Keywords
Tsimane, Low-Grade Inflammation, Eifel studies, Non-communicable diseases
Tsimane, Low-Grade Inflammation, Eifel studies, Non-communicable diseases
In our revised manuscript, we strengthen the notion that Tsimane do not face the usual risk factors for NCDs that Westeners do. Moreover, we have been more careful with our formulations in the revised manuscript, refraining from making any causal claims.
We agree with the reviewers that our hypothesis concerning the forest bathing effect is currently only speculative until further measurements have been made. We have re-phrased the Outlook section accordingly. The same is true for our second hypothesis. Our future research is planned to more specifically address the forest bathing hypothesis.
In context of our third hypothesis, we have included the additional mechanism proposed by the reviewers in our discussion and re-wrote a large part of the third hypothesis. Our revision now also distinguishes more clearly between the chronic high CRP levels of the Tsimane and the acute elevations observed in the Eifel studies.
We agree that there are no data showing that chronic inflammation in Tsimans protects them against NCD (correlation is not causation). We have erased this claim. Rather, we agree that the best explantion is probably the absence of typical NCD risk factors. We also state in the revision that the data are not able to provide evidence for one of our hypotheses over any other, so that future studies should particularly put these hypotheses to test.
Finally, we agree that it is unclear if and when the elevated CRP levels found in the Eifel study participants would have decreased again. However, a similar study has found increased CRP levels after a 10-day trip through the wilderness. This is stated now in the last two sentences of the conclusions section.
See the authors' detailed response to the review by Colette Berbesque and Baptiste Sadoughi
See the authors' detailed response to the review by Michael Gurven and Caleb Finch
CRP, C-reactive protein; NCD, non-communicable diseases; NK cells, natural killer cells; LGI, low-grade inflammation; LPS, lipopolysaccharides; NFκB, nuclear-factor-kappa-B
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 NCDs2–4.
Compared to US reference values, Tsimane exhibit markedly high levels of eosinophilic and neutrophilic granulocytes, B lymphocytes and natural killer cells. The leukocyte counts of Tsimans (8,600–12,000 cells/μL) are 1.5 times, and lymphocytes 1.2 to 1.6 times higher than in the US population (6,700–7,900 cells/μL)5,6. Eosinophilic granulocytes, primarily indicative of parasitic infections, are 7-fold elevated. Consequently, the immunoglobulin E values are also significantly higher (150–200-fold). Important biomarkers for inflammation, such as neutrophil granulocytes (1.2 to 1.6-fold), blood sedimentation (30 mm/h to 15–20 mm/h) and C-reactive protein (CRP) values (higher from infant to adolescence), are also upregulated6. The high CRP levels in Tsimane are in contrast to other indigenous people such as the Hadza hunter-gatherers in Tansania7 or the Shuar hunter-horticulurists in Ecuador8 who show no obvious signs of chronic low-grade inflammation. Thus, chronically high CRP levels in the Tsimane pose an apparent paradox, as high CRP levels due to LGI in Westernized societies correlate with NCD risk. The paradox could be resolved if one assumes that chronic systemic inflammation is a necessary, but not sufficient component in NCD development if certain other factors are simultaneously present. In particular, in the Tsimane the chronic state of infection is thought to stem from a high prevalence of intestinal worms which would i) decrease the absorption of macronutrient in the gut, ii) increase the amount of type 2 anti-inflammatory T helper cells and iii) raise basal metabolic rate, reducing the risk for obesity9. However, the major protective factor against NCD appears to be their lifestyle which prevents the development of typical NCD risk factors such as insulin resistance and adiposity.
In 2013 and 2014, we carried out two field studies (Eifel studies) with Westerners who returned to a simulated Palaeolithic lifestyle in a National park for 4 days10,11. Contrary to our expectations, in both studies, CRP, the main liver-derived biomarker that displays nonspecific inflammation, had increased by 170% and 67%, respectively. The essential components of these interventions consisted of (i) the conversion to a paleo diet; (ii) the high range of locomotion (15 km/day in the Eifel study 2013, 16.4 km/day in the Eifel study 2014); (iii) a fasting period from 12 to 14 hours per day in conjunction with a low meal frequency resulting in undercaloric energy intake (1567 kcal in the Eifel study 2013, 1747 kcal in the Eifel study 2014). All mentioned factors have been shown to have anti-inflammatory effects12–16.
There are two interesting observations concerning the indigenous Tsimane in Bolivia and Westeners who returned to a paleolithic lifestyle in the Eifel studies: The former have chronically elevated CRP levels despite being practically free of NCDs, while the latter were found to have acutely elevated CRP levels despite other physiological changes that would usually be interpreted as protective against NCDs. We provide the following hypothetical explanations for the stimulation of the immune system in the Eifel studies, which are likely to influence one another:
1. Phyto-antibiotics (phytoncides), which plants release into the atmosphere to protect themselves against bacteria and insects, could have stimulated the innate immune system17. As studies from Japan and Korea have shown, so-called "forest bathing" (a multi-day hike through a forest) promotes the formation of high levels of natural killer cells (NK cells). This effect persists for up to 30 days after the intervention18,19. In addition, forest bathing also increases the activity of the cytolytic proteins perforin, granzyme A and granulysin in NK cells. Walks in the city, on the other hand, do not change the NK cell population or its activity19. These effects could have contributed to the increase in CRP levels in the Eifel studies, as most of the time participants spent in a forest area.
2. The radical change from a near-sterile to a natural environment may have prompted the innate immune system to anticipate and prophylactically protect the organism against pathogens such as bacteria, parasites, fungi, and other microorganisms. Danger signals, called exogenous pathogen associated molecular patterns and endogenous danger associated molecular patterns, activate the innate immune system via Toll-like receptors, which can trigger a rapid antibacterial inflammatory response. This mechanism of action may have led to the development of an acute phase response. In contrast to LGI, substances such as lipoxins, resolvins and protectins are formed in acute inflammation in order to end the inflammatory process20,21. Since no follow-up measurements were made in the Eifel studies, this hypothesis is currently only speculative.
3. Despite the fact that the participants in the Eifel studies were in good mental and physical health, the level of physical stress due to the high workload combined with calorie restriction conditions could have induced a moderate acute phase response. Indeed, acute and transient elevations of CRP levels, inflammatory cytokines (in particular IL-6) and shifts in leucocyte patterns typically occur after strenuous exercise22–24. The latter include elevations in neutrophils and decreases in eopsinophils and lymphocytes, changes that have also been observed in our Eifel study participants10,11. Therefore, this hypothesis appears to be the best confirmed by the data. The acute increase in CRP levels could thereby be caused by several mechanisms including increased catecholamine and cortisol levels23 or endotoxemia through bacterial lipopolysaccharides (LPS) caused by increased cell destruction and gut leakage25. LPS activate the innate immune system via Toll-like receptors and stimulate the activation of nuclear-factor-kappa-B (NFκB) intracellularly, leading to pro-inflammatory cytokine secretion26. A by-product of cell destruction is uric acid, which stimulates the release of CRP in the liver as part of the acute immune response27,28. In turn, CRP stimulates the production of antibodies from B lymphocytes to kill pathogens29. Due to the high range of locomotion in both Eifel studies, uric acid might have played a prominent role in stimulating the immune system. Since uric acid has not been measured, future studies should include this marker to provide a possible confirmation of this hypothesis.
The fact that a chronic inflammatory situation in Tsimans persists despite practical non-existence of NCDs, while it is associated with NCDs in Westerners, appears paradoxical. A second apparent paradox concerns the acutely elevated CRP levels in Westeners returning to a Paleolithic lifestyle despite otherwise beneficial metabolic effects usually associated with a decrease in LGI. We have discussed three different hypotheses to solve this second paradox. While the “forest-bathing” and “danger anticipation” hypotheses are currently only speculative due to the lack of relevant measurements, a mild-to-moderate acute-phase response due to the strenuous physical activity is consistent with the available data. However, the data cannot clearly constitute evidence for one of these hypotheses against any other, in part because their likelihood under the “forest-bathing” and “danger anticipation” hypotheses remains to be determined. Finally it remains to be examined if, when and how the acute elevations in CRP levels would resolve if the participants would remain in Paleolithic living conditions. Interestingly, a study similar to the Eifel studies involving a 10-day trip through the Pyrenees also reported a significant mild increase in CRP levels after the trip, showing that the acute phase repsonse could be sustained at least up to 10 days30,31.
No data are associated with this article.
Views | Downloads | |
---|---|---|
F1000Research | - | - |
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Is the topic of the opinion article discussed accurately in the context of the current literature?
Yes
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?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: human biology; global health; biomarkers; immunology; cardiovascular disease
Competing Interests: No competing interests were disclosed.
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. Freese J, Pardi D, Ruiz-Núñez B, Schwarz S, et al.: 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 TextCompeting Interests: No competing interests were disclosed.
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, et al.: Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists.PLoS One. 2009; 4 (8): e6590 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed.
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | |||
---|---|---|---|
1 | 2 | 3 | |
Version 2 (revision) 06 Aug 18 |
read | read | |
Version 1 01 Mar 18 |
read | read |
Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
Sign up for content alerts and receive a weekly or monthly email with all newly published articles
Already registered? Sign in
The email address should be the one you originally registered with F1000.
You registered with F1000 via Google, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Google account password, please click here.
You registered with F1000 via Facebook, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Facebook account password, please click here.
If your email address is registered with us, we will email you instructions to reset your password.
If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance.
Comments on this article Comments (0)