Last Friday I was, as is always the case listening to an enthusiastic talk given by one of the PhD students from my department. As part of her PhD work, she is trying to understand why periodontitis, an inflammatory disease where gums get swollen as a consequence of bacterial infection, is essentially painless. This is rather sensible, as her rationale is the absence of pain associated with the inflammation could possibly be the consequence of a kind of counterbalancing endogenous analgesia triggered by the own individual. She then started to enumerate some factors that could account for such analgesia and got caught by one of them that was oblivious to me. She just showed a slide including the first page of a manuscript entitled “Lactobacillus acidophilus modulates intestinal pain and induces opioids and cannabinoid receptors” published in 2007 in the prestigious journal Nature medicine.
Why is this publication so interesting, you may be guessing? Well, it just turns out that most of us are consuming this probiotic bacterial strain (mostly the so called NCFM), which has been produced commercially since the mid-1970s and is present in conventional foods like milk or yogurt 1. Furthermore, we can also find it in combination with other strains within the dairy product called kefir, used by many people (including myself) to produce yogurt from milk. In the paper, the authors try to disclose why consumption of certain probiotics hampers the visceral pain associated with irritable bowel syndrome (IBS). This is the most common gastrointestinal disease (affecting 7-21% of the population) being characterized by chronic abdominal pain, bloating and alteration of bowel habits.
By using as analogy an experimental model of colitis where opioid (μ-, δ- and κ-) and cannabinoid (CB2) receptors have been shown to alleviate pain and inflammation, they hypothesize that probiotics may up-regulate the expression of similar receptors on epithelial cells which are responsible for the transmission of nociceptive information to the intestinal nervous system 2. To this end, they first look at five representative probiotic bacteria from the Lactobacillus and Bifidobacterium genera (L. acidophilus NCFM, L. sadivarius Ls-33, L. paracasei Lpc-37, B. lactis Bi-07 and B. lactis Bl-04) and their ability to modify the expression of these receptors involved in analgesia when cultured along with a human epithelial cell line. Among all, only L. acidophilus NCFM was shown to increase both the expression of OPRM1 and CNR2 mRNA (genes coding for μ-opioid and CB2 receptors, respectively), but more importantly a 25-60% from all epithelial cells had the receptors (meaning the mRNA is also translated) with no major adverse effects in the intestinal tract. Furthermore, by using a transgenic fibroblast mouse cell line in which the NF- signalling pathway was impaired, the effect could be prevented (highlighting the critical role of the pro-inflammatory pathway for the gene receptor expression to happen).
Perhaps more interesting were the results they got when assessing an in vivo visceral pain model called the colorectal distension test. In this model, a flexible latex balloon is inserted intra-anally to the rat under anaesthesia to achieve colorectal distension by inflating the balloon with air 3. In untreated rats, a distension of 50±2 mm Hg is required to reach the pain threshold while NCFM treated rats for 15 days showed a 20% increase in pain threshold. That means the intensity of the pain stimulus has to be higher in order for the animal to feel pain. The sensation of pain was also shown to be dose-dependent, so the more colony-forming units (CFU) were administered, the higher was the threshold. Administration of 109 CFU led to analgesia after 10 days and lasted throughout the treatment, to only disappear 3 days after discontinuation. In a model mimicking IBS (butyrate enemas), colorectal distension threshold was increased up to 44% when compared to untreated rats. This antinociceptive effect was comparable to the one achieved after subcutaneous injection of the equivalent to 1mg/kg morphine. A selective CB2, but not opioid receptor antagonist prevented the analgesia, pointing to the cannabinoid receptor as the one responsible for the observed analgesia.
Perhaps, the most striking finding from this study is the involvement of epithelial cells expressing CB2 receptors as the triggering event ultimately leading to analgesia, instead of the classic sensory neural mechanism we may have first thought of. This is somehow surprising and it gives room to speculate as to whether it could be an evolutionary mechanism by which harmful bacteria could avoid being detected by the sensory system in order to not be fought by the host. A similar strategy (analgesia induction by bacteria) has been shown recently in the case of Mycobacterium ulcerans causing extensive skin lesions, which happen to be painless 4. It seems the bacterium secretes a molecule activating a signalling pathway through type 2-angiotensin receptor, which ultimately leads to inhibition of primary afferents by hyperpolarizing their membrane. Even though the molecular mechanism is completely different, it essentially leads to analgesia so there could be other strategies aiming the same goal.
A second interesting finding is how potent as analgesic is L. acidophilus, unfolding its potential as a safe and inexpensive treatment against abdominal pain. Last, but not least it could also be of interest to explore whether the microbiome of certain people may naturally protect them against this type of pain, purely based in the presence of a certain bacterial strain with similar properties to the ones from L. acidophilus.
- Sanders ME, Klaenhammer TR: Invited review: the scientific basis of Lactobacillus acidophilus NCFM functionality as a probiotic. J Dairy Sci 2001; 84: 319-331. ↩
- Rousseaux C, Thuru X, Gelot A et al: Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007; 13: 35-37. ↩
- Yang JP, Yao M, Jiang XH, Wang LN: Establishment of model of visceral pain due to colorectal distension and its behavioral assessment in rats. World J Gastroenterol 2006; 12: 2781-2784. ↩
- Marion E, Song OR, Christophe T et al: Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways. Cell 2014; 157: 1565-1576. ↩