Acute infections represent frequent and violent tissue perturbations from which the immune system must rapidly rebound. Fonseca et. al.
Researchers have long believed that infections can kick off inflammatory diseases, but the link between an infection and a long term illness has been hard to substantiate. How infections could turn into a long-term inflammatory state has been mostly a mystery as well. A recent study that dug deep into the gut, however, is providing some answers.
Fonseca DM, Hand TW, Han SJ, Gerner MY, Glatman Zaretsky A, Byrd AL, Harrison OJ, Ortiz AM, Quinones M, Trinchieri G, Brenchley JM, Brodsky IE, Germain RN, Randolph GJ, Belkaid Y. Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity
. Cell (2015).
This mouse study found that a single gut infection was capable of permanently altering the structure of the gut and the gut flora. That didn’t happen in all the mice and it wouldn’t happen in all humans but it shows how an infection that has been successfully fought off could set the stage for a later disease.
The study was not conceptually difficult. The researchers simply dedicated themselves to very, very closely examining the changes that occurred in the gut during an infection.
One bad bug caused long term effects in many of the mice in the study.
They infected mice with a bacterium called Yersinia pseudotuberculosis which causes a tuberculosis-like illness (but not TB). The symptoms it produces include fever, abdominal pain, joint stiffness and skin problems. (It’s very close genetically to the bacterium that causes plague.)
They knew that Y. Pseudotuberculosis would reach its peak load in about a week, that the adaptive immune response would kick in at about two weeks, and the infection would be fully controlled in about three.
It all went like clockwork. All the mice successfully cleared the virus but as they did so a significant number of them developed what the researchers termed “immune scarring” in their lymphatic vessels.
The researchers knew that the lymphatic vessels would undergo huge changes as the immune system swarmed to attack the invader. Human studies have found that an Y. Pseudotuberculosis infection results in swollen, abscess-ridden lymph vessels.
No one had ever determined, though, if those changes remained after the infection or what consequences they might have for the patients immune health. This kind of single-minded approach – focusing almost entirely on the dynamics of fighting the infection – while ignoring the possible consequences of that fight has permeated infectious disease research.
Immune System Takes a Hit
This study found, though, that the immune response to the infection had consequences long after the infection had cleared. Nine months later the lymphatic vessels still demonstrated dramatic structural alterations and remained swollen and abcess ridden. One gut infection had permanently altered the structure of one of the major players in the immune systems of 70% of the mice.
The effects of the altered lymphatic regions were significant. The mice with the lymphatic damage were unable to produce normal levels of the regulatory T cells which suppress inflammation and prevent allergic responses. That alone could set them (or a human) up for an inflammatory disease later on.
Upon challenge testing the mice displayed a delayed type hypersensitivity reaction; i.e. an exaggerated immune response. Anaphylaxis and allergy are two forms of a hypersensitivity reaction, and the authors suggested that allergic responses to food could result. (Both the big CFI immune and the recent McNaughton immune study found elevated levels of eotaxin – an allergic factor – in ME/CFS patients.)
The immune system knocked out the invader – and damaged the body at the same time.
The TH17 response that helps clear infection and plays a role in autoimmunity was dramatically impaired. Pathogen recognition was hindered. The dendritic cells (DC’s) had trouble conveying antigens to the immune cells in the altered lymph vessels. In fact, some of them missed the now strange-looking lymphatic vessels entirely and ended up in the fatty tissues -where they were doing no good at all.
Without the DC’s conveying evidence of a pathogen to the T-cells inside the lymph vessels the adaptive immune response might never kick in. That suggested the mice would probably have trouble fighting off infections.
The lymph vessels had also been so altered by the infection that they leaked substances back into the gut.
The authors stated that the gut problems seen could result in multiple immune defects including the development of Th17 cells, T-regulatory and B cell responses in the GI tract.
The Gut Flora Connection
“…these data reveal a central role for the microbiota in the maintenance of the immune defects induced by acute infection. Fonseca et. al.
The bacterial composition of the gut was helping to maintain the immune damage. Altering the gut flora helped the immune damage go away.
The most interesting part of the study came, though, when they altered the gut flora. Knocking out the mouse’s gut flora with an antibiotic resulted in major improvements in the lymph vessels. The success of the antibiotic suggested that manipulating the gut flora using probiotics could reverse much of the “immune scarring” and inflammation the infection had left behind.
Because the gut flora of the mice which developed inflammation did not differ from the mice which did not, it appears that the infection itself permanently altered the composition of the gut flora. The authors suggested the leaky lymphatic vessels might be to blame.
Conclusions
The study found that a single gut infection can drastically and permanently alter the structure of the lymphatic vessels in mice. The altered lymph vessels could result in chronic inflammation and increased difficulty in finding and fighting off further infections. They also appear to negatively alter the gut flora in such a way as to maintain the “immune scarring” that occurred.
The good news in this otherwise seemingly bleak scenario is that altering the gut flora may be able to reverse much of the “immune scarring” that took place – and return the immune system to normal.
The study was done in mice, but it suggests what some researchers have been contemplating for quite a while: that some of those gut infections could predispose some of us to chronic illnesses years later. As the authors of the study pointed out children tend to experience many gut infections. Children who experience immune scarring as a result of them could be set for chronic inflammatory diseases (such as ME/CFS and FM?) years later. It’s perhaps notable that gut disturbances are common in both diseases.
That kind of time lag is not unusual at all. Early life stressors have been shown to predispose people to a increased risk of inflammatory and other disorders decades later. In a recent Simmaron Research Institute talk, Ian Lipkin explained how events at different times during pregnancy can have effects years later. A bout of infectious mononucleosis/glandular fever as a teenager increases the risk of coming down with multiple sclerosis as an adult.
Gut infections later in life such as giardiasis have been associated with chronic fatigue syndrome. It could be, though, that a gut infection early in life could set one up for a poor response to another type of infection later in life. It’s possible that the infection which appeared to have begun your illness may not have been the ultimate source at all.
This study will surely prompt more research into the already hot field that’s examining the effects of probiotics and gut flora manipulation on health.
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very interesting comments, thanks V.
I’m waiting for an analysis of my gut bacteria from a stool sample sent to Ubiome. They may still be having a sale, unfortunately after I sent mine in, for five analyses for one, about $90 bucks, an astounding discount. I wanted to see what was in my gut on my normal diet but it would take six weeks after stopping to wash out the probiotics I take daily so I did it to see what’s in my gut while on probiotics. It will be interesting to see how many of the 15 hopefully beneficial bacteria actually make it to my gut. Will let you all know but these people take weeks.
Fascinating article, Cort.
A lot of us had mono, never like to hear correlated with bad stuff like MS.
I think the good news with that is that the consequence of your mono was probably ME/CFS. From talking to doctors very few people diagnosed with ME/CFS end up with MS.
Why do you guys think MS is more devastating than CFS? From my observations, I’d rather have MS. It’s respected, it’s funded, and HSCT stem cell transplants – bone marrow transplant WITH CHEMO – effects a complete remission. So there is treatment and something close to a cure. While both illnesses create tremendous suffering, We with CFS are in many cases sicker, or at least more debilitated – how many MS patients are bedbound? My best friend had MS — and now she doesn’t. The bone marrow transplant WITH CHEMO that
she had would probably cure me too, but we are 20 years away from anyone funding that trial.
I had Giardia in my 20’s, but what seemed to ‘kick off’ ME, was an undiagnosed (for at least six months) abcess under a root canal. D
I had Giardia as well about four years before I came down with ME/CFS. Years later tests suggested it was still active. Perhaps it was the primary source for me…(???)
Where it gets really complicated is that Yersinia Pseudotuberculosis, as well as its close relative, Yersinia Enterocolitica, can both cause chronic infection. So it would have been interesting if they had compared the results in the mice that cleared the infection with mice that have been genetically modified so that they fail to clear the infection. This might provide some clues as to which type of situation we are looking at in particular cases of ME.
I am actually IgA positive for Yersinia Enterocolitica, which suggests a chronic infection. The news that the immune changes caused by a brief infection can be annuled is reassuring, hopefully it is the same with chronic infection too, but again it would be good to see a study showing this.
Anyway, interesting article and good write up!
Very interesting article, thank you. I was diagnosed with ME/CFS in 2001 after being treated for yersinia pseudotuberculosis which I caught whilst travelling in Mongolia. Ever since, I have had a predisposition for gut troubles included giardiasis, blastocystis and tuphoid and find it really hard to fight off colds and infections. I would be very interested to hear more about related research and would be happy to be involved in any research should this be of value. With thanks. Lucy Bent
Hi Lucy, I caught Yersinia in Vietnam – travel can be a dangerous thing. It triggered my ME too. Do you have reason to believe you cleared your Yersinia infection?
One thing we know is that mold makes mycotoxins in order to alter the biome of the environment – to kill off competitive bacteria and other fungi so that it can grow more freely.
And we know that mycotoxins can alter the inner microbiome as well – as in the antibiotics that are made from mycotoxins (e.g. penicillin).
And we also know that mold that is inhaled is eliminated through the digestive tract. That is the theory behind using cholestyramine, for instance.
Those things being the case, the idea that environmental toxic mold exposures may be causing major changes to the microbiome seems pretty logical.
I found that my own chronic severe candida issues came under control much more easily once I got clear of my moldy house and took other steps to avoid mold, too.
So I am going to posit that insofar as people are being exposed to large amount of environmental mycotoxins, or insofar as they still have a lot of these mycotoxins in their digestive systems as a result of not being able to detoxify them appropriately, a negative effect on the microbiome is going to result.
I don’t think this is the only way that mycotoxins exert negative effects on the system, but it does seem to be a big one.
I wish that there were researchers interested in pursuing this line of thought, therefore.
Lisa Petrison, Ph.D.
ParadigmChange.me
Lisa, there is one dr who was very much pursuing that thought. Can’t remember the name at the moment.
can you please comment on Harvard and Tufts neuroscientist Dr. Michael Van ElZakker’s paper Chronic Fatigue from Vagus Nerve Infection: A Psychoneuroimmunological Hypothesis? Have you already posted about this??
Mmmmm. I had a horrible stomach illness a few years before I got ill, when I was out in Malaysia; never found out what it was. I recently used probiotic pills, bone broth and kefir to see if it helped, but can’t say it did.
Have you tested for parasites. They can be quite difficult to find in stool samples and persistence and sending numerous samples to a reputable lab might result in a positive diagnosis. Genova Diagnostics is great at bacterial cultures but unfortunately, they found me negative for parasites when I was running to the bathroom, with diarrhea, mucus and blood and doubling over with pain. i was simultaneously infected with giardia, entamoeba histolytica and ascaris worms, all missed by the lab. I was finally diagnosed by a parasitologist who examined me by rectal swab in his office. Viracor Labs now offers PCR tests for both Giardia and cryptosporidium and that is progress in parasite diagnosis. I wish they had PCR testing for E histolytica and other parasites as well. I first developed symptoms of what could be called, ME/CFS when I acquired the parasitic infections. I had also acquired blastocystis hominis.
Hi,
Long time ago! However, did clearing these parasites with antibiotics fix or help your cfs/me symptoms?
Please respond 🙂
Thanks
Lucie
Interesting and probable theory since the majority of our immune system resides in the gut. I, too, had some kind of severe stomach ailment in late 2007. For 6 weeks I was literally unable to eat any solid food and had lots of facial pain. I seemed to fully recover until I had an URI in late 2010 which continued on and off until Spring 2011 when massive pain took over and I was subsequently diagnosed with FM and then CFS. I still have trouble from time to time with my stomach but usually after eating dairy, meat or gluten, and I seem to be good when I avoid those. Although I had no issues with any of these foods prior to 2011. All that being said, I had a Tdap vaccine in mid-2006 that I had a reaction to. IMO, It could have potentially permanently compromised my immune system. So which came first? I would be interested to see how many CFS patients have a history with vaccines and adverse reactions
I had a tdap in 2010 and I have been super sick since then. 12 doctors are now assigning me to the nut house. They could not help me. They started to get nasty when my questions continued. Why am I fatigued? why the joint pain brain fog the whole cfs range of symptoms.
That doctor who gave the tdap said it would not hurt my body. I was two years in bed practically after that shot. doctors would not even consider the impact on my body. They will not even talk to me now. I have the whole thing on my medical records labeling me a nut just because I ask questions about why I am still sick and tired.
Hi Bev,
My daughter had a hep A and B combined shot prior to intended travel at a later date. We noticed she was distended in the thyroid area on a Friday afternoon, (two days after the shot).however, as she did not feel unwell she attended school camp from the Monday ….and caught a virus…. 7 years later she is still tired! Though now not sleeping the 20 plus hours a day of the initial bout!
She is now almost 20 years old. Every single day of her teen years have been literally robbed from her as the virus was contracted on her 13th birthday! So sad.
Have tried an endless variety of doctors, practitioner and supplements. All I can say is she is on a plateau with little variation. Functions sub optimally and I fear she will never hold down a normal job as one day of effort renders her incapable for the next three days.
Cort, since you launched the new website I’m getting generic avatars on the left side of the comments sections obscuring enough that I can’t read them – any ideas what to do?
Same thing for me, the avatar space covers the print making it impossible to read the comments.
Thak’s Cort for a very interesting article.
This study correlates very well with my owne experience of reducing FM and ME/CFS with lymfatic drainage.
Five years ago I developed ME/CFS and FM after have gotten infected with Tularemi, a bacterial infection similar to plauge. My lymfatic system got infected and swollen and I got very high fever. The infection got under control with high doses of intravenous antibiotics but I never recovered after that I just became sicker and sicker and last year I got diagnosed with ME/CFS.
All the time I’ve been sick I have reduced my symhtoms by prefoming lymphatic drainage on my self every day. That reduces my brain fog and reduces my pain significantly. Last year I started getting more frenetic in my lymfatic drainage and I massaged on my FM points and I noticed that my FM started to disappear. After massageing my FM points just a few weeks every day my FM was all gone! Tho if I stopped massageing my FM came back.
After getting diagnosed with ME/CFS I dramaticaly changed my diet and cutted out almost all carbohydrates from my food and all inflammatory creating foods. I also started takeing terapeutic doses of vitamins and minerals to make my gut heal and give my immunesystem nutrition enough to do it’s job and heal my body.
Since I’ve made that change I have become better and better and I have today gone from 40% aktivity level to 70% and I’ve started working again.
When I eat this very restricted diet I don’t need to do my lymfatic drainage massage to stay healthy and free from FM but if I cheat in my diet I immediately get my pain and brainfog back and have to preform lymfatic drainage massage on my self to make it disappear.
During this time, on a very strict diet and with lots of probiotics, my gut lining have started to heal and now I tolerate more of the bad foods then I did earlier and can cheat occasionaly without haveing to pay for it afterwards with pain and brainfog.
But still the lymfatic drainage plays a big role for me in inproving my health and my theory is that when the gutlining is too permeable and large protein chaines leak through the gut wall and out in the body, they get stuck in the tissues because the lymfatic system is owerloaded and can not bring them out, and inflammations occurs.
Then the lymfatic system gets overloaded it can not bring out all of the toxins and waste products from our bodies and we get very toxic and that affects the whole system of our bodies.
Haha…I read what I wrote and I have to apologize for my very poor english!
Your English was certainly good enough to spark my interest! Can you tell us anymore about how and where you massage your FM-related points? Never heard this approach.
I agree Lena, I am intrigued…..I have tried lymphatic massage and it had s very noticeable effect on me – all of a sudden my sinuses were draining like crazy but I did not even know I was stopped up! I’d like to hear more about your routine as well.
I like this comment the story is reassuring. I will look into healing with massage. the theory in the article is a sound one about the lymph vessels.
Do you have any idea about which antibiotics were used in the study?
Hi Lena. Please give more info on lymphatic drainage
Funny, I remember having gut infection as a young kid. 13 mono severe , tested postitive for previous EBV, but reading symptoms of CMV virus I believe that was the one that caused it. Also chronic strep, bronchitis, all ear infections, my Lymph nodes are constantly swollen, along with sore throat. Stomach issues since 15 finally tested for hyplori, better..last severe infection before fibro and ME was resistant MRSA….though had MRI of head 2007 which showed bacterial infection from inner air and back of it, nasal passages also, in 2011 still there? All I know is my pitituary hormones, thyroid, hormones are way off and I don’t know who to see to get it taken care of, Rita
Would mumps, while pregnant with my first child be considered to have this later effect, do you think please Cort?
Also had H Pylori bacteria and subsequent Gastric episode treated with dose of 2 antibiotics together about 20 years ago.
I became ill with ME/CFS 9 years ago. I do believe Probiotics work for me.
I think it’s possible that any significant infection could have this effect and I think the research largely bears this out. Of course we’ve all had many infections over time and most are probably cleared with no problem but it does appear that a small percentage of people do experience ongoing problems because of them.
The history of M.E. prior to CDC involvement — that is, pre-1988, pre-Holmes — indicates that the numerous outbreaks quite likely featured enteroviruses. As you can guess from the name, these are gastro-intestinal loving viruses of the same family as Poliomyelitis, Coxsackie B, and the enterovirus 68 and 73 that rose seemingly from nowhere last winter to kill some 14 children in the US. In fact, numerous historic outbreaks occurred in association with polio outbreaks from the last years of the 19th century onward (polio emerged in Sweden around 1895, I have read.) Dr John Chia discovered enterovirus infection in gastrointestinal biopsies of 82% of M.E. patients but has not been able to get funding for further study and no one has tried to replicate this. Importantly, Dr. Chia practices in Southern California, an area struck by an ME and polio outbreak around 1934. Alas, little work has been done on enteroviruses since Dr. Salk’s polio virus was introduced in 1955. Reportedly 1000s of enterovirus specialists abandoned their enterovirus investigations and sought alternate employment on release of the Salk vaccine.