Spirulina and LPS; and, Maybe Trans Fats are Not the Devil?

One of the very minor controversies in Paleo-land is whether algal foods or supplements are healthful. For what it's worth, pond algae appeared in the Paleolithic menu (according to the 2008 book Feast: why humans share food by Martin Jones). Spirulina and Chlorella supplements have both been used in the treatment of Hepatitis C with interesting results:
(music - Free Kim Dotcom by The Puddle featuring Matthew Bannister)


Efficacy and safety of Chlorella supplementation in adults with chronic hepatitis C virus infection http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581996/

Eighteen adults with chronic infection by HCV genotype 1 received daily oral supplementation of Chlorella for 12 wk. Changes in the RNA levels of HCV, as well as those of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were evaluated following this treatment period. Paired t tests were conducted to compare the means of the different variables at the beginning and end of the study. Side effects and quality of life aspects were also compared between weeks 0 and 12 of the study period.

RESULTS: A majority 84.61% of the patients had a significant decrease in their ALT levels from week 0 to week 12. Evaluation of side effects showed that Chlorella was well tolerated. Quality of life assessment showed that 76.9 of the participants reported an improvement in their energy levels and 46.1% reported an improvement in their perception of general health. Although 69.23% also showed a decrease in their AST levels, this was not statistically significant. Most patients that exhibited an improvement in their ALT and AST levels also showed a tendency toward a decreased HCV viral load. The HCV RNA levels showed a decrease in 69.23% of the patients, which along with changes in AST/ALT ratios from week 0 to week 12, these results were not statistically significant.

One very interesting outcome, not captured in the abstract was that those subjects who had not undergone previous treatment with interferon almost all (5/6) saw significant drops in viral load, whereas the 7 subjects that had previously used, and failed to respond to, interferon had no such reaction (see Table 1). 

What effect of algae could account for these results? Both spirulina and chlorella express PAMPs (Braun polysaccharides in the case of spirulina, and glycoprotein in the case of chlorella) that possess activity at TLR2. TLR2 is interesting because, as well as its immune system signalling role, it also promotes the intestinal detoxification of benzopyrene carcinogens. But that curious fact need not concern us here.

[One hundred years ago the birth of immunology was made official by the Nobel Prize award to Elie Metchnikoff and Paul Ehrlich. Metchnikoff discovered phagocytosis by macrophages and microphages as a critical host-defense mechanism and thus is considered the father of cellular innate immunity. He also was interested in the impact of normal flora on well-being and in pre- and probiotic diet and their influence on the normal flora. Ehrlich described the side-chain theory of antibody formation and the mechanisms of how antibodies neutralize toxins and induce bacterial lysis with the help of complement and thus is considered one of the fathers of humoral adaptive immunity.]

TLR2 activation by algal ligands activates elements of the innate immune system; natural killer T cells (NKT) and interferon (PDF). This will be responsible for the drops in viral load (in people whose immune systems are not already either unresponsive to interferons, or damaged by exposure to the supraphysiological levels of interferon-alpha used in HCV therapy). 

HCV core protein is a pro-inflammatory TLR2 ligand; this allows the immune system to recognise the virus and respond appropriately. Most HCV exposures (antibody+) will be cleared in the first 6 months, but chronic infection means that the virus has managed to subvert these responses. So supplying algal TLR2 ligands is a way of switching back on (or turning up) responses that the virus has managed to dim.
But TLR2 is also expressed on Treg cells (regulatory T Cells), able to induce immune tolerance (less Th17 inflammation, lower antibody production) to specific immune triggers, so HCV core protein's interaction with Treg TLR2 could be a way of numbing the immune system to the presence of HCV. This can be a good thing in some ways; sometimes "fighting the dragon" aggressively is just too destructive a strategy to be sustainable.

Another way in which HCV is able to reduce the host immune response is by the binding of HCV core protein to the C1q complement receptor; this inhibits complement activation, resulting in depletion of the C3 complement factor, and inhibits proliferation of T cells. 

Strikingly, this inhibitory effect of core on lymphocyte proliferation was observed at a concentration of core protein as low as 1.3 nM. 

This (I hypothesise) may result in compensatory increase in uptake of, and sensitivity to, LPS, as activation of both TLR4 and the alternate complement pathway by LPS are default ways for the immune system to maintain adequate activity (uptake of LPS from the intestine is not normally an accident, but a regulated and pseudo-hormonal activity). Thus restoring immune activation through TLR2 may decrease the LPS sensitivity which drives liver inflammation, as well as improving immune surveillance of and response to the ongoing HCV infection. As well as spirulina, probiotic bacteria such as Lactobacillus Rhamnosus also have TLR2 activity (PDF). 

My own suggestion would be to combine live Rhamnosus and/or Del-immune V with sprirulina or chlorella. The quantity of chlorella consumed in that paper seems rather daunting, and spirulina is a rich source of iron, so it will be good if lower intakes are effective. My own experience is that spirulina and probiotics go well together. Spirulina is also a very good source of mixed carotenoids, and high carotenoid intakes are (independently of retinol) associated with lower rates of hepatocellular cancer in chronic hep C populations; it is also a source of vitamin K2. (It is important to buy algal products from reputable suppliers who will test them for hepatotoxic contaminants).

Fatty liver, or steatosis, is a metabolic phenomenon and mainly diet driven and is a virtual precondition for hepatic fibrosis. Fibrosis itself, on the other hand, seems to be an immunological phenomenon, with the aspects of diet that have most influence being concerned with the microbiota (probiotics, prebiotics, parasites, pathogens, spices, and active foods like algae), the movement of LPS into the liver (polyunsaturated vs saturated fats), and the immune response to these (vitamins A and D, niacinamide and herbal medicines), as well as glucose and insulin regulation. 

(Note: in this neural stem cell paper http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010496 "the diet supplemented with spirulina was able to negate ...an acute systemic inflammatory insult of lipopolysaccharide")

(More Music: Sketches of Spain by Miles Davis)

Maybe Trans Fats are Not the Devil

Trans-palmitoleic acid isn't a special trans-fat like CLA (which everyone agrees is good). It's found in both dairy fat and partially hydrogenated vegetable oil. So why do people with the highest levels of TPA have a halved risk of developing diabetes?

Am J Clin Nutr. 2013 Apr;97(4):854-61. doi: 10.3945/ajcn.112.045468. Epub 2013 Feb 13.

trans-Palmitoleic acid, other dairy fat biomarkers, and incident diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

Mozaffarian D, de Oliveira Otto MC, Lemaitre RN, Fretts AM, Hotamisligil G, Tsai MY, Siscovick DS, Nettleton JA.

Source

Division of Cardiovascular Medicine and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, Harvard School of Public Health, Boston, MA.

Abstract

BACKGROUND:

Dairy consumption is linked to a lower risk of type 2 diabetes, but constituents responsible for this relation are not established. Emerging evidence suggests that trans-palmitoleate (trans 16:1n-7), a fatty acid in dairy and also partially hydrogenated oils, may be associated with a more favorable metabolic profile and less incident diabetes.

OBJECTIVE:

We investigated the association of trans-palmitoleate with metabolic risk and incident diabetes in a multiethnic US cohort.

DESIGN:

Phospholipid fatty acids and metabolic risk factors were measured in 2000-2002 among 2617 adults in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of white, black, Hispanic, and Chinese Americans. In 2281 participants free of baseline diabetes, we also prospectively assessed the risk of new-onset diabetes (205 cases) from baseline to 2005-2007.

RESULTS:

trans-Palmitoleate concentrations correlated positively with self-reported consumption of whole-fat dairy, butter, margarine, and baked desserts and with other circulating biomarkers of both dairy fat and partially hydrogenated oil consumption, which suggested mixed dietary sources. After multivariable adjustment, trans-palmitoleate concentrations were associated with higher LDL cholesterol (quintile 5 compared with quintile 1: +6.4%; P-trend = 0.005), lower triglycerides (-19.1%; P-trend < 0.001), lower fasting insulin (-9.1%; P-trend = 0.002), and lower systolic blood pressure (-2.4 mm Hg; P-trend = 0.01). In prospective analyses, trans-palmitoleate was independently associated with lower incident diabetes (P-trend = 0.02), including a 48% lower risk in quintile 5 compared with quintile 1 (HR: 0.52; 95% CI: 0.32, 0.85). All findings were similar between men and women and between different race-ethnic subgroups.

CONCLUSIONS:

Circulating trans-palmitoleate is associated with higher LDL cholesterol but also with lower triglycerides, fasting insulin, blood pressure, and incident diabetes in a multiethnic US cohort. Our findings support the need for further experimental and dietary intervention studies that target circulating trans-palmitoleate. The MESA trial was registered at clinicaltrials.gov as NCT000054

see also: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056495/

Trans-palmitoleate was associated with substantially lower incidence of diabetes, with multivariable-hazard-ratios=0.41 (95%CI=0.27–0.64) and 0.38 (95%CI=0.24–0.62) in quintile-4 and quintile-5, versus quintile-1.

One might surmise that in this case either the health benefits of increased fat intake override any negatives from hydrogenated vegetable oils (backed up by the finding that palmitoleate from DNL is associated with negative effects that are the inverse of those associated with trans-palmitoleate), or the health benefits of dairy fat are so profound that the negative effects of hydrogenated oils are swallowed up by them.

P.S. A few thoughts on the MESA trans-palmitoleate and palmitoleate studies.
I've looked at some of the other MESA research (there is a great deal of it) and this group's epidemiological work stands out for these reasons:
1) They are measuring an accurately quantifiable factor that is diet-dependent, not relying on food frequency questionaires.
2) They have verified that that factor does correlate with reported dietary intake
3) They are using an actual disease diagnosis (DM2) as the end-point, as well as differences in serum markers.
4) These are prospective studies.
5) Given the short follow-up period (5 years) the odds ratios for DM2 incidence are striking. 
6) There is little in the way of a priori assumptions to colour the interpretation of the data.