intent to propose that the immune profile of the latter is a good model for the former. 

    Competing Interests: No competing interests were disclosed. Close
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How to cite this report:
Gurven MD and Finch C. Referee Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]. F1000Research 2018, 7:252
(doi: 10.5256/f1000research.15283.r31343)
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Referee Report  12 Mar 2018
Michael D. 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 0
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
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 risk 1. More recently, we reported minimal coronary artery calcification that progressed 25 years more slowly than in the US,, and again, without any relationship with CRP STACY Handbag FURLA DRAWSTRING Black M OqqwYCU.
 
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.
 
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 CRP 5.

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 levels 8. A small sample of Hadza hunter-gatherers also showed reasonably low CRP levels (74% of 23 adults had CRP < 3 mg/L) 9.
 
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 stimuli 10. 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 injury 11.
  • Is the topic of the opinion article discussed accurately in the context of the current literature?

    Partly

  • Are all factual statements correct and adequately supported by citations?

    Yes

  • Are arguments sufficiently supported by evidence from the published literature?

    Partly

  • Are the conclusions drawn balanced and justified on the basis of the presented arguments?

    No

References

1. Gurven M, Kaplan H, Winking J, Eid Rodriguez D, Vasunilashorn S, Kim JK, Finch C, Crimmins E: Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists.PLoS One. 2009; 4 (8): e6590 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
2. Kaplan H, Thompson R, Trumble B, Wann L, Allam A, Beheim B, Frohlich B, Sutherland M, Sutherland J, Stieglitz J, Rodriguez D, Michalik D, Rowan C, Lombardi G, Bedi R, Garcia A, Min J, Narula J, Finch C, Gurven M, Thomas G: Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet. 2017; 389 (10080): 1730-1739 Publisher Full Text
3. Gurven MD, Trumble BC, Stieglitz J, Blackwell AD, Michalik DE, Finch CE, Kaplan HS: Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?. Evol Med Public Health. 2016. Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
4. Vasunilashorn S, Crimmins EM, Kim JK, Winking J, Gurven M, Kaplan H, Finch CE: Blood lipids, infection, and inflammatory markers in the Tsimane of Bolivia.Am J Hum Biol. 22 (6): 731-40 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
5. Steptoe A, Hamer M, Chida Y: The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis.Brain Behav Immun. 2007; 21 (7): 901-12 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
6. Gurven M, Kaplan H, Winking J, Finch C, Crimmins EM: Aging and inflammation in two epidemiological worlds.J Gerontol A Biol Sci Med Sci. 2008; 63 (2): 196-9 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8
7. Blackwell AD, Trumble BC, Maldonado Suarez I, Stieglitz J, Beheim B, Snodgrass JJ, Kaplan H, Gurven M: Immune function in Amazonian horticulturalists.JUST Handbag CAVALLI CAVALLI Black JUST Ann Hum Biol. 2016; 43 (4): 382-96 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
8. McDade TW, Tallman PS, Madimenos FC, Liebert MA, Cepon TJ, Sugiyama LS, Snodgrass JJ: Analysis of variability of high sensitivity C-reactive protein in lowland Ecuador reveals no evidence of chronic low-grade inflammation.Am J Hum Biol. 24 (5): 675-81 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
9. Raichlen DA, Pontzer H, Harris JA, Mabulla AZ, Marlowe FW, Josh Snodgrass J, Eick G, Colette Berbesque J, Sancilio A, Wood BM: Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers.Am J Hum Biol. 2017; 29 (2). Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
10. Schaller M, Miller GE, Gervais WM, Yager S, Chen E: Mere visual perception of other people's disease symptoms facilitates a more aggressive immune response.Psychol Sci. 2010; 21 (5): 649-52 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text
11. Kushner I, Rzewnicki D, Samols D: What does minor elevation of C-reactive protein signify?. Am J Med. 2006; 119 (2): 166.e17-28 Leather Saint Kate Monogram Bag Body Stud Small Cross Moroccan Brown Vintage Laurent TgTwFqx8 | Publisher Full Text

Competing Interests: No competing interests were disclosed.

We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.
Close
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HOW TO CITE THIS REPORT
Gurven MD and Finch C. Referee Report For: The inflammation paradox: Why are Tsimane protected against Western diseases while Westerners are not? [version 1; referees: 2 approved with reservations]. F1000Research 2018, 7:252 (doi: 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
    Black JUST CAVALLI CAVALLI Handbag JUST 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 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 riskPOLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. 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 Tsimane3,Handbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. 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 CRPClassic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd.

    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 course6CAVALLI Handbag CAVALLI JUST JUST Black ,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).“
    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 risk POLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. More recently, we reported minimal coronary artery calcification that progressed 25 years more slowly than in the US,, and again, without any relationship with CRP 2.
     
    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 , Handbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. 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 CRP Classic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd.

    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 levels 8. 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 stimuli 10. 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 injury 11.

    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).“
    Competing Interests: No competing interests were disclosed. Close
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 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 riskPOLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. 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.
     
    JUST JUST Handbag CAVALLI CAVALLI Black
    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 Tsimane3,Handbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. 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 CRPClassic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd.

    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 course6,7, 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.
    JUST Black CAVALLI Handbag CAVALLI JUST

    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).“
    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 risk POLLINI Handbag Bronze Handbag POLLINI dxwqxUHS. More recently, we reported minimal coronary artery calcification that progressed 25 years more slowly than in the US,, and again, without any relationship with CRP 2.
     
    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 , Handbag Handbag Black PIECES PIECES PIECES Handbag Handbag Black PIECES Black wY1TP1xn. 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 CRP Classic Metal Black Tassel Handbag Quilted Trim Women's SHwxdqd.

    MOSCHINO Black Handbag Black Handbag MOSCHINO MOSCHINO Handbag Black Black Handbag MOSCHINO wSqYn 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 levels 8. 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 stimuli 10. 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 injury 11.

    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).“
    Competing Interests: No competing interests were disclosed. Close

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Version 2
VERSION 2 PUBLISHED 01 Mar 2018
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  1. Michael D. Gurven , University of California, Santa Barbara, USA
    Caleb Finch, University of Southern California, USA
  2. Colette Berbesque , University of Roehampton, UK
    Baptiste Sadoughi, University of Roehampton, UK

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