Gut Bacteria protect your Bones

Osteoporosis, which is a bone weakness, mostly occurring in elderly people characterized by an imbalance between the bone-forming cells and the bone-eating ones - the osteoclasts.
It also seems to run in my family as my mum, and my aunt suffer from it.
Malnutrition often leads to this disease. Unfortunately, one the disease starts to develop, the common supplementation of Calcium and Vitamin D3 did not help very much. At least not for my mum or aunt. Therefore, my mum got prescribed an immune system inhibitor called Denosumab that blocks the activation of Osteoclasts.
As I am studying the immune system in my P.hD. I was naturally curious what it actually does.
Denosumab is an antibody that binds and blocks a protein called RANKL. RANKL is the protein that leads to a differentiation and activation of Osteoclasts. Something that strict me was that RANKL is a pro-inflammatory protein, secreted by cells of the immune cells and that other known inflammatory proteins induces the production of RANKL.

                  Mechanism by which immune cells and inflammation modulates osteoclasts formation [1]

                  Mechanism by which immune cells and inflammation modulates osteoclasts formation [1]


So, my mum takes medication to suppress her immune system, which in turn shall improve her bone density.
And in fact, it did by about 25% in ... months.
But here are the two caveats:
First: My mum told me that according to the doctor, she can only take the medication for a certain time period before it needs to be stopped again, which potentially will relapse her osteoporosis.
And Second, my aunt, whose osteoporosis is far worse than my mothers, could not tolerate the medication and developed all kinds of side effects with eventually stopping the medication.

By the time my mum told me all this, my fascination about the microbiome already started and I was reading many books about it.

The immune system controls bone absorption

By now it is clear to me that our microbiome controls our immune system as I show in many videos and blogs. Hence, I started my research on osteoporosis by understanding the connection between the immune system and bone formation and found that there are studies out there showing how inflammatory proteins promote the formation of osteoclasts [2].

Osteoclasts formation by pro-inflammatory proteins (IL-1, IL-3, IL-6, GM-CSF and SCF) [2]

Osteoclasts formation by pro-inflammatory proteins (IL-1, IL-3, IL-6, GM-CSF and SCF) [2]

A study from 2001 actually shows that our immune cells activate osteoclast formation [3]. The researchers proved that activated T cells - which are cells of our adaptive immune system - are sufficient to induce a strong formation of osteoclasts.

 
Activated T cells increase the formation of Osteoclasts. Modified after [3]

Activated T cells increase the formation of Osteoclasts. Modified after [3]

 

Commonly, osteoporosis starts after the menopause in women as estrogen levels go down.
Researchers showed that by inhibiting pro-inflammatory proteins, they could completely prevent bone loss in postmenstrual rats, by decreasing the number of active osteoclasts [4]

 
Inflammatory protein inhibitors increase bone density [4]

Inflammatory protein inhibitors increase bone density [4]

 

Several inflammatory diseases such as rheumatoid arthritis and inflammatory bowel have been associated with low bone density [5]. The risk of hip fracture, for instance, in patients with the inflammatory disease is 86% higher! [6]

Take home message:
The immune system controls the bone density!

But what about the microbiome?

While I was doing some research about my GoodGutFeeling project I came across an article in a German Lab-Journal with the headline: "Knochenschutz durch Ballastoff" – which is translated: Bone protection through fiber.
This article referred to some very interesting studies that clearly show how you can improve bone density with the use of your microbiome.

Short-Chain Fatty acids and High fiber diet increase bone density

The team around Dr. Mario Zaiss from the University of Nürnberg hypothesized that our microbiome plays a big role in bone formation [11].
As a first experiment, they used Short-Chain Fatty Acids (SCFAs). SCFAs are produced in the colon when our bacteria ferment the ingested fiber. It has been shown that these fatty acids possess a variety of health benefits, such as weight loss, reducing inflammation levels and lower the risk for colon cancer. I have written a specific blog about this topic.

However, the researchers simply added little concentrations of SCFAs to the water of mice and what they found was almost breathtaking:
1.    The bone density of the mice significantly increased.
2.    The number of osteoclasts was reduced. Especially when the mice drank acetate and butyrate

 
All SCFAs - Acetate (C2), Propionate (C3) and Butyrate (C4) improve bone density (BV/TV (%)) and reduce the number of osteoclasts (N. Oc. / B.Pm.). Modified after [11].

All SCFAs - Acetate (C2), Propionate (C3) and Butyrate (C4) improve bone density (BV/TV (%)) and reduce the number of osteoclasts (N. Oc. / B.Pm.). Modified after [11].

 

But not just a supplementation of the SCFAs showed an improvement in bone density but simply adding fiber to the diet could show the same effect. Mice on a high fiber diet showed an increase in bone density and a reduction in the number of osteoclasts.

 
High fiber diet (HFD) improves bone density (BV/TV (%)) and reduce the number of osteoclasts (N. Oc. / B.Pm.). Modified after [11].

High fiber diet (HFD) improves bone density (BV/TV (%)) and reduce the number of osteoclasts (N. Oc. / B.Pm.). Modified after [11].

 

An imbalance of gut bacteria lowers SCFA production and reduces bone density

While it was shown that a specific bacteria species, called P. copri, is increased in patients with Rheumatoid arthritis, little is know about an imbalance of the microbiome affecting your bones. Therefore, Zaiss and his group introduced different strains of P. copri in healthy mice and measured the bone density after 8 weeks. The scientist observed that the bone density decreased by about 25%, together with an almost 50% drop in most SCFAs!

Transfer of three different Prevotella copri species decreases SCFA production (C2, C3, C4) and decreases bone density (BV/TV (%)). [11]

Transfer of three different Prevotella copri species decreases SCFA production (C2, C3, C4) and decreases bone density (BV/TV (%)). [11]

Finally, the scientist from Germany wondered if they could use SCFA as well as a high fiber diet to treat Rheumatoid arthritis. And they could! SCFA decreased the inflammation in the joint of arthritic mice together with a decrease in the number of osteoclasts, while the bone density increased! And again, same was seen on a high fiber diet!

I guess that is what you call a good line of evidence!

Take home message:

A healthy microbiome and a high fiber diet can protect our bones. Beneficial bacteria ferment the ingested fiber to SCFAs, which in turn regulate the immune system and can improve osteoporosis and arthritis.

What to do?

I don’t know what you do. You are probably fine like it is, as chances are high that you are young and don’t have weak bones… yet.  
For my mum, on the other hand, I already bought some apple cider vinegar as it provides her directly with the SCFA acetate. And multiple studies show the benefits of drinking it [12].
I am also considering to try sodium butyrate supplements.

But as always, supplements are supposs to give you or in this case my mum a quick start but don’t solve the cause. Therefore, I’ll try to ban processed foods from her diet and re-introduce good bacteria by probiotics and prebiotics (fiber).

 I'll keep you updated when she has her next bone measurement!

 

References

  1. Lacativa and de Farias, Osteoporosis and inflammation, Arq Bras Endocrinol Metabol., 2010
  2. Matayoshi et al., Human blood-mobilized hematopoietic precursors differentiate into osteoclasts in the absence of stromal cells, PNAS, 1996
  3. Weitzmann et al., T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and -independent mechanisms., J. Bone. Miner, 2001
  4. Kimble et al., Simultaneous block of IL-1 and TNF is required to completely prevent bone loss in Early Postovariectomy period, Endocrinology, 1995
  5. Lacativa and de Farias, Osteoporosis and inflammation, Arq Bras Endocrinol Metabol., 2010
  6. Rodríguez-Bores L, Barahona-Garrido J, Yamamoto-Furusho JK. Basic and clinical aspects of osteoporosis in inflammatory bowel disease. World J Gastroenterol. 2007
  7. Slingerland et al., Clinical Evidence for the Microbiome in Inflammatory Diseases., Frontiers in Immunology, 2017
  8. Vaghef-Mehrabany et al., Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis, Nutrition, 2013
  9. Scher et al., Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis, eLIFE, 2013
  10. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature, 2013
  11. Lucas et al., Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss, Nature Communications, 2018
  12. Kondo et al., Vinegar Intake Reduces Body Weight, Body Fat Mass, and Serum Triglyceride Levels in Obese Japanese Subjects, Bioschi. Biotechnol. Biochem., 2009