GUT is one of my favourite journals, as they regularly explore the ‘alternative’ approaches to colon health management with a vigour that appeases the clinician in me, and a rigour that calms the scientist.
A paper published in early 2012[1] add’s further knowledge to the role that probiotics and the active components produced by lactic acid bacteria have on mucosal health and intestinal balance. An especially pleasing discovery – for an old long term user of this word – is their inclusion of the term dysbiosis, with a summary explanation in the opening paragraph, as there is no abstract. I have reproduced it below:
The mammalian gastrointestinal tract harbours a vast number of bacterial residents, recently referred to as the microbiota, which are instrumental in supporting energy metabolism and immune function of the host. A large number of studies have highlighted the fact that certain (pathogenic) micro-organisms can be harmful to the health of their host, while more recently an increasing number of papers have attributed direct beneficial health effects to the gut microbial community. As these bacteria encode 100 times more genes than present in the human genome, the partnership of the host with its microbiota constitute a ‘superorganism’.[2]
Homoeostasis in this superorganism is sustained through an optimal cohabitation of the host with this microbiota, keeping the balance between commensals and pathogens, but also between proinflammatory and regulatory responses. The composition of the gut microbiota has indeed been shown to be an important determinant of Th17:Treg balance and may thus influence intestinal immunity and tolerance.[3]
Disturbing alterations in the composition of the microbiota (a process known as dysbiosis) will compromise such homoeostasis and promote the development of various inflammatory disorders, such as inflammatory bowel disease, diabetes, cardiovascular disease and mental health. An in-depth understanding of the mechanisms underlying host–symbiont relationships will be pivotal for the development of new therapeutic or prophylactic interventions targeting the intestinal microbiota.
Why is this paper so interesting to practitioners?
The art and the science of health care sometimes work in synergy and sometimes hey clash, in non-pharmaceutical medicine the favouring of the art can sometimes be used to diminish the validity of the intervention and in turn the use of mechanism and targeted therapy without the art may be levelled at current western dominated medical practice.
One type of medicine that falls between the two is the mystical art and complex science of manipulation of the ecological companions we carry in our gut, at one end we have faecal transplantation, an inelegant therapy with often outstanding results in complex infection, and the other the consumption of bacteria deemed to have beneficial potential on our health.
Pro-biotics have been consumed as part of our diet for thousands of years, it was not until Metchnikoff and colleagues raised the possibility of them possessing a positive health quality and the idea of manufacturing them begin to develop.
These days in Europe, Asia and the USA probiotics either in capsule, powder, liquid, food or bound to functional agents are increasingly available. But despite many years of research the vast majority still rely on the art of ecological infusion – that is, swallow a random selection of different species and strains and hope for the best.
There is little to no risk in this approach, but also little assured effect. As such, many probiotics being swallowed today by people seeking distinct therapeutic gain, may as well miss out the ‘middle man’ and be flushed down the toilet! A little harsh I agree, but substantively true, why do you select the bacterial strains you do – what determines the choice?, it is unlikely to be because of compelling clinical evidence as this data remains pretty thin on the ground other than for a few select strains.
GUT has published a paper in Feb 2012 that extends development of the relevant knowledge to assist us in applying in what to some may be seen as a reductionist approach to strain selection, but which to me, opens the possibility for ancient wisdom to meet contemporary medicine in a manner that permits the patient to be the ultimate winner.
Dendritic cells are the key
Lurking in the epithelial tissues of our digestive tract are a group of professional antigen presenting cells known as dendritic cells.[4] These octopuses of the colon and intestine are subdivided into a number of specialist sub sets and then once identified, immunologists, as is their bent, issue a series of numbers and letters to assist identification. They are divided and categorised because they have unique roles in the maintenance of local and systemic health.
Two distinct subsets of DCs have now been defined in the gut on the basis of the expression of mutually exclusive markers, the integrin CD103 and the fractalkine receptor CX3CR1.[5]
- CD103+ DCs serve classical DC functions and initiate adaptive immune responses in local lymph nodes, whereas
- CX3CR1+ populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.
These are subtle but important differences in the journey to exploit the mucosal immune system using probiotics as these two subsets are the only ones able to migrate through the lamina propria to meet the naïve Tcells awaiting their immunological imprinting. Targeting their receptors through the use of selected probiotic strains may well confer an additional and immune specific response. This will permit us additional control in the achieving the homeostatic balance defined as health that relies on the balance of immunity and tolerance.
As most us comprehend, the introduction of probiotics into the lumen, mainly lactobacilli and bifidobacteria, impacts on the immune system. Depending on the strain, probiotics may exert beneficial effects by altering gut microbial diversity, improving the intestinal barrier, producing effector by product molecules (postbiotic)[6] or modulating the host’s immune responses. By modulating immunological functions of dendritic cells (DCs), certain probiotics seem able to promote cellular effector cell subsets: T helper 1 (Th1) responses,[7] while others have clearly been shown to induce tolerogenic DCs (DCreg) and regulatory T (Treg) response.[8],[9]
Vitamin A: the switch, IDO: the socket
The active component of vitamin A is retinoic acid and the DC subset CD103 drives the naïve Tcell into a Treg and so enhances immune tolerance in conjunction with TGFbeta a cytokine required for tolerance and inflammation control. In addition this subset promotes the production of a key regulator of the switch between effector and regulator cells – namely indolamine 2,3 dioxygenase.
From a clinical perspective, loss of tolerance underlies many of today’s chronic inflammatory conditions that extend well beyond the confines of the gut lumen and identifying organisms that favour this outcome would confer clinical advantage.
Bifidobacterium infantis 35624 appears to be able to do the above and promote IL-10 through the binding to specific pattern recognition receptors.[10] Whilst it is likely that other strains will impact the same mechanisms, this accuracy of application has yet to be elucidated. Is it powerful enough to impact chronic inflammatory conditions independent of prebiotic manipulation through food selection – I suspect that this is unlikely but that a combination of foods and probiotics will as previously determined have the greatest immunological effect.
Comment
It is now clear that probiotic administration can modify the distribution, the phenotype and function of DC subsets. This will need further expansion through human trials but the concept of reprogramming key immune cells to uncouple destructive inflammation has already been demonstrated in faecal transplantation, this may bridge the gap between historical ecological administration, heroic total repopulation and wellness care.
References
[1] Grangette C. Bifidobacteria and subsets of dendritic cells: friendly players in immune regulation! Gut. 2012 Mar;61(3):331-2. Epub 2011 Dec 1. No abstract available
[2] Eberl G. A new vision of immunity: homeostasis of the superorganism. Mucosal Immunol 2010;3:450–60
[3] Ivanov II, Frutos Rde L, Manel N, et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008;4:337–49.
[4] Niess JH, Reinecker HC. Dendritic cells: the commanders-in-chief of mucosal immune defenses. Curr Opin Gastroenterol. 2006 Jul;22(4):354-60. Review. View Abstract
[5] Schulz O, Jaensson E, Persson EK, et al . Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med 2009;206:3101–14. View Full Paper
[6] Tsilingiri K, Barbosa T, Penna G, Caprioli F, Sonzogni A, Viale G, Rescigno M. Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model. Gut. 2012 Feb 1. View Abstract
[7] Mohamadzadeh M, Olson S, Kalina WV, et al. Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization. Proc Natl Acad Sci U S A 2005;102:2880–5 View Full Paper
[8] Kwon HK, Lee CG, So JS, et al. Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc Natl Acad Sci U S A 2010;107:2159–64. View Full Paper
[9] O’Mahony C, Scully P, O’Mahony D, et al. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation. PLoS Pathog 2008;4:e1000112. View Full Paper
[10] Koniecznia P, Groeger D, Ziegler M, et al . Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells. Gut 2012;61:354–66. View Full Paper
