Probiotics/Prebiotics – Very good for Some, but no Panacea

This is another post that I had waiting for completion; it is not saying do not use pre/probiotics, it is just saying make sure you know what you are doing.  Plenty of people appear to be wasting their money on ineffective bacteria, some people are making themselves sick, but others get a genuine benefit worth paying for. The is no one-size fits all. Some bacteria are good for some people and bad for others.

It gets more expensive the further you live
from Switzerland, but with the right oral 
bacteria you need a very modest amount.

One of today’s studies shows that spending money on stool tests for bacteria to fine tune a therapy may be a waste of money, unless you do your homework first. 

There is currently a lot written about the role of the gut microbiome on human health. Unfortunately, it tends to get simplified into just good bacteria and bad bacteria.  Advice like “take a good bacteria” is not very useful.

The reality is that some people take a store-bought pre/probiotic bacterium and it does nothing, for some it makes them feel worse and for others it makes them feel better.

It is rather like taking a random drug from the pharmacy and hoping for the best. In the case of autism, it is clear that some people make their child’s life worse with these pills, while sometimes it makes them better.

The idea of custom-made personalized probiotics sounds interesting, but it assumes that the bacteria found in a stool sample is representative of what is living in different parts of your intestines. Unfortunately, a recent study in humans that took samples from different parts along the intestines and compared the result with a non-invasive stool sample, found that the results did not correlate. In other words, drawing too many conclusions from the bacteria found in stool samples is unwise. This challenges the business case for   custom-made personalized probiotics.Modifying bacteria in your body has huge therapeutic potential for some people, but the science is still in its infancy. There are also promising results from fecal transplants (Bacteriotherapy), which is another way to modify the gut microbiome.

https://www.hopkinsmedicine.org/gastroenterology_hepatology/clinical_services/advanced_endoscopy/fecal_transplantation.html

“As of 2013, fecal transplantation is currently not routinely performed for indications other than recurrent C. difficile colitis. More research studies are still needed to determine if fecal transplantation should be performed for other clinical indications. Fecal transplantation for other clinical indications should be considered experimental, and performed only as part of a research study where your safety is closely monitored.”

                                                                                             

          Gut Microbiome Studies Question Influence of Probiotics

"Although all of our probiotic-­consuming volunteers showed probiotics in their stool, only some of them showed them in their gut, which is where they need to be," co-author Eran Segal from Weizmann added. "If some people resist and only some people permit them, the benefits of the standard probiotics we all take can't be as universal as we once thought.

Probiotics labelled 'quite useless'

A group of scientists in Israel claim foods that are packed with good bacteria - called probiotics - are almost useless.

Their study is among the most detailed analyses of what happens when we consume probiotics.

They are seen as healthy and good for the gut, but the results found they had little or no effect inside the body.

The researchers said probiotics of the future would need tailoring to the needs of each individual.

The team at the Weizmann Institute of Science made their own probiotic cocktail using 11 common good bacteria including strains of Lactobacillus and Bifidobacteria.

It was given to 25 healthy volunteers for a month.

They were then sedated and samples were surgically taken from multiple places in the stomach and small and large intestines.

The researchers were looking to see where bacteria successfully colonised and whether they led to any changes in the activity of the gut.

The results in the journal Cell, showed in half of cases the good bacteria went in the mouth and straight out the other end.

                                                          

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features

Highlights

• The murine & human gut mucosal microbiome only partially correlates with stool
• Mice feature an indigenous-microbiome driven colonization resistance to probiotics
• Humans feature a person-specific gut mucosal colonization resistance to probiotics
• Probiotic colonization is predictable by pre-treatment microbiome & host features

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.

In this work, we profiled the homeostatic mucosal, luminal, and fecal microbiome along the entirety of the gastrointestinal tract of mice and humans. We demonstrated that solely relying on stool sampling as a proxy of mucosal GI composition and function may yield limited conclusions.

Our results highlight several important concepts. First, we expand the scope of description of the human microbiome bio-geographical compositional and functional landscape, and indicate that extrapolation from stool microbiome communities to those of specific GI mucosal and luminal niches may lead, in some cases, to inaccurate conclusions. By directly comparing the stool and mucosal presence of 11 probiotic strains of the most commonly used probiotic genera, we conclude that probiotic strain expansion in stool, highlighted by most previous studies to be a sign of probiotics efficacy, cannot distinguish between true probiotic-permissive and resistant individuals, in which probiotics in stool represent a transient ‘‘washout’’ of non-colonizing strains passing throughout the GI lumen without significantly adhering to the host mucosal layer.

Second, the marked and person-specific mucosal colonization resistance to probiotics noted in our study may explain the high variability in probiotics effects on the host or its microbiome noted in previous works. One important feature shown in our studies to play a central role in impacting individualized probiotic mucosal colonization is the indigenous gut microbiome, which may drive the observed person-, strain-, and region-specific colonization resistance patterns to probiotics, as previously suggested. Similarly, we have recently demonstrated that person-specific variations in microbiome composition and function may contribute to the variability in glycemic responses to a variety of foods

Finally, the identified baseline microbial and host factors potentially enabling prediction of a probiotics-permissive or -resistant state merit validation in larger cohorts and call for consideration of a transition from anempiric ‘‘one size fits all’’ probiotics regimen design, to one which is based on the consumer. Such a measurement-based approach would enable integration of person-specific features in tailoring particular probiotics interventions for a particular person at differing clinical contexts.

Probiotics can cause SIBO (small intestine bacterial overgrowth)

In the recent study below, it is suggested that probiotic use can lead to small intestine bacterial overgrowth (SIBO) and the elevated levels of D-lactic acid in blood, then leads to “brain fogginess”. Stopping taking the probiotic (and taking an antibiotic) pretty much solves the problem.

Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis

Conclusions

We describe a syndrome of Brain Fogginess (BF), gas and bloating, possibly related to probiotic use, SIBO, and D-lactic acidosis in a cohort without short bowel. Patients with BF exhibited higher prevalence of SIBO and D-lactic acidosis. Symptoms improved with antibiotics and stopping probiotics. Clinicians should recognize and treat this condition.

Bacteria to calibrate the immune system

We saw in earlier posts that the bacteria the fetus and baby are exposed to are used to calibrate the future immune response, which is then pretty much fixed for life. During evolution humans have developed expecting to be exposed to certain bacteria, that today we might regard as just dirt. By living in an ultra-clean environment, we are doing the next generation no favours.

Exposure to bacteria from pets and farmyard animals is very healthy, but only when this is done during pregnancy and shortly thereafter. Once the child’s immune system has been programmed to expect almost no bacteria it is maladapted to cope with future allergens and challenges to the immune system. The result is it over-reacts and produces eczema, asthma, food allergies and many other auto-immune diseases.    

An example showing the benefit of applying knowledge of bacteria

At the risk of digression, here is an example of truly beneficial oral bacteria.

Some years ago, in this blog I reviewed the evidence that drinking beetroot juice boosts exercise endurance and lowers blood pressure.  I was intrigued by this idea, since it is a really simple, healthy and it is easy to measure your blood pressure. Beetroot is rich in nitrates (NO₃^-) and your body coverts these to nitrites (NO₂^-) and then later on it uses an enzyme called eNOS (endothelial nitric oxide synthase) to produce nitric oxide in your blood vessels. This dilates them (opens them up) and lets more blood through. This allows endurance cyclists, or marathon runners, to keep going longer and for couch potatoes it lowers their blood pressure. People with vascular conditions like vascular dementia should also benefit from more NO, they may lack the enzyme eNOS if they are elderly. We saw this is my post on Arginine, which suggests that older adults should be taking ALA or NAC, rather than blood pressure reducing meds.

Arginine and its Derivatives in Cognitive Impairment

the progressive impairment in endothelium-dependent vasodilation is caused by a progressive alteration of the L-arginine-NO pathway. Only in old age (after ≈60 years) does the production of oxidative stress appear, leading to the complete compromise of NO availability.  

For the scientist among you, things are actually much more complex.

Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis

“Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here, we investigated a potential cross-talk between these two pathways in the regulation of vascular function.”

For the rest of us, basically, we are cheating to improve vascular NO homeostasis. Nitrates are present in other food like spinach and kale, foods many people would avoid, just as would beetroot.

I did an experiment to see if a modest dose (200ml) of beetroot juice would reduce my own blood pressure; it did and by more than a trivial amount. So, I thought I would actually continue with it.

Having now done all my homework I have got the blood pressure benefit from just 80ml of beetroot juice a day, along with an understanding of the bacteria in my mouth that converts the nitrate into nitrite. This means I can reduce my beetroot consumption by more than half to a non-bothersome amount.

Any kind of mouthwash will kill the bacteria needed to make nitrite (NO₂^-), as will toothpaste. Unless you really want to drink a large glass of beetroot juice every day, you just take 80 ml of beetroot juice and slowly swirl it around in you mouth to react with the bacteria that has been multiplying overnight, before you brush your teeth in the morning.

I finally found a 100% beetroot juice that actually tastes pleasant. It is Swiss and so at least it is consistently the same, unlike the others I tried which ended up being more apple juice than beetroot juice or just tasting vile.

The advantages of an 80ml beetroot juice “mouth rinse”: -

·        Lower systolic blood pressure by about 10 mmHG

·        Lower LDL cholesterol, via the flavonoids

·        The betanin (the red colour) protects against Alzheimer’s in animal models

·        Likely has other (neuro) vascular benefits, perhaps including reducing vascular dementia

                                                                                                                 

The bacteria science, as an example of what you can figure out from publicly available sources: -

From Nitrate to Nitric Oxide: The Role of Salivary Glands and Oral Bacteria.

Abstract

The salivary glands and oral bacteria play an essential role in the conversion process from nitrate (NO₃^-) and nitrite (NO₂^-) to nitric oxide (NO) in the human body. NO is, at present, recognized as a multifarious messenger molecule with important vascular and metabolic functions. Besides the endogenous L-arginine pathway, which is catalysed by complex NO synthases, nitrate in food contributes to the main extrinsic generation of NO through a series of sequential steps (NO₃^--NO₂^--NO pathway). Up to 25% of nitrate in circulation is actively taken up by the salivary glands, and as a result, its concentration in saliva can increase 10- to 20-fold. However, the mechanism has not been clearly illustrated until recently, when sialin was identified as an electrogenic 2NO₃^-/H⁺ transporter in the plasma membrane of salivary acinar cells. Subsequently, the oral bacterial species located at the posterior part of the tongue reduce nitrate to nitrite, as catalysed by nitrate reductase enzymes. These bacteria use nitrate and nitrite as final electron acceptors in their respiration and meanwhile help the host to convert nitrate to NO as the first step. This review describes the role of salivary glands and oral bacteria in the metabolism of nitrate and in the maintenance of NO homeostasis. The potential therapeutic applications of oral inorganic nitrate and nitrite are also discussed.

The role of salivary glands and oral bacteria in the NO3--NO2--NO pathway. Up to 25% of the circulating nitrate is actively taken up by the salivary glands and concentrated ∼10- to 20-fold in the saliva to maintain the enterosalivary circulation of NO3--NO2--NO. This key process is mediated by sialin, which is an electrogenic NO3-/H+ transporter in the plasma membrane of salivary acinar cells. When saliva nitrate is secreted into the oral cavity with dietary nitrate—which is reduced to nitrite by the commensal facultative anaerobic bacteria at the posterior aspect of the tongue—some of the nitrite is converted into NO at the stomach. However, most of the remaining nitrate and nitrite are absorbed in the intestine and directly enter the systemic circulation, generating NO in blood and tissues under physiologic hypoxia and playing biological effects.

Role of Oral Bacteria on Nitrate Reduction to Nitrite

Humans, unlike prokaryotes, are believed to lack the enzymatic machinery to reduce nitrate back to nitrite. However, due to the commensal bacteria that reside within the human body, it has been demonstrated that these bacteria can reduce nitrate, thereby providing an alternative source of nitrite. Bacteria are vital in the process of converting nitrate to nitrite—the crucial first step in the NO3--NO2--NO pathway.

Location of Nitrate-Reducing Bacteria in the Mouth

After an oral nitrate loading, gastric NO concentration increases continually. The importance of oral bacteria in gastric NO generation has been clearly illustrated in experiments using germ-free sterile rats, in which gastric NO formation is negligible even after a dietary load of nitrate. The experiment also showed that NO is very low in rats treated topically with an antiseptic mouthwash.

Interestingly, the gastroprotective effects of dietary nitrate, discussed in the section below, virtually disappeared in rats treated with antiseptic mouthwash solutions. The posterior surface of the tongue is responsible for the majority of nitrate reduction, while in the entire oral cavity the nitrate reduction is found to vary widely among individuals. Studies on rats have also shown that nitrate reductase activity occurs on the posterior surface of the tongue and that significantly higher proportions of gram-negative bacteria were found deep within the tongue clefts as compared with the surface.

Composition of Nitrate-Reducing Bacteria

The major nitrate-reducing bacteria can be classified into 2 broad categories—the strict anaerobes (Veillonella atypica and Veillonella dispar) and the facultative anaerobes (Actinomyces odontolyticus and Rothia mucilaginosa;). The facultative anaerobe A. odontolyticus also displays markedly greater ability to reduce nitrate following incubation under anaerobic conditions. However, it is the strict anaerobes (Veillonella spp.) that have been found to be the most prevalent nitrate reducers on the tongue and therefore may be a major contributor to nitrate reduction in the oral cavity. Recently, by using 16S rRNA gene pyrosequencing and whole genome

shotgun sequencing and analysis, scientists have found a higher abundance of Prevotella, Neisseria, and Haemophilus than Actinomyces on the posterior surface of the tongue.

Saliva Nitrate Protecting against Gastric Damage

Nitrate secreted from the salivary glands is found to have an unprecedented function in protecting against stress-induced gastric damage. A water immersion–restraint stress assay in rats shows decreased blood flow in gastric mucosa and induced hemorrhagic erosions after bilateral parotid and submandibular duct ligature. In animals that had received either cardiac ligation or oral treatment with povidone-iodine, a potent bactericidal agent, administration of nitrate failed to increase gastric levels of NO and to inhibit the mucosal injury. NO that is formed close to the gastric mucosa can easily diffuse through the mucosa to the submucosal arterioles, causing vasodilatation and thus increasing gastric mucosal blood flow. This process protects gastric epithelial cells from necrosis. In addition, the decrease of mucosal myeloperoxidase activity and the expression of induced NO synthase with nitrate pretreatment imply that nitrate can reduce tissue inflammation, making this mechanism a possible way of gastric protection. In the absence of a dietary nitrate intake, salivary nitrate originates mainly from NO synthase. Thus, oxidized NO from the endothelium and elsewhere is recycled to regulate gastric mucus homeostasis.

Conclusion

There are some very clever things that can be done by modifying the bacteria in your gut, but if you get it wrong you can very easily make things worse. In some cases, people create a problem where non-existed.

Taking probiotics is not so different to taking drugs, care is needed.

You cannot just produce a general list of good bacteria and bad bacteria. The effects of some bacteria are very specific, and an ever so slightly different variant of one bacterium can do something completely different. Also, what is a good bacterium for one person can be a bad bacterium for the next person.

If you go back to when there was a lot of discussion in this blog about probiotics, this pretty much fits in with the comments. A few people had a good result, some people had a horrific experience and for many there was no effect, except on their wallet.

Many supplements actually contain a relatively tiny number of bacteria and by the time you consume them, you have no idea how many are still alive.

Growing your own bacteria gets around the potency problem, once you have found one that actually gives a benefit.

I do think there is great promise to treat a small number of people by transplanting the microbiome of a healthy person. Only a small number of people are going to need this.

The safest way to “improve” your microbiome is through eating a healthy varied diet, with fruits, vegetables and fiber, which many people resist doing.

Regular exposure to pets and their dust/dirt during pregnancy is on my list of how to minimize future autism. Pets are also calming which should lower oxidative stress and of course dogs make you go for long walks.

For late middle-aged people and older, beetroot juice really is a good intervention and for the really committed add a glass of natural yoghurt with teaspoon of turmeric and high flavanol cocoa (if you can find it), otherwise it is rather expensive Cocoavia from Mars. The yoghurt increases the bioavailability of the turmeric ten times, apparently.